Molecular cell biology

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Format:	Buch
Sprache:	English
Veröffentlicht:	New York Freeman 2008
Ausgabe:	6. ed.
Schlagworte:	Cells Molecular Biology Cellular Biology Biología molecular Citología Molekularbiologie Cytologie Zelle CD-ROM Bibliografie Lehrbuch
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Datensatz im Suchindex

DE-BY-TUM_call_number	1002/BIO 200f 2008 B 1725(6)
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adam_text	CONTENTS Part I Chemical and Molecular Foundations 1 Cells Grow and Divide Ceils Die from Aggravated Assault or an Internal Program The Diversity and Commonality of Cells All Cells Are Prokaryotic or Eukaryotic Unicellular Organisms Help and Hurt Us Viruses Are the Ultimate Parasites Changes in Cells Underlie Evolution Even Single Cells Can Have Sex We Develop from a Single Cell Stem Cells, Fundamental to Forming Tissues and Organs, Offer Medical Opportunities The Molecules of a Cell Small Molecules Carry Energy, Transmit Signals, and Are Linked into Macromolecules Proteins Give Cells Structure and Perform Most Cellular Tasks Nucleic Acids Carry Coded Information for Making Proteins at the Right Time and Place The Genome Is Packaged into Chromosomes and Replicated During Cell Division Mutations May Be Good, Bad, or Indifferent The Work of Cells Cells Build and Degrade Numerous Molecules and Structures Animal Cells Produce Their Own External Environment and Glues Cells Change Shape and Move Cells Sense and Send Information Cells Regulate Their Gene Expression to Meet Changing Needs Investigating Cells and Their Parts Cell Biology Reveals the Size, Shape, Location, and Movements of Cell Components Biochemistry and Biophysics Reveal the Molecular Structure and Chemistry of Purified Cell Constituents Genetics Reveals the Consequences of Damaged Genes Genomics Reveals Differences in the Structure and Expression of Entire Genomes Developmental Biology Reveals Changes in the Properties of Cells as They Specialize Choosing the Right Experimental Organism for the Job The Most Successful Biological Studies Use Multiple Approaches A Genome Perspective on Evolution Metabolic Proteins, the Genetic Code, and Structures Are Nearly Universal Darwin s Ideas About the Evolution of Whole Animals Are Relevant to Genes Many Genes Controlling Development Are Remarkably Similar in Humans and Other Animals Human Medicine Is Informed by Research on Other Organisms 2 31 ££\| Covalent Bonds and Noncovalent Interactions The Electronic Structure of an Atom Determines the Number and Geometry of Covalent Bonds It Can Make CONTENTS XV Electrons in Covalent Bonds Are Much Stronger and More Stable Than Noncovalent Interactions Ionic Interactions Are Attractions between Oppositely Charged Ions Hydrogen Bonds Determine the Water Solubility of Uncharged Molecules Van Transient Dipoles The Molecules to Adhere to One Another Molecular Complementarity Mediated via Noncovalent Interactions Permits Tight, Highly Specific Binding of Biomolecules Chemical Building Blocks of Cells Amino Compose Proteins Five Different Nucleotides Are Used to Build Nucleic Acids Monosaccharides Joined by Glycosidic Bonds Form Linear and Branched Polysaccharides Phospholipids Associate Noncovalently to Form the Basic Bilayer Structure of £Щ Equilibrium Constants Reflect the Extent of a Chemical Reaction Chemical Reactions in Cells Are at Steady State Dissociation Constants of Binding Reactions Reflect the Affinity of Interacting Molecules Biological Fluids Have Characteristic Hydrogen Ions Are Released by Acids and Taken Up by Bases Buffers Maintain the Extracellular Fluids Biochemical Energetics Several Forms of Energy Are Important in Biological Systems Cells Can Transform One Type of Energy into Another The Change in Free Energy Determines the Direction of a Chemical Reaction The from Its K, eq The Rate of a Reaction Depends on the Activation Energy Necessary to Energize the Reactants into a Transition State 41 44 44 46 49 50 50 50 51 52 52 54 54 55 55 56 56 Life Depends on the Coupling of Unfavorable Chemical Reactions with Energetically Favorable Reactions Hydrolysis of ATP Releases Substantial Free Energy and Drives Many Cellular Processes ATP Is Generated During Photosynthesis and Respiration NAD+ and FAD Couple Many Biological Oxidation and Reduction Reactions 3 FUNCTION ^^\| Hierarchical Structure of Proteins The Primary Structure of a Protein Is Its Linear Arrangement of Secondary Structures Are the Core Elements of Protein Architecture Overall Folding of a Polypeptide Chain Yields Its Tertiary Structure Different Ways of Depicting the Conformation of Proteins Convey Different Types of Information Structural Motifs Are Regular Combinations of Secondary and Tertiary Structures Structural and Functional Domains Are Modules of Tertiary Structure Proteins Associate into Macromolecular Assemblies Members of Protein Families Have a Common Evolutionary Ancestor ^^] Protein Folding Planar Which Proteins Can Fold Information Directing a Protein s Folding Is Encoded in Its Folding of Proteins in Vivo Is Promoted by Chaperones Alternatively Folded Proteins Are Implicated in Diseases ЩЛ Specific Binding of Ligands Underlies the Functions of Most Proteins Enzymes Are Highly Efficient and Specific Catalysts An Enzyme s Active Site Binds Substrates and Carries Out Catalysis Serine Enzyme s Active Site Works Enzymes in a Common Pathway Are Often Physically Associated with One Another xvi CONTENTS Enzymes into Motion Regulating Protein Function I: Protein Degradation Regulated Synthesis and Degradation of Proteins is a Fundamental Property of Cells The Proteasome Is a Complex Molecular Machine Used to Degrade Proteins Ubiquitin Marks Cytosolic Proteins for Degradation in Proteasomes Q9I Regulating Protein Function II: Noncovalent and Covalent Modifications Noncovalent Binding Permits Allosteric, or Cooperative, Regulation of Proteins Noncovalent Binding of Calcium and GTP Are Widely Used As Allosteric Switches to Control Protein Activity Phosphorylation and Dephosphorylation Covalently Regulate Protein Activity Proteolytic Cleavage Irreversibly Activates or Inactivates Some Proteins Higher-Order Regulation Includes Control of Protein Location and Concentration QQ Purifying, Detecting, and Characterizing Proteins Centrifugation Can Separate Particles and Molecules That Differ in Mass or Density Electrophoresis Separates Molecules on the Basis of Their Charge-to-Mass Ratio Liquid Chromatography Resolves Proteins by Mass, Charge, or Binding Affinity Highly Specific Enzyme and Antibody Assays Can Detect Individual Proteins Radioisotopes Are Biological Molecules Mass Spectrometry Can Determine the Mass and Sequence of Proteins Protein Primary Structure Can Be Determined by Chemical Methods and from Gene Sequences Protein Conformation Is Determined by Sophisticated Physical Methods Proteomics Proteomics Is the Study of All or a Large Subset of Proteins in a Biological System Advanced Techniques in Mass Spectrometry Are Critical to Proteomic Analysis Part II Genetics and Molecular Biology 4 MECHANISMS Structure of Nucleic Acids A Nucleic Acid Strand Is a Linear Polymer with End-to-End Directionality Native Antiparallel DNA Torsionai Different Types of Conformations Related to Their Functions Q3 Transcription of Protein-Coding Genes and Formation of Functional mRNA Organization of Genes Differs in Prokaryotic and Eukaryotic Eukaryotic Precursor mRNAs Are Processed to Form Functional mRNAs Alternative Proteins Expressed from a Single Eukaryotic Gene ШШШ A Template Complementary Messenger Three-Letter Genetic Code The Folded Structure of tRNA Promotes Its Decoding Functions Nonstandard Base Codons Amino Linked to tRNAs Stepwise Synthesis of Proteins on Ribosomes 120 127 129 130 131 132 132 CONTENTS XVII Meth¡onyl-tRNA¡MET Translation Initiation Usually Occurs at the First AUG During Chain Elongation Each Incoming Aminoacyl-tRNA Moves Through Three Ribosomal Sites Translation Is Terminated by Release Factors When a Stop Codon Is Reached Polysomes and Rapid Ribosome Recycling Increase the Efficiency of Translation IQ DNA DNA Polymerases Replication Duplex Formed at the Several Proteins Participate in DNA Each Origin ÜQ DNA DNA and Also Correct Them Chemical and Radiation Damage to Lead to Mutations High-Fidelity DNA Recognize and Repair Damage Base Excision Repairs TG Mismatches and Damaged Bases Mismatch Excision Repairs Other Mismatches and Small Insertions and Deletions Nucleotide Excision Repairs Chemical Adducts That Distort Normal Two Systems Utilize Recombination to Repair Double-Strand Breaks in Homologous Recombination Can Repair Damage and Generate Genetic Diversity Viruses: Parasites of the Cellular Genetic System Most Viral Host Ranges Are Narrow Viral Capsids Are Regular Arrays of One or a Few Types of Protein Viruses Can Be Cloned and Counted in Plaque Assays Lytic Viral Growth Cycles Lead to the Death of Host Cells Viral in Some Nonlytic Viral Growth Cycles 5 Genetic Analysis of Mutations to Identify and Study Genes Recessive and Dominant Mutant Have Opposite Effects on Gene Function Segregation of Mutations in Breeding Experiments Reveals Their Dominance or Recessivity Conditional Mutations Can Be Used to Study Essential Genes in Yeast Recessive Lethal Mutations in Diploids Can Be Identified by Inbreeding and Maintained in Hétérozygotes Complementation Tests Determine Whether Different Recessive Mutations Are in the Same Gene Double Mutants Are Useful in Assessing the Order in Which Proteins Function Genetic Suppression and Synthetic Lethality Can Reveal Interacting or Redundant Proteins Genes Can Be Identified by Their Map Position on the Chromosome 171 173 174 ЩЦЩ Restriction Enzymes and Insertion of E. coli Plasmid Isolated cDNA Libraries Represent the Sequences of Protein-Coding Genes cDNAs Prepared by Reverse Transcription of Cellular mRNAs Can Be Cloned to Generate cDNA Libraries DNA to an Oligonucleotide Probe Yeast Genomic Libraries Can Be Constructed with Shuttle Vectors and Screened by Functional Complementation Gel Electrophoresis Allows Separation of Vector DNA f Cloned by the Dideoxy Chain-Termination Method The Polymerase Chain Reaction Amplifies a Specific DNA ШВШ to Study Gene Expression Hybridization Techniques Permit Detection of Specific DNA Microarrays Expression of Many Genes at One Time XVIII CONTENTS Cluster Identifies Co-regulated Genes E. coli Quantities of Proteins from Cloned Genes Plasmid Expression Vectors Can Be Designed for Use in Animal Cells Identifying and Locating Human Disease Genes Many Inherited Diseases Show One of Three Major Patterns of Inheritance DNA Human Mutations Linkage Studies Can Map Disease Genes with a Resolution of About Further Analysis Is Needed to Locate a Disease Gene in Cloned Many Inherited Diseases Result from Multiple Genetic Defects HQ Inactivating the Function of Specific Genes in Eukaryotes Normal Yeast Genes Can Be Replaced with Mutant Alíeles Transcription of Genes Promoter Can Be Controlled Experimentally Specific Genes Can Be Permanently Inactivated in the Germ Line of Mice Somatic Cell Recombination Can Inactivate Genes in Specific Tissues Dominant-Negative Inhibit Some Genes RNA Destroying the Corresponding mRNA 6 CHROMOSOMES Eukaryotic Gene Structure 217 Most Eukaryotic Genes Contain mRNAs Encoding Single Proteins Simple and Complex Transcription Units Are Found in Eukaryotic Genomes Protein-Coding Genes May Be Solitary or Belong to a Gene Family Heavily Used Gene Products Are Encoded by Multiple Copies of Genes Nonprotein-Coding Genes Encode Functional RNAs ^2al Chromosomal Organization of Genes and Noncoding Genomes of Many Organisms Contain Much Nonfunctional Most Simple-Sequence DNAs Are Concentrated in Specific Chromosomal Locations DNA in Length of Simple-Sequence DNAs Unclassified Spacer Portion of the Genome (•Щ Elements Movement of Mobile Elements Involves a DNA DNA and Eukaryotes LTR Retrotransposons Behave Like Intracellular Retroviruses Non-LTR Retrotransposons Transpose by a Distinct Mechanism Other DNA 234 Mobile Evolution ЦІ Mitochondria Contain Multiple mtDNA Molecules mtDNA Is Inherited Cytoplasmically The Size, Structure, and Coding Capacity of mtDNA Vary Considerably Between Organisms Products of Mitochondrial Genes Are Not Exported Mitochondria Evolved from a Single Endosymbiotic Event Involving a Mitochondrial Genetic Codes Differ from the Standard Nuclear Code Mutations in Mitochondrial Genetic Diseases in Humans Chloroplasts Contain Large DNAs Often Encoding More Than a Hundred Proteins Q3 Genomics: Genome-wide Analysis of Gene Structure and Expression Stored Sequences Suggest Functions of Newly Identified Genes and Proteins CONTENTS XIX Comparison of Related Sequences from Different Species Can Give Clues to Evolutionary Relationships Among Proteins Genes Can Be Identified Within Genomic Sequences The Number of Protein-Coding Genes in an Organism s Genome Is Not Directly Related to Its Biological Complexity Single Nucleotide Polymorphisms and Gene Copy- Number Variation Are Important Determinants of Differences Between Individuals of a Species Structural Organization of Eukaryotic Chromosomes 244 244 245 246 247 248 Chromatin Exists in Extended and Condensed Forms Modifications of Histone Tails Control Chromatin Condensation and Function Nonhistone Proteins Provide a Structural Scaffold for Long Chromatin Loops Additional Nonhistone Proteins Regulate Transcription and Replication Small Molecules Regulate Expression of Many Bacterial Genes via DNA-Binding Repressors and Activators Transcription Initiation from Some Promoters Requires Alternative Sigma Factors Transcription by aS4-RNA Polymerase Is Controlled by Activators That Bind Far from the Promoter Many Bacterial Responses Are Controlled by Two-Component Regulatory Systems EQI Overview of Eukaryotic Gene Control and Regulatory Elements in Eukaryotic Both Close to and Many Transcription Start Sites Three Eukaryotic Polymerases Catalyze Formation of Different RNAs The Largest Essential Carboxyl-Terminal Repeat RNA Sequences Corresponding to the \|эдЦ of Eukaryotic Chromosomes Chromosome Number, Size, and Shape at Metaphase Are Species-Specific During Metaphase, Chromosomes Can Be Distinguished by Banding Patterns and Chromosome Painting Chromosome Painting and the Evolution of Chromosomes Interphase Polytene Amplification Three Functional Elements Are Required for Replication and Stable Inheritance of Chromosomes Centromere Sequences Vary Greatly in Length Addition of Telomeric Sequences by Telomerase Prevents Shortening of Chromosomes TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION 269 Control of Gene Expression in Bacteria Transcription Initiation by Bacterial Requires Association with a Sigma Factor Initiation of lac Operon Transcription Can Be Repressed and Activated 271 271 271 Цц\| Coding Genes The TATA Box, Initiators, and CpG Islands Function as Promoters in Eukaryotic Promoter-Proximal Elements Help Regulate Eukaryotic Genes Distant Enhancers Often Stimulate Transcription by Most Eukaryotic Genes Are Regulated by Multiple Transcription-Control Elements Activators and Repressors of Transcription 263 Interactions Activators Are Modular Proteins Composed of Distinct Functional Domains and Promote Transcription Repressors Inhibit Transcription and Are the Functional Converse of Activators DNA-Binding Domains Can Be Classified into Numerous Structural Types Structurally Diverse Activation and Repression Domains Regulate Transcription Transcription Factor Interactions Increase Gene-Control Options Multiprotein Complexes Form on Enhancers 282 282 282 284 285 286 286 288 290 290 293 294 295 xx CONTENTS Transcription Initiation Polymerase II 296 General Transcription Polymerase II Sequential Assembly of Proteins Forms the Pol II Transcription Preinitiation Complex in Vitro In Vivo Transcription Initiation by Pol II Requires Additional Proteins Mitochondrial and Transcribed by Organelle-Specific Polymerases 317 8 CONTROL Molecular Mechanisms of Transcription Repression and Activation Formation of Heterochromatin Silences Gene Expression at Telomeres, Near Centromeres, and in Other Regions Repressors Can Direct Histone Deacetylation and Methylation at Specific Genes Activators Can Direct Histone Acetylation and Methylation at Specific Genes Chromatin-Remodeling Factors Help Activate or Repress Transcription 299 299 303 305 306 Histone Modifications Vary Greatly in Their Stabilities The Mediator Complex Forms a Molecular Bridge Between Activation Domains and Pol II 307 Transcription of Many Genes Requires Ordered Binding and Function of Activators and Co-activators The Yeast Two-Hybrid System Exploits Activator Flexibility to Detect cDNAs That Encode Interacting Proteins Regulation of Transcription-Factor Activity Ali Structure 312 Nuclear-Receptor Response Elements Contain Inverted or Direct Repeats Hormone Binding to a Nuclear Receptor Regulates Its Activity as a Transcription Factor Regulated Elongation and Termination of Transcription Transcription of the an Antitermination Mechanism Promoter-Proximal Pausing of Occurs in Some Rapidly Induced Genes Other Eukaryotic Transcription Systems Transcription Initiation by Pol I and Pol HI Is Analogous to That by Pol II 313 314 315 316 316 316 Processing of Eukaryotic Pre-mRNA The Transcription Initiation A Diverse Set of Proteins with Conserved RNA-Binding Domains Associate with Pre-mRNAs Splicing Occurs at Short, Conserved Sequences in Pre-mRNAs via Two Transesterification Reactions During Splicing, snRNAs Base-Pair with Pre-mRNA Spliceosomes, Assembled from snRNPs and a Pre-mRNA, Carry Out Splicing Chain Elongation by to the Presence of RNA-Processing Factors SR Proteins Contribute to Exon Definition in Long Pre-mRNAs Self-Splicing Group II Evolution of snRNAs 3 Are Tightly Coupled Nuclear Exonucleases Degrade Out of Pre-mRNAs Ц2Л Processing Alternative Splicing Is the Primary Mechanism for Regulating mRNA Processing A Cascade of Regulated Drosophila Splicing Repressors and Activators Control Splicing at Alternative Sites RNA Some Pre-mRNAs £Q Transport of mRNA Across the Nuclear Envelope Nuclear Pore Complexes Control Import and Export from the Nucleus Pre-mRNAs in Spliceosomes Are Not Exported from the Nucleus HłV Viral mRNAs CONTENTS XXI Cytoplasmic transcriptional Control Micro RNAs Repress Translation of Specific mRNAs RNA Complementary mRNAs Cytoplasmic Polyadenylation Promotes Translation of Some mRNAs Degradation of mRNAs in the Cytoplasm Occurs by Several Mechanisms Protein Synthesis Can Be Globally Regulated Sequence-Specific RNA-Binding Proteins Control Specific mRNA Translation Surveillance Mechanisms Prevent Translation of Improperly Processed mRNAs Localization of mRNAs Permits Production of Proteins at Specific Regions Within the Cytoplasm jjjjf Processing of rRNA and tRNA Pre-rRNA Genes Function as Nucleolar Organizers and Are Similar in All Eukaryotes Small Nucleolar RNAs Assist in Processing Pre-rRNAs Self-Splicing Group I Examples of Catalytic Pre-tRNAs Undergo Extensive Modification in the Nucleus Nuclear Bodies Are Functionally Specialized Nuclear Domains Part III Cell Structure and Function VISUALIZING, FRACTIONATING, AND CULTURING CELLS Organelies The Plasma Membrane Has Many Common Functions in All Cells Endosomes Take Up Soluble Macromolecules from the Cell Exterior Lysosomes Are Acidic Battery of Degradative Enzymes Peroxisomes Degrade Fatty Acids and Toxic Compounds The Endoplasmic Reticulum Is a Network of Interconnected Internal Membranes The Golgi Complex Processes and Sorts Secreted and Membrane Proteins Plant Cell to Elongate Rapidly The Nucleus Contains the Synthetic Apparatus, and a Fibrous Matrix Mitochondria Are the Principal Sites of ATP Production in Aerobic Nonphotosynthetic Cells Chloroplasts Contain Internal Compartments in Which Photosynthesis Takes Place Light Microscopy: Visualizing Cell Structure and Localizing Proteins Within Cells The Resolution of the Light Microscope Is About 0.2 381 Phase-Contrast and Differential Interference Contrast Microscopy Visualize Unstained Living Cells Fluorescence Microscopy Can Localize and Quantify Specific Molecules in Live Cells Imaging Subcellular Details Often Requires that the Samples Be Fixed, Sectioned, and Stained Immunofluorescence Microscopy Can Detect Specific Proteins in Fixed Cells Confocal and Deconvolution Microscopy Enable Visualization of Three-Dimensional Objects Graphics and Informatics Have Transformed Modern Microscopy Qfl Electron Microscopy: Methods and Applications Resolution of Transmission Electron Microscopy is Vastly Greater Than That of Light Microscopy Cryoelectron Microscopy Allows Visualization of Particles Without Fixation or Staining Electron Microscopy of Metal-Coated Specimens Can Reveal Surface Features of Cells and Their Components Purification of Cell Disruption of Cells Releases Their Organelles and Other Contents Centrifugation Can Separate Many Types of Organelles Organelle-Specific Antibodies Are Useful in Preparing Highly Purified Organelles xx» CONTENTS gşm of Metazoan Cells Flow Cytometry Separates Different Cell Types Culture of Animal Cells Requires Nutrient-Rich Media and Special Solid Surfaces Primary Cell Cultures Can Be Used to Study Cell Differentiation Primary Cell Cultures and Cell Strains Have a Finite Life Span Transformed Cells Can Grow Indefinitely in Culture Some Cell Lines Undergo Differentiation in Culture Hybrid Cells Called Monoclonal Antibodies HAT Medium Is Commonly Used to Isolate Hybrid Cells Classic Experiment 10 409 Lipid-Binding Motifs Help Target Peripheral Proteins to the Membrane Proteins Can Be Removed from Membranes by Detergents or High-Salt Solutions QQ\| Phospholipids, Sphingolipids, and Cholesterol: Synthesis and Intracellular Movement Fatty Acids Synthesis Is Mediated by Several Important Enzymes Small Cytosolic Proteins Facilitate Movement of Fatty Acids Incorporation of Fatty Acids into Membrane Lipids Takes Place on Flippases Move Phospholipids from One Membrane Leaflet to the Opposite Leaflet Cholesterol Is Synthesized by Enzymes in the Cytosol and Cholesterol and Phospholipids Are Transported Between ШШ and Phospholipids Spontaneously Form Bilayers Phospholipid Bilayers Form a Sealed Compartment Surrounding an Internal Aqueous Space Biomembranes of Lipids Most Lipids and Many Proteins Are Laterally Mobile in Lipid Properties of Membranes Lipid and Cytosolic Leaflets Cholesterol and Sphingolipids Cluster with Specific Proteins in Membrane Biomembranes: and Basic Functions Proteins Interact with Membranes in Three Different Ways Most Membrane-Spanning Multiple Membrane-Spanning Barrels Covalently Attached Hydrocarbon Chains Anchor Some Proteins to Membranes All Asymmetrically Oriented in the Bilayer 11 OF IONS AND SMALL MOLECULES Overview of Membrane Transport Only Small by Simple Diffusion Membrane Proteins Mediate Transport of Most Molecules and All Ions Across Biomembranes Uniport Transport of Glucose and Water Several Features Distinguish Uniport Transport from Simple Diffusion GLUT1 Uniporter Transports Glucose into Most Mammalian Cells The Human Genome Encodes a Family of Sugar- Transporting GLUT Proteins Transport Proteins Can Be Enriched Within Artificial Membranes and Cells Osmotic Pressure Causes Water to Move Across Membranes Aquaporins Increase the Water Permeability of Cell Membranes CONTENTS XXIII ATP-Powered Pumps and the Intracellular lonk Environment Different Classes of Pumps Structural and Functional Properties ATP-Powered Ion Pumps Generate and Maintain Ionic Gradients Across Cellular Membranes Muscle Relaxation Depends on Ca2+ ATPases That Pump Ca2+ from the Cytosol into the Sarcoplasmk Reticulum Calmodulin Regulates the Plasma Membrane Ca2+ Pumps That Control Cytosolic Ca2 1 Concentrations Na+/K+ ATPase Maintains the Intracellular Na+ and K+ Concentrations in Animal Cells V-Class H+ ATPases Maintain the Acidity of Lysosomes and Bacterial Permeases Are ABC Proteins That Import a Variety of Nutrients from the Environment The Approximately Play Diverse and Important Roles in Cell and Organ Physiology Certain ABC Proteins Flip Phospholipids and Other Lipid-Soluble Substrates from One Membrane Leaflet to the Opposite Leaflet Bacterial Symporter Structure Reveals the Mechanism of Substrate Binding Na+-Linked Ca2+ Antiporter Exports Ca2+ from Cardiac Muscle Cells Several Cotransporters Regulate Cytosolic A Putative Cation Exchange Protein Plays a Key Role in Evolution of Human Skin Pigmentation Numerous Transport Proteins Enable Plant Vacuoles Transepithelial Transport Multiple Transport Proteins Are Needed to Move Glucose and Epithelia Simple Rehydration Therapy Depends on the Osmotic Gradient Created by Absorption of Glucose and Na+ Parietal Cells Acidify the Stomach Contents While Maintaining a Neutral Cytosolic Classic Experiment Active Transport 12 479 Nongated Ion Channels and the Resting Membrane Potential Selective Movement of Ions Creates a Transmembrane Difference The Membrane Potential in Animal Cells Depends Largely on Potassium Ion Movements Through Open Resting K+ Channels Ion Channels Contain a Selectivity Filter Formed from Conserved Patch Clamps Permit Measurement of Ion Movements Through Single Channels Novel Ion Channels Can Be Characterized by a Combination of Oocyte Expression and Patch Clamping Na+ Entry into Mammalian Cells Has a Negative Change in Free Energy Cotransport by Symporters and Antiporters Na+-Linked Symporters Import Glucose into Animal Cells Against High Concentration Gradients First Steps of Glucose and Fatty Acid Catabolism: Glycolysis and the Citric Acid Cycle During Glycolysis (Stage I), Cytosolic Enzymes Convert Glucose to Pyruvate The Rate of Glycolysis Is Adjusted to Meet the Cell s Need for ATP Glucose Is Fermented Under Anaerobic Conditions Under Aerobic Conditions, Mitochondria Efficiently Oxidize Pyruvate and Generate ATP (Stages II-IV) Mitochondria Are Dynamic Structurally and Functionally Distinct Membranes In Stage II, Pyruvate Is Oxidized to CO2 and High- Energy Electrons Stored in Reduced Coenzymes Transporters in the Inner Mitochondrial Membrane Help Maintain Appropriate Cytosolic and Matrix Concentrations of NAD+ and NADH Mitochondrial Oxidation of Fatty Acids Generates ATP Peroxisomal Oxidation of Fatty Acids Generates No ATP 480 481 483 485 485 485 487 489 491 491 xxiv CONTENTS The Electron Transport Chain and Generation of the Proton-Motive Force Stepwise Electron Transport Efficiently Releases the Energy Stored in NADH and FADH2 Electron Transport in Mitochondria Is Coupled to Proton Pumping Electrons Flow from FADH2 and NADH to O2 Through Four Multiprotein Complexes Reduction Potentials of Electron Carriers Favor Electron Flow from NADH to O2 Experiments Using Purified Complexes Established the Stoichiometry of Proton Pumping The Translocated as Electrons Flow Through Complex III The Proton-Motive Force in Mitochondria Is Due Largely to a Voltage Gradient Across the Inner Membrane Toxic By-products of Electron Transport Can Damage Cells ЦЮІ Force for Energy-Requiring Processes The Mechanism of ATP Synthesis Is Shared Among Bacteria, Mitochondria, and Chloroplasts ATP Synthase Comprises Two Multiprotein Complexes Termed Fo and F1 Rotation of the F, Proton Movement Through Fo, Powers ATP Synthesis ATP-ADP Exchange Across the Inner Mitochondrial Membrane Is Powered by the Proton-Motive Force Rate of Mitochondrial Oxidation Normally Depends on ADP Levels Brown-Fat Mitochondria Use the Proton-Motive Force to Generate Heat Photosynthesis and Light-Absorbing Pigments Thylakoid Membranes in Chloroplasts Are the Sites of Photosynthesis in Plants Three of the Four Stages in Photosynthesis Occur Only During Illumination Each Photon of Light Has a Defined Amount of Energy Photosystems Associated Light-Harvesting Complexes 511 511 511 513 5Î4 Photoelectron Transport from Energized Reaction- Center Chlorophyll a Produces a Charge Separation Internal Antenna and Light-Harvesting Complexes Increase the Efficiency of Photosynthesis ЮЭ Photosystems 517 The Single Generates a Proton-Motive Force but No O2 Linear Electron Flow Through Both Plant PSII and O2, and NADPH An Oxygen-Evolving Complex Is Located on the Center Cells Use Multiple Mechanisms to Protect Against Damage from Reactive Oxygen Species During Photoelectron Cyclic Electron Flow Through Proton-Motive Force but No NADPH or O2 Relative Activities of Regulated ЮЗ Photosynthesis Rubisco Fixes CO2 in the Chloroplast Synthesis of Sucrose Using Fixed CO2 Is Completed in the Cytosol Light and Rubisco Fixation Photorespiration, Photosynthesis, Is Reduced in Plants That Fix CO2 by the C4 Pathway 13 MEMBRANES AND ORGANELLES Translocation Across the A Nascent Secretory Proteins to the Cotransiational GTP-Hydrolyzing Proteins Passage of Growing Polypeptides Through the Translocon Is Driven by Energy Released During Translation CONTENTS XXV ATP Hydrolysis Powers Post-translational Translocation Insertion of Proteins into the ER Several Topological Classes of Integral Membrane Proteins Are Synthesized on the Internal Stop-Transfer and Signal-Anchor Sequences Determine Topology of Single-Pass Proteins Multipass Proteins Have Multiple Internal Topogenic Sequences A Phospholipid Anchor Tethers Some Cell-Surface Proteins to the Membrane The Topology of a Membrane Protein Often Can Be Deduced from Its Sequence Protein Modifications, Folding, and Quality Control in the A Preformed W-Linked Oligosaccharide Is Added to Many Proteins in the Rough Oligosaccharide Side Chains May Promote Folding and Stability of Glycoproteins Disulfide Bonds Are Formed and Rearranged by Proteins in the Chaperones and Other and Assembly of Proteins Improperly Folded Proteins in the Expression of Protein-Folding Catalysts Unassembled or Misfolded Proteins in the Often Transported to the Cytosol for Degradation Sorting of Proteins to Mitochondria and Chloroplasts Amphipathic N-Terminal Signal Sequences Direct Proteins to the Mitochondrial Matrix 558 Mitochondrial Protein Import Requires Outer-Membrane Receptors and Translocons in Both Membranes Studies with Chimeric Proteins Demonstrate Important Features of Mitochondrial Import Three Energy Inputs Are Needed to Import Proteins into Mitochondria Multiple Signals and Pathways Target Proteins to Submitochondrial Compartments Targeting of Chloroplast Stromal Proteins Is Similar to Import of Mitochondrial Matrix Proteins Proteins Are Targeted to Thylakoids by Mechanisms Related to Inner Membrane Sorting of Peroxisomal Proteins Cytosolic Receptor Targets Proteins with an SKL Sequence at the C-Terminus into the Peroxisomal Matrix Peroxisomal Membrane and Matrix Proteins Are Incorporated by Different Pathways Transport into and out of the Nucleus Large and Small Molecules Enter and Leave the Nucleus via Nuclear Pore Complexes Importins Transport Proteins Containing Nuclear- Localization Signals into the Nucleus Exportins Transport Proteins Containing Nuclear-Export Signals out of the Nucleus Most mRNAs Are Exported from the Nucleus by a Ran-lndependent Mechanism 14 AND ENDOCYTOSIS Techniques for Studying the Secretory Pathway Transport of a Protein Through the Secretory Pathway Can Be Assayed in Living Cells Yeast Mutants Define Major Stages and Many Components in Vesicular Transport Cell-Free Transport Assays Allow Dissection of Individual Steps in Vesicular Transport Molecular Mechanisms of Vesicular Traffic Assembly of a Protein Coat Drives Vesicle Formation and Selection of Cargo Molecules A Conserved Set of GTPase Switch Proteins Controls Assembly of Different Vesicle Coats Targeting Sequences on Cargo Proteins Make Specific Molecular Contacts with Coat Proteins Rab Membranes Paired Sets of SNARE Proteins Mediate Fusion of Vesicles with Target Membranes Dissociation of SNARE Complexes After Membrane Fusion Is Driven by ATP Hydrolysis xxvi CONTENTS Early Stages of the Secretory Pathway 592 COPII to the Golgi COPI Vesicles Mediate Retrograde Transport within the Golgi and from the Golgi to the Anterograde Transport Through the Golgi Occurs by Cistemal Maturation Later Stages of the Secretory Pathway Vesicles Coated with Clathrin and/or Adapter Proteins Mediate Several Transport Steps Dynamin Is Required for Pinching Off of Clathrin Vesicles Mannose 6-Phosphate Residues Target Soluble Proteins to Lysosomes Study of Lysosomal Storage Diseases Revealed Key Components of the Lysosomal Sorting Pathway Protein Aggregation in the frans-Golgi May Function in Sorting Proteins to Regulated Secretory Vesicles Some Proteins Undergo Proteolytic Processing After Leaving the trans-Golgi Several Pathways Sort Membrane Proteins to the Apical or Basolateral Region of Polarized Cells ^QjU Cells Take Up Lipids from the Blood in the Form of Large, Weil-Defined Lipoprotein Complexes Receptors for Low-Density Lipoprotein and Other Ligands Contain Sorting Signals That Target Them for Endocytosis The Acidic Receptor-Ligand Complexes to Dissociate The Endocytic Pathway Delivers Iron to Cells without Dissociation of the Receptor-Transferrin Complex in Endosomes Directing Membrane Proteins and Cytosolic Materials to the Lysosome Multivesicular Endosomes Segregate Membrane Proteins Destined for the Lysosomal Membrane from Proteins Destined for Lysosomal Degradation Retroviruses Bud from the Plasma Membrane by a Process Similar to Formation of Multivesicular Endosomes 15 TRANSDUCTION AND SHORT-TERM CELLULAR RESPONSES From Extracellular Signal to Cellular Response Signaling Cells Produce and Release Signaling Molecules Signaling Molecules Can Act Locally or at a Distance Binding of Signaling Molecules Activates Receptors on Target Cells Щ5Щ Receptors Receptor Proteins Bind Ligands Specifically The Dissociation Constant Is a Measure of the Affinity of a Receptor for Its Ligand Binding Assays Are Used to Detect Receptors and Determine Their Affinities for Ligands Maximal Cellular Response to a Signaling Molecule Usually Does Not Require Activation of All Receptors Sensitivity of a Cell to External Signals Is Determined by the Number of Surface Receptors and Their Affinity for Ligand Receptors Can Be Purified by Affinity Techniques Classic Experiment Out of the Cell 621 ЮЗ of Intracellular Signal-Transduction Pathways GTP-Binding Proteins Are Frequently Used As On/Off Switches Protein Kinases and Phosphatases are Employed in Virtually All Signaling Pathways Second Messengers Carry and Amplify Signals from Many Receptors General Elements of Coupled Receptor Systems G Family with a Common Structure and Function G GTP for GDP on the Protein Different and in Turn Regulate Different Effector Proteins CONTENTS XXVII щ^З That Regulate Ion Channels Acetylcholine Receptors in the Heart Muscle Activate Light Activates G^-Coupled Rhodopsins Activation of Rhodopsin Induces Closing of cGMP-Gated Cation Channels Rod Cells Adapt to Varying Levels of Ambient Light Because of Opsin Phosphorylation and Binding of Insulin and Glucagon Work Together to Maintain a Stable Blood Glucose Level 658 Classic Experiment Transduction—GTP Stimulation of cAMP Synthesis 16 PATHWAYS THAT CONTROL GENE ACTIVITY Ц22Я Activate or Inhibit Adenylyl Cyclase Adenylyl Cyclase Is Stimulated and Inhibited by Different Receptor-Ligand Complexes Structural Studies Established How G^GTP Binds to and Activates Adenylyl Cyclase cAMP Activates Protein Kinase A by Releasing Catalytic Subunits Glycogen Metabolism Is Regulated by Hormone-Induced Activation of Protein Kinase A cAMP-Mediated Activation of Protein Kinase A Produces Diverse Responses in Different Cell Types Signal Amplification Commonly Occurs in Many Signaling Pathways Several Mechanisms Down-Regulate Signaling from Anchoring Proteins Localize Effects of cAMP to Specific Regions of the Cell QQI Activate Phospholipase Phosphorylated Derivatives of Inositol Are Important Second Messengers Calcium Ion Release from the Reticulum is Triggered by IP3 The Ca2+/Calmodulin Complex Mediates Many Cellular Responses to External Signals Diacylglycerol (DAG) Activates Protein Kinase C, Which Regulates Many Other Proteins Signal-Induced Relaxation of Vascular Smooth Muscle Is Mediated by cGMP-Activated Protein Kinase Integrating Responses of Cells to Environmental Influences Integration of Multiple Second Messengers Regulates Glycogenolysis TGFß Activation of Smads A of an Inactive Precursor Radioactive Tagging Was Used to Identify Receptors Activated Transcription Factors Negative Feedback Loops Regulate Signaling Loss of in Cancer Cytokine Receptors and the JAK/STAT Pathway Cytokines Influence Development of Many Cell Types Cytokine Receptors Have Similar Structures and Activate Similar Signaling Pathways JAK Complementation Genetics Revealed That JAK Signals Signaling from Cytokine Receptors Is Regulated by Negative Signals Mutant Erythropoietin Receptor That Cannot Be Turned Off Leads to Increased Numbers of Erythrocytes Receptor Tyrosine Kinases Ligand Binding Leads to Phosphorylation and Activation of Intrinsic Kinase in RTKs Overexpression of HER2, a Receptor Tyrosine Kinase, Occurs in Some Breast Cancers XXVIII CONTENTS Conserved Domains Are Important for Binding Signal- Transduction Proteins to Activated Receptors Down-regulation of RTK Signaling Occurs by Endocytosis and Lysosomal Degradation Activation of Pathways Ras, a and Inactive States Receptor Tyrosine Kinases Are Linked to Adapter Proteins Genetic Studies in Signal-Transducing Proteins in the Ras/MAP Kinase Pathway Binding of Conformational Change That Activates Signals Pass from Activated Protein Kinases MAP Kinase Regulates the Activity of Many Transcription Factors Controlling Early-Response Genes G MAP Kinase in Yeast Mating Pathways Scaffold Proteins Separate Multiple MAP Kinase Pathways in Eukaryotic Cells The Ras/MAP Kinase Pathway Can Induce Diverse Cellular Responses ЮЗ Transducers Phospholipase Cytokine Receptors Recruitment of PI-3 Kinase to Hormone-Stimulated Receptors Leads to Synthesis of Phosphorylated Phosphatidylinositols Accumulation of PI 3-Phosphates in the Plasma Membrane Leads to Activation of Several Kinases Activated Protein Kinase Cellular Responses The PI-3 Kinase Pathway Is Negatively Regulated by PTEN Phosphatase Hedgehog Signaling Relieves Repression of Target Genes 700 QQI Pathways That Involve Signal-Induced Protein Cleavage Degradation of an Inhibitor Protein Activates the NF-kB Transcription Factors Ligand-Activated Notch Is Cleaved Twice, Releasing a Transcription Factor Matrix Metalloproteases Catalyze Cleavage of Many Signaling Proteins from the Cell Surface Inappropriate Cleavage of Amyloid Precursor Protein Can Lead to Alzheimer s Disease Regulated Intramembrane Proteolysis of SREBP Releases a Transcription Factor That Acts to Maintain Phospholipid and Cholesterol Levels 17 MOVEMENT I: Microfilaments Structures Actin Is Ancient, Abundant, and Highly Conserved G-Actin Monomers Assemble into Long, Helical F-Actin Polymers F-Actin Has Structural and Functional Polarity Dynamics of Actin Filaments Actin Polymerization in Vitro Proceeds in Three Steps Actin Filaments Grow Faster at (-) Actin Filament Treadmilling Is Accelerated by Profilin Thymosin-ß4 Polymerization Capping Proteins Block Assembly and Disassembly at Actin Filament Ends 720 721 722 722 Activation of Gene Transcription by Seven-Spanning Cell-Surface Receptors CREB Links cAMP and Protein Kinase A to Activation of Gene Transcription GPCR-Bound Arrestin Wnt Signals Trigger Release of a Transcription Factor from Cytosolic Protein Complex Mechanisms of Actin Filament Assembly Formins Assemble Unbranched Filaments The Arp2/3 Complex Nucleates Branched Filament Assembly Intraceliular Movements Can Be Powered by Actin Polymerization CONTENTS XXIX Toxins That Perturb the Pool of Actin Monomers Are Useful for Studying Actin Dynamics 726 Chemotactic Gradients Induce Altered Phosphoinositide Levels Between the Front and Back of a Cell Organization of Actin-Based Cellular Structures Cross-Linking Proteins Organize Actin Filaments into Bundles or Networks Adaptor Proteins Link Actin Filaments to Membranes Myosins: Actin-Based Motor Proteins Myosins Have Head, Neck, and Tail Domains with Distinct Functions Myosins Make Up a Large Family of Mechanochemical Motor Proteins Conformational Changes in the Myosin Head Couple ATP Hydrolysis to Movement Myosin Heads Take Discrete Steps Along Actin Filaments Myosin V Walks Hand Over Hand Down an Actin Filament Myosin-Powered Movements Myosin Thick Filaments and Actin Thin Filaments ¡n Skeletal Muscle Slide Past One Another During Contraction Skeletal Muscle Is Structured by Stabilizing and Scaffolding Proteins Contraction of Skeletal Muscle Is Regulated by Ca2+ and Actin-Binding Proteins Actin and Myosin II Form Contractile Bundles in Nonmuscle Cells Myosin-Dependent Mechanisms Regulate Contraction in Smooth Muscle and Nonmuscle Cells Myosin-V-Bound Vesicles Are Carried Along Actin Filaments Cell Migration: Signaling and Chemotaxis 743 745 Cell Migration Coordinates Force Generation with Cell Adhesion and Membrane Recycling The Small GTP-Binding Proteins Cdc42, Control Actin Organization Cell Migration Involves the Coordinate Regulation of Cdc42, Migrating Cells Are Steered by Chemotactic Molecules Classic Experiment Contraction 755 18 MOVEMENT II: MICROTUBULES AND INTERMEDIATE FILAMENTS Microtubule Structure and Organization Microtubule Walls Are Polarized Structures Built from Microtubules Are Assembled from MTOCs to Generate Diverse Organizations ЩЮЦ Microtubules Are Dynamic Structures Due to Kinetic Differences at Their Ends Individual Microtubules Exhibit Dynamic Instability Localized Assembly and Search-and-Capture Help Organize Microtubules Drugs Affecting Tubulin Polymerization Are Useful Experimentally and to Treat Diseases Regulation of Microtubule Structure and Dynamics Microtubules Are Stabilized by Side- and End-Binding Proteins Microtubules Are Disassembled by End Binding and Severing Proteins Kinesins and Dyneins: Microtubule- Based Motor Proteins Organelles in Microtubules in Both Directions Kinesin-1 Powers Anterograde Transport of Vesicles Down Microtubules Kinesins Form a Large Protein Family with Diverse Functions Kinesin-1 Is a Highly Dynein Motors Transport Organelles Toward the End of Microtubules Kinesins and Dyneins Cooperate in the Transport of Organelles Throughout the Cell xxx CONTENTS QQI Cilia Based Surface Structures Eukaryotic Cilia and Microtubules Bridged by Dynein Motors Ciliary and Controlled Sliding of Outer Doublet Microtubules Intraflagellar Transport Moves Material Up and Down Cilia and Defects in Intraflagellar Transport Cause Disease by Affecting Sensory Primary Cilia ЦВДІ Mitosis Can Be Divided into Six Phases Centrosomes Duplicate Early in the Cell Cycle in Preparation for Mitosis The Mitotic Spindle Contains Three Classes of Microtubules Microtubule Dynamics Increases Dramatically in Mitosis Microtubules Treadmill During Mitosis The Kinetochore Captures and Helps Transport Chromosomes Duplicated Chromosomes Are Aligned by Motors and Treadmilling Microtubules Anaphase Microtubule Shortening Anaphase Action of Kinesins and Dynein Additional Mechanisms Contribute to Spindle Formation Cytokinesis Splits the Duplicated Cell in Two Plant Cells Reorganize Their Microtubules and Build a New Cell Wall in Mitosis ЦЦ2Л Intermediate Filaments Are Assembled from Subunit Intermediate Filaments Proteins Are Expressed in a Tissue-Specific Manner Intermediate Filaments Are Dynamic Defects in Lamins and Keratins Cause Many Diseases Microfilaments Transport Melanosomes Cdc42 Coordinates Microtubules and During Cell Migration 778 19 TISSUES 801 779 780 щущ An Overview 803 Cell-Adhesion Molecules Bind to One Another and 781 to Intracellular Proteins 803 782 The Extracellular Matrix Participates in Adhesion, Signaling, and Other Functions 805 783 The Evolution of Multifaceted Adhesion Molecules Enabled the Evolution of Diverse Animal Tissues 807 784 ЦЦ 784 and Their Adhesion Molecules 808 785 Epithelial Cells Have Distinct Apical, Lateral, and 786 Basal Surfaces 808 Three Types of Junctions Mediate Many Cell-Cell 788 and Cell-ECM Interactions 809 Cadherins Mediate Cell-Cell Adhesions in Adherens 789 Junctions and Desmosomes 810 Tight Junctions Seal Off Body Cavities and Restrict 789 Diffusion of Membrane Components 814 Integrins 816 789 Gap Junctions Composed of Connexins Allow Small 789 Molecules to Pass Directly Between Adjacent Cells 817 Ц2Л The Basal Lamina The Basal Lamina Provides a Foundation for Assembly of Cells into Tissues Laminin, a Multiadhesive Matrix Protein, Helps Cross-link Components of the Basal Lamina Sheet-Forming Type IV Collagen Is a Major Structural Component of the Basal Lamina Perlecan, a Proteoglycan, Cross-links Components of the Basal Lamina and Cell-Surface Receptors Coordination and Cooperation between Cytoskeletal Elements Intermediate Filament-Associated Proteins Contribute to Cellular Organization ЕИ Connective and Other Tissues Fibrillar in the ECM of Connective Tissues CONTENTS XXXI Fibrillar Fibrils Outside of the Cell Type I and II Collagens Proteoglycans and Their Constituent GAGs Play Diverse Roles in the ECM Hyaluronan Resists Compression, Facilitates Cell Migration, and Gives Cartilage Its Gel-like Properties Fibronectins Interconnect Cells and Matrix, Influencing Cell Shape, Differentiation, and Movement Adhesive Interactions in Motile and Nonmotile Cells Integrins Three-Dimensional Environment Regulation of Integrin-Mediated Adhesion and Signaling Controls Cell Movement Connections Between the ECM and Cytoskeleton Are Defective in Muscular Dystrophy IgCAMs Mediate Cell-Cell Adhesion in and Other Tissues Leukocyte Movement into Tissues Is Orchestrated by a Precisely Timed Sequence of Adhesive Interactions Plant Tissues The Plant Cell Wall Is a Laminate of Cellulose Fibrils in a Matrix of Glycoproteins Loosening of the Cell Wall Permits Plant Cell Growth Plasmodesmata Directly Connect the Cytosols of Adjacent Cells in Higher Plants Only a Few Adhesive Molecules Have Been Identified in Plants Part IV Cell Growth and Development 20 CELL CYCLE Overview of the Cell Cycle and Its Control The Cell Cycle Is an Ordered Series of Events Leading to Cell Replication Regulated Protein Phosphorylation and Degradation Control Passage Through the Cell Cycle Diverse Experimental Systems Have Been Used to Identify and Isolate Cell-Cycle Control Proteins Control of Mitosis by Cyclins and MPF Activity Maturation-Promoting Factor (MPF) Stimulates Meiotic Maturation in Oocytes and Mitosis in Somatic Cells Mitotic Cyclin Was First Identified in Early Sea Urchin Embryos Cyclin Promoting Factor (MPF) Change Together in Cycling Xenopus Egg Extracts Anaphase-Promoting Complex (APC/C) Controls Degradation of Mitotic Cyclins and Exit from Mitosis Cyclin-Dependent Kinase Regulation During Mitosis MPF Components Are Conserved Between Lower and Higher Eukaryotes Phosphorylation of the CDK Kinase Activity of MPF Conformational Changes Induced by Cyclin Binding and Phosphorylation Increase MPF Activity Molecular Mechanisms for Regulating Mitotic Events Phosphorylation of Nuclear Lamins and Other Proteins Promotes Early Mitotic Events Unlinking of Sister Chromatids Initiates Chromosome Decondensation and Reassembly of the Nuclear Envelope Depend on Dephosphorylation of MPF Substrates Cyclin-CDK and Ubiquitin-Protein Ligase A Cyclin-Dependent Kinase (CDK) Is Critical for S-Phase Entry in Three to Form S-Phase-Promoting Factors xxxii CONTENTS Degradation Replication Multiple Cyclins Regulate the Kinase Activity of S. cerevisiae CDK During Different Cell-Cycle Phases Replication at Each Origin Is Initiated Only Once During the Cell Cycle gţjiBSfl Cells Mammalian Restriction Point Is Analogous to START in Yeast Cells Multiple CDKs and Cyclins Regulate Passage of Mammalian Cells Through the Cell Cycle Regulated Expression of Two Classes of Genes Returns Go Mammalian Cells to the Cell Cycle Passage Through the Restriction Point Depends on Phosphorylation of the Tumor-Suppressor Rb Protein Cyclin A Is Required for for Entry into Mitosis Two Types of Cyclin-CDK Inhibitors Contribute to Cell-Cycle Control in Mammals ЕШЛ Regulation The Presence of Unreplicated into Mitosis Improper Assembly of the Mitotic Spindle Prevents the Initiation of Proper Segregation of Daughter Chromosomes Is Monitored by the Mitotic Exit Network Cell-Cycle Arrest of Cells with Damaged on Tumor Suppressors ЩЦ Division 892 892 Key Features Distinguish Meiosis from Mitosis Repression of Kinase Promote Premeiotic Recombination and a Meiosis-Specific Cohesin Are Necessary for the Specialized Chromosome Segregation in Meiosis I Special Properties of Rec8 Regulate Its Cleavage in Meiosis I and II The Kinetochores in Meiosis I Tension on Spindle Microtubules Contributes to Proper Spindle Attachment 895 896 898 898 Classic Experiment from the Sea: The Discovery of Cyclins 21 DEATH The Birth of Cells: Stem Cells, Niches, and Lineage Stem Cells Give Rise to Both Stem Cells and Differentiating Cells Cell Fates Are Progressively Restricted During Development The Complete Cell Lineage of Heterochronic Mutants Provide Clues About Control of Cell Lineage Cultured Embryonic Stem Cells Can Differentiate into Various Cell Types Adult Stem Cells for Different Animal Tissues Occupy Sustaining Niches Meristems Are Plants ЩЩ Mating-Type Transcription Factors Specify Cell Types MCM1 and Transcription аг-МСМІ Pheromones Induce Mating of Generate a Third Cell Type Specification and Differentiation of Muscle Embryonic Somites Give Rise to Myoblasts Myogenic Genes Were First Identified in Studies with Cultured Two Classes of Regulatory Factors Act in Concert to Guide Production of Muscle Cells Differentiation of Myoblasts Is Under Positive and Negative Control Cell-Cell Signals Are Crucial for Determination and Migration of Myoblasts bHLH Regulatory Proteins Function in Creation of Other Tissues Regulation of Asymmetric Cell Division Yeast Mating-Type Switching Depends upon Asymmetric Cell Division CONTENTS XXXIII Proteins Opposite Ends of Dividing Neuroblasts in Cell Death and Its Regulation Programmed Cell Death Occurs Through Apoptosis Neurotrophins Promote Survival of Neurons A Cascade of Caspase Proteins Functions in One Apoptotic Pathway Pro-Apoptotic Regulators Permit Caspase Activation in the Absence of Trophic Factors Some Trophic Factors Induce Inactivation of a Pro-Apoptotic Regulator Tumor Necrosis Factor and Related Death Signals Promote Cell Murder by Activating Caspases 22 OF DEVELOPMENT Highlights of Development (ЩЩ Germ-line Cells Are All That We Inherit Fertilization Unifies the Genome Genomic Imprinting Controls Gene Activation According to Maternal or Paternal Chromosome Origin Too Much of a Good Thing: The X Chromosome Is Regulated by Dosage Compensation in Early Vertebrate Embryos Cleavage Leads to the First Differentiation Events The Genomes of Most Somatic Cells Are Complete Gastrulation Creates Multiple Tissue Layers, Which Become Polarized Signal Gradients May Induce Different Cell Fates Signal Antagonists Influence Cell Fates and Tissue Induction A Cascade of Signals Distinguishes Left from Right 950 Development Progresses from Egg and Sperm to an Early Embryo As the Embryo Develops, Cell Layers Become Tissues and Organs Genes That Regulate Development Are at the Heart of Evolution 952 953 953 955 958 958 959 960 961 961 963 965 966 Control of Body Segmentation: Themes and Variations in Insects and Vertebrates Early Transcriptional Control Specifies the Embryo s Anterior and Posterior Translation Inhibitors Reinforce Anterior-Posterior Patterning Insect Segmentation Is Controlled by a Cascade of Transcription Factors Vertebrate Segmentation Is Controlled by Cyclical Expression of Regulatory Genes Differences Between Segments Are Controlled by Hox Genes Hox-Gene Expression Is Maintained by a Variety of Mechanisms Flower Development Requires Spatially Regulated Production of Transcription Factors Cell-Type Specification in Early Neural Development Neurulation Begins Formation of the Brain and Spinal Cord Signal Gradients and Transcription Factors Specify Cell Types in the Neural Tube and Somites Most Neurons in the Brain Arise in the Innermost Neural Tube and Migrate Outward Lateral Inhibition Mediated by Notch Signaling Causes Early Neural Cells to Become Different Growth and Patterning of Limbs Hox Genes Determine the Right Places for Limbs to Grow Limb Development Depends on Integration of Multiple Extracellular Signal Gradients Hox Genes Also Control Fine Patterning of Limb Structures So Far, So Good Classic Experiment Mutations to Study Development 990 991 992 994 999 23 949 Neurons and Blocks of the Nervous System Information Flows Through Neurons from to xxxiv CONTENTS Information Moves as Pulses of Ion Flow Called Action Potentials Information Flows Between Neurons via Synapses The Nervous System Uses Signaling Circuits Composed of Multiple Neurons Q29 Voltage-Gated Ion Channels and the Propagation of Action Potentials in Nerve Cells The Magnitude of the Action Potential Is Close to £Na Sequential Opening and Closing of Voltage- Gated Na+ and K+ Channels Generate Action Potentials Action Potentials Are Propagated Unidirectionally Without Diminution Nerve Cells Can Conduct Many Action Potentials in the Absence of ATP All Voltage-Gated Ion Channels Have Similar Structures Voltage-Sensing S4 to Membrane Depolarization Movement of the Channel-Inactivating Segment into the Open Pore Blocks Ion Flow Myelination Increases the Velocity of Impulse Conduction Action Potentials Jump from Node to Node in Myelinated Glia QQI Communication at Synapses Formation of Synapses Requires Assembly of Presynaptic and Postsynaptic Structures Neurotransmitters Vesicles by H^Linked Antiport Proteins Synaptic Vesicles Loaded with Are Localized near the Plasma Membrane Influx of Ca2+ Triggers Release of Neurotransmitters A Calcium-Binding Protein Regulates Fusion of Synaptic Vesicles with the Plasma Membrane Signaling at Synapses Is Terminated by Degradation or Reuptake of Fly Mutants Lacking Dynamin Cannot Recycle Synaptic Vesicles Opening of Acetylcholine-Gated Cation Channels Leads to Muscle Contraction All Five Subunits in the Nicotinic Acetylcholine Receptor Contribute to the Ion Channel Nerve Cells Make an All-or-None Decision to Generate an Action Potential Gap Junctions Also Allow Neurons to Communicate ЕЭД Hearing, Tasting, and Smelling The Eye Features Light-Sensitive Nerve Cells Eyes Reflect Evolutionary History Integrated Information from Multiple Ganglion Cells Forms Images of the World Mechanosensory Cells Detect Pain, Heat, Cold, Touch, and Pressure Inner Ear Cells Detect Sound and Motion Five Primary Tastes Are Sensed by Subsets of Cells in Each Taste Bud A Plethora of Receptors Detect Odors The Path to Success: Controlling Axon Growth and Targeting The Growth Cone Is a Motorized Sensory Guidance Structure The Retinotectal Map Revealed an Ordered System of Axon Connections There Are Four Families of Axon Guidance Molecules Developmental Regulators Also Guide Axon Guidance Molecules Cause the Growth Cone to Turn 24 1055 ОЛ Pathogens Enter the Body Through Different Routes and Replicate at Different Sites Leukocytes Circulate Throughout the Body and Take Up Residence in Tissues and Lymph Nodes Mechanical and Chemical Boundaries Form a First Layer of Defense Against Pathogens Innate Immunity Provides a Second Line of Defense After Mechanical and Chemical Barriers Are Crossed Inflammation Is a Complex Response to Injury That Encompasses Both Innate and Adaptive Immunity Adaptive Immunity, the Third Line of Defense, Exhibits Specificity CONTENTS XXXV QQI Immunoglobulins: and Function Immunoglobulins Have a Conserved Structure Consisting of Heavy and Light Chains Multiple Immunoglobulin Each with Different Functions Each Immunoglobulin Immunoglobulin Domains Have a Characteristic Fold Composed of Two by a Disulfide Bond The Three-Dimensional Structure of Antibody Molecules Accounts for Their Exquisite Specificity An Immunoglobulin s Constant Region Determines Its Functional Properties Generation of Antibody Diversity and B-Cell Development A Functional Light-Chain Gene Requires Assembly of V and Rearrangement of the Heavy-Chain Locus Involves V, D, and Somatic Hypermutation Allows the Generation and Selection of Antibodies with Improved Affinities B-Cell Development Requires Input from a Pre-B Cell Receptor During an Adaptive Response, from Making Membrane-Bound Secreted В They Make The MHC and Antigen Presentation The MHC Determines the Ability of Two Unrelated Individuals of the Same Species to Accept or Reject Grafts The Killing Activity of Cytotoxic Specific and MHC Restricted T Guided by Two Distinct Classes of MHC Molecules MHC Molecules Bind and Interact with the Antigen Presentation Is the Process by Which Protein Fragments Are Complexed with MHC Products and Posted to the Cell Surface Class I MHC Pathway Presents Cytosolic Antigens Class II MHC Pathway Presents Antigens Delivered to the Endocytic Pathway 1082 1082 1084 T and The Structure of the the F(ab) Portion of an Immunoglobulin TCR Genes Are Rearranged in a Manner Similar to Immunoglobulin Genes Т of Their Variable Residues Encoded in the Junctions between V, D, and Signaling via Antigen-Specific Receptors Triggers Proliferation and Differentiation of T Develop Through a Process of Positive and Negative Selection T for Full Activation Cytotoxic and Are Specialized for Killing T Signals to Other Immune Cells CD4 Based on Their Cytokine Production and Expression of Surface Markers Leukocytes Move in Response to Chemotactic Cues Provided by Chemokines Collaboration of Immune-System Cells in the Adaptive Response Toll-Like Receptors Perceive a Variety of Pathogen-Derived Macromolecular Patterns Engagement of Toll-Like Receptors Leads to Activation of Antigen-Presenting Cells Production of High-Affinity Antibodies Requires Collaboration Between Vaccines Elicit Protective Immunity Against a Variety of Pathogens Classic Experiment Somatic Rearrangement of Immunoglobulin Genes 25 1107 Tumor Cells and the Onset of Cancer 1109 Metastatic Tumor Cells Are Invasive and Can Spread Cancers Usually Originate in Proliferating Cells Cancer Stem Cells Can Be a Minority Population Tumor Growth Requires Formation of New Blood Vessels 1111 xxxvi CONTENTS Specific into Tumor Cells A Multi-hit Model of Cancer Induction Is Supported by Several Lines of Evidence Successive Oncogenic Mutations Can Be Traced in Colon Cancers DNA Microarray Reveal Subtle Differences Between Tumor Cells ££2Ш Gain-of-Function Mutations Convert Proto-oncogenes into Oncogenes Cancer-Causing Viruses Contain Oncogenes or Activate Cellular Proto-oncogenes Loss-of-Function Mutations in Tumor-Suppressor Genes Are Oncogenic Inherited Mutations in Tumor-Suppressor Genes Increase Cancer Risk Aberrations in Signaling Pathways That Control Development Are Associated with Many Cancers ^Ц£\| Promoting Proteins Oncogenic Receptors Can Promote Proliferation in the Absence of External Growth Factors Viral Activators of Growth-Factor Receptors Act as Oncoproteins Many Oncogenes Encode Constitutively Active Signal-Transduction Proteins Inappropriate Production of Nuclear Transcription Factors Can Induce Transformation Molecular Cell Biology Is Changing How Cancer Is Treated О2Я Growth-Inhibiting and Cell-Cycle Controls Mutations That Promote Unregulated Passage from G, to Loss-of-Function Mutations Affecting Chromatin- Remodeling Proteins Contribute to Tumors Loss of p53 Abolishes the DNA-Damage Checkpoint Apoptotic Genes Can Function as Proto-oncogenes or Tumor-Suppressor Genes Failure of Cell-Cycle Checkpoints Often Leads to Aneuploidy in Tumor Cells Carcinogens and Caretaker Genes in Cancer Carcinogens Induce Cancer by Damaging Some Carcinogens Have Been Linked to Specific Cancers Loss of DNA-Repair Systems Can Lead to Cancer Telomerase Expression Contributes to Immortalization of Cancer Cells GLOSSARY G-1 INDEX CONTENTS XXXVII
adam_txt	CONTENTS Part I Chemical and Molecular Foundations 1 Cells Grow and Divide Ceils Die from Aggravated Assault or an Internal Program The Diversity and Commonality of Cells All Cells Are Prokaryotic or Eukaryotic Unicellular Organisms Help and Hurt Us Viruses Are the Ultimate Parasites Changes in Cells Underlie Evolution Even Single Cells Can Have Sex We Develop from a Single Cell Stem Cells, Fundamental to Forming Tissues and Organs, Offer Medical Opportunities The Molecules of a Cell Small Molecules Carry Energy, Transmit Signals, and Are Linked into Macromolecules Proteins Give Cells Structure and Perform Most Cellular Tasks Nucleic Acids Carry Coded Information for Making Proteins at the Right Time and Place The Genome Is Packaged into Chromosomes and Replicated During Cell Division Mutations May Be Good, Bad, or Indifferent The Work of Cells Cells Build and Degrade Numerous Molecules and Structures Animal Cells Produce Their Own External Environment and Glues Cells Change Shape and Move Cells Sense and Send Information Cells Regulate Their Gene Expression to Meet Changing Needs Investigating Cells and Their Parts Cell Biology Reveals the Size, Shape, Location, and Movements of Cell Components Biochemistry and Biophysics Reveal the Molecular Structure and Chemistry of Purified Cell Constituents Genetics Reveals the Consequences of Damaged Genes Genomics Reveals Differences in the Structure and Expression of Entire Genomes Developmental Biology Reveals Changes in the Properties of Cells as They Specialize Choosing the Right Experimental Organism for the Job The Most Successful Biological Studies Use Multiple Approaches A Genome Perspective on Evolution Metabolic Proteins, the Genetic Code, and Structures Are Nearly Universal Darwin's Ideas About the Evolution of Whole Animals Are Relevant to Genes Many Genes Controlling Development Are Remarkably Similar in Humans and Other Animals Human Medicine Is Informed by Research on Other Organisms 2 31 ££\| Covalent Bonds and Noncovalent Interactions The Electronic Structure of an Atom Determines the Number and Geometry of Covalent Bonds It Can Make CONTENTS XV Electrons in Covalent Bonds Are Much Stronger and More Stable Than Noncovalent Interactions Ionic Interactions Are Attractions between Oppositely Charged Ions Hydrogen Bonds Determine the Water Solubility of Uncharged Molecules Van Transient Dipoles The Molecules to Adhere to One Another Molecular Complementarity Mediated via Noncovalent Interactions Permits Tight, Highly Specific Binding of Biomolecules Chemical Building Blocks of Cells Amino Compose Proteins Five Different Nucleotides Are Used to Build Nucleic Acids Monosaccharides Joined by Glycosidic Bonds Form Linear and Branched Polysaccharides Phospholipids Associate Noncovalently to Form the Basic Bilayer Structure of £Щ Equilibrium Constants Reflect the Extent of a Chemical Reaction Chemical Reactions in Cells Are at Steady State Dissociation Constants of Binding Reactions Reflect the Affinity of Interacting Molecules Biological Fluids Have Characteristic Hydrogen Ions Are Released by Acids and Taken Up by Bases Buffers Maintain the Extracellular Fluids Biochemical Energetics Several Forms of Energy Are Important in Biological Systems Cells Can Transform One Type of Energy into Another The Change in Free Energy Determines the Direction of a Chemical Reaction The from Its K, eq The Rate of a Reaction Depends on the Activation Energy Necessary to Energize the Reactants into a Transition State 41 44 44 46 49 50 50 50 51 52 52 54 54 55 55 56 56 Life Depends on the Coupling of Unfavorable Chemical Reactions with Energetically Favorable Reactions Hydrolysis of ATP Releases Substantial Free Energy and Drives Many Cellular Processes ATP Is Generated During Photosynthesis and Respiration NAD+ and FAD Couple Many Biological Oxidation and Reduction Reactions 3 FUNCTION ^^\| Hierarchical Structure of Proteins The Primary Structure of a Protein Is Its Linear Arrangement of Secondary Structures Are the Core Elements of Protein Architecture Overall Folding of a Polypeptide Chain Yields Its Tertiary Structure Different Ways of Depicting the Conformation of Proteins Convey Different Types of Information Structural Motifs Are Regular Combinations of Secondary and Tertiary Structures Structural and Functional Domains Are Modules of Tertiary Structure Proteins Associate into Macromolecular Assemblies Members of Protein Families Have a Common Evolutionary Ancestor ^^] Protein Folding Planar Which Proteins Can Fold Information Directing a Protein's Folding Is Encoded in Its Folding of Proteins in Vivo Is Promoted by Chaperones Alternatively Folded Proteins Are Implicated in Diseases ЩЛ Specific Binding of Ligands Underlies the Functions of Most Proteins Enzymes Are Highly Efficient and Specific Catalysts An Enzyme's Active Site Binds Substrates and Carries Out Catalysis Serine Enzyme's Active Site Works Enzymes in a Common Pathway Are Often Physically Associated with One Another xvi CONTENTS Enzymes into Motion Regulating Protein Function I: Protein Degradation Regulated Synthesis and Degradation of Proteins is a Fundamental Property of Cells The Proteasome Is a Complex Molecular Machine Used to Degrade Proteins Ubiquitin Marks Cytosolic Proteins for Degradation in Proteasomes Q9I Regulating Protein Function II: Noncovalent and Covalent Modifications Noncovalent Binding Permits Allosteric, or Cooperative, Regulation of Proteins Noncovalent Binding of Calcium and GTP Are Widely Used As Allosteric Switches to Control Protein Activity Phosphorylation and Dephosphorylation Covalently Regulate Protein Activity Proteolytic Cleavage Irreversibly Activates or Inactivates Some Proteins Higher-Order Regulation Includes Control of Protein Location and Concentration QQ Purifying, Detecting, and Characterizing Proteins Centrifugation Can Separate Particles and Molecules That Differ in Mass or Density Electrophoresis Separates Molecules on the Basis of Their Charge-to-Mass Ratio Liquid Chromatography Resolves Proteins by Mass, Charge, or Binding Affinity Highly Specific Enzyme and Antibody Assays Can Detect Individual Proteins Radioisotopes Are Biological Molecules Mass Spectrometry Can Determine the Mass and Sequence of Proteins Protein Primary Structure Can Be Determined by Chemical Methods and from Gene Sequences Protein Conformation Is Determined by Sophisticated Physical Methods Proteomics Proteomics Is the Study of All or a Large Subset of Proteins in a Biological System Advanced Techniques in Mass Spectrometry Are Critical to Proteomic Analysis Part II Genetics and Molecular Biology 4 MECHANISMS Structure of Nucleic Acids A Nucleic Acid Strand Is a Linear Polymer with End-to-End Directionality Native Antiparallel DNA Torsionai Different Types of Conformations Related to Their Functions Q3 Transcription of Protein-Coding Genes and Formation of Functional mRNA Organization of Genes Differs in Prokaryotic and Eukaryotic Eukaryotic Precursor mRNAs Are Processed to Form Functional mRNAs Alternative Proteins Expressed from a Single Eukaryotic Gene ШШШ A Template Complementary Messenger Three-Letter Genetic Code The Folded Structure of tRNA Promotes Its Decoding Functions Nonstandard Base Codons Amino Linked to tRNAs Stepwise Synthesis of Proteins on Ribosomes 120 127 129 130 131 132 132 CONTENTS XVII Meth¡onyl-tRNA¡MET Translation Initiation Usually Occurs at the First AUG During Chain Elongation Each Incoming Aminoacyl-tRNA Moves Through Three Ribosomal Sites Translation Is Terminated by Release Factors When a Stop Codon Is Reached Polysomes and Rapid Ribosome Recycling Increase the Efficiency of Translation IQ DNA DNA Polymerases Replication Duplex Formed at the Several Proteins Participate in DNA Each Origin ÜQ DNA DNA and Also Correct Them Chemical and Radiation Damage to Lead to Mutations High-Fidelity DNA Recognize and Repair Damage Base Excision Repairs TG Mismatches and Damaged Bases Mismatch Excision Repairs Other Mismatches and Small Insertions and Deletions Nucleotide Excision Repairs Chemical Adducts That Distort Normal Two Systems Utilize Recombination to Repair Double-Strand Breaks in Homologous Recombination Can Repair Damage and Generate Genetic Diversity Viruses: Parasites of the Cellular Genetic System Most Viral Host Ranges Are Narrow Viral Capsids Are Regular Arrays of One or a Few Types of Protein Viruses Can Be Cloned and Counted in Plaque Assays Lytic Viral Growth Cycles Lead to the Death of Host Cells Viral in Some Nonlytic Viral Growth Cycles 5 Genetic Analysis of Mutations to Identify and Study Genes Recessive and Dominant Mutant Have Opposite Effects on Gene Function Segregation of Mutations in Breeding Experiments Reveals Their Dominance or Recessivity Conditional Mutations Can Be Used to Study Essential Genes in Yeast Recessive Lethal Mutations in Diploids Can Be Identified by Inbreeding and Maintained in Hétérozygotes Complementation Tests Determine Whether Different Recessive Mutations Are in the Same Gene Double Mutants Are Useful in Assessing the Order in Which Proteins Function Genetic Suppression and Synthetic Lethality Can Reveal Interacting or Redundant Proteins Genes Can Be Identified by Their Map Position on the Chromosome 171 173 174 ЩЦЩ Restriction Enzymes and Insertion of E. coli Plasmid Isolated cDNA Libraries Represent the Sequences of Protein-Coding Genes cDNAs Prepared by Reverse Transcription of Cellular mRNAs Can Be Cloned to Generate cDNA Libraries DNA to an Oligonucleotide Probe Yeast Genomic Libraries Can Be Constructed with Shuttle Vectors and Screened by Functional Complementation Gel Electrophoresis Allows Separation of Vector DNA f Cloned by the Dideoxy Chain-Termination Method The Polymerase Chain Reaction Amplifies a Specific DNA ШВШ to Study Gene Expression Hybridization Techniques Permit Detection of Specific DNA Microarrays Expression of Many Genes at One Time XVIII CONTENTS Cluster Identifies Co-regulated Genes E. coli Quantities of Proteins from Cloned Genes Plasmid Expression Vectors Can Be Designed for Use in Animal Cells Identifying and Locating Human Disease Genes Many Inherited Diseases Show One of Three Major Patterns of Inheritance DNA Human Mutations Linkage Studies Can Map Disease Genes with a Resolution of About Further Analysis Is Needed to Locate a Disease Gene in Cloned Many Inherited Diseases Result from Multiple Genetic Defects HQ Inactivating the Function of Specific Genes in Eukaryotes Normal Yeast Genes Can Be Replaced with Mutant Alíeles Transcription of Genes Promoter Can Be Controlled Experimentally Specific Genes Can Be Permanently Inactivated in the Germ Line of Mice Somatic Cell Recombination Can Inactivate Genes in Specific Tissues Dominant-Negative Inhibit Some Genes RNA Destroying the Corresponding mRNA 6 CHROMOSOMES Eukaryotic Gene Structure 217 Most Eukaryotic Genes Contain mRNAs Encoding Single Proteins Simple and Complex Transcription Units Are Found in Eukaryotic Genomes Protein-Coding Genes May Be Solitary or Belong to a Gene Family Heavily Used Gene Products Are Encoded by Multiple Copies of Genes Nonprotein-Coding Genes Encode Functional RNAs ^2al Chromosomal Organization of Genes and Noncoding Genomes of Many Organisms Contain Much Nonfunctional Most Simple-Sequence DNAs Are Concentrated in Specific Chromosomal Locations DNA in Length of Simple-Sequence DNAs Unclassified Spacer Portion of the Genome (•Щ Elements Movement of Mobile Elements Involves a DNA DNA and Eukaryotes LTR Retrotransposons Behave Like Intracellular Retroviruses Non-LTR Retrotransposons Transpose by a Distinct Mechanism Other DNA 234 Mobile Evolution ЦІ Mitochondria Contain Multiple mtDNA Molecules mtDNA Is Inherited Cytoplasmically The Size, Structure, and Coding Capacity of mtDNA Vary Considerably Between Organisms Products of Mitochondrial Genes Are Not Exported Mitochondria Evolved from a Single Endosymbiotic Event Involving a Mitochondrial Genetic Codes Differ from the Standard Nuclear Code Mutations in Mitochondrial Genetic Diseases in Humans Chloroplasts Contain Large DNAs Often Encoding More Than a Hundred Proteins Q3 Genomics: Genome-wide Analysis of Gene Structure and Expression Stored Sequences Suggest Functions of Newly Identified Genes and Proteins CONTENTS XIX Comparison of Related Sequences from Different Species Can Give Clues to Evolutionary Relationships Among Proteins Genes Can Be Identified Within Genomic Sequences The Number of Protein-Coding Genes in an Organism's Genome Is Not Directly Related to Its Biological Complexity Single Nucleotide Polymorphisms and Gene Copy- Number Variation Are Important Determinants of Differences Between Individuals of a Species Structural Organization of Eukaryotic Chromosomes 244 244 245 246 247 248 Chromatin Exists in Extended and Condensed Forms Modifications of Histone Tails Control Chromatin Condensation and Function Nonhistone Proteins Provide a Structural Scaffold for Long Chromatin Loops Additional Nonhistone Proteins Regulate Transcription and Replication Small Molecules Regulate Expression of Many Bacterial Genes via DNA-Binding Repressors and Activators Transcription Initiation from Some Promoters Requires Alternative Sigma Factors Transcription by aS4-RNA Polymerase Is Controlled by Activators That Bind Far from the Promoter Many Bacterial Responses Are Controlled by Two-Component Regulatory Systems EQI Overview of Eukaryotic Gene Control and Regulatory Elements in Eukaryotic Both Close to and Many Transcription Start Sites Three Eukaryotic Polymerases Catalyze Formation of Different RNAs The Largest Essential Carboxyl-Terminal Repeat RNA Sequences Corresponding to the \|эдЦ of Eukaryotic Chromosomes Chromosome Number, Size, and Shape at Metaphase Are Species-Specific During Metaphase, Chromosomes Can Be Distinguished by Banding Patterns and Chromosome Painting Chromosome Painting and the Evolution of Chromosomes Interphase Polytene Amplification Three Functional Elements Are Required for Replication and Stable Inheritance of Chromosomes Centromere Sequences Vary Greatly in Length Addition of Telomeric Sequences by Telomerase Prevents Shortening of Chromosomes TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION 269 Control of Gene Expression in Bacteria Transcription Initiation by Bacterial Requires Association with a Sigma Factor Initiation of lac Operon Transcription Can Be Repressed and Activated 271 271 271 Цц\| Coding Genes The TATA Box, Initiators, and CpG Islands Function as Promoters in Eukaryotic Promoter-Proximal Elements Help Regulate Eukaryotic Genes Distant Enhancers Often Stimulate Transcription by Most Eukaryotic Genes Are Regulated by Multiple Transcription-Control Elements Activators and Repressors of Transcription 263 Interactions Activators Are Modular Proteins Composed of Distinct Functional Domains and Promote Transcription Repressors Inhibit Transcription and Are the Functional Converse of Activators DNA-Binding Domains Can Be Classified into Numerous Structural Types Structurally Diverse Activation and Repression Domains Regulate Transcription Transcription Factor Interactions Increase Gene-Control Options Multiprotein Complexes Form on Enhancers 282 282 282 284 285 286 286 288 290 290 293 294 295 xx CONTENTS Transcription Initiation Polymerase II 296 General Transcription Polymerase II Sequential Assembly of Proteins Forms the Pol II Transcription Preinitiation Complex in Vitro In Vivo Transcription Initiation by Pol II Requires Additional Proteins Mitochondrial and Transcribed by Organelle-Specific Polymerases 317 8 CONTROL Molecular Mechanisms of Transcription Repression and Activation Formation of Heterochromatin Silences Gene Expression at Telomeres, Near Centromeres, and in Other Regions Repressors Can Direct Histone Deacetylation and Methylation at Specific Genes Activators Can Direct Histone Acetylation and Methylation at Specific Genes Chromatin-Remodeling Factors Help Activate or Repress Transcription 299 299 303 305 306 Histone Modifications Vary Greatly in Their Stabilities The Mediator Complex Forms a Molecular Bridge Between Activation Domains and Pol II 307 Transcription of Many Genes Requires Ordered Binding and Function of Activators and Co-activators The Yeast Two-Hybrid System Exploits Activator Flexibility to Detect cDNAs That Encode Interacting Proteins Regulation of Transcription-Factor Activity Ali Structure 312 Nuclear-Receptor Response Elements Contain Inverted or Direct Repeats Hormone Binding to a Nuclear Receptor Regulates Its Activity as a Transcription Factor Regulated Elongation and Termination of Transcription Transcription of the an Antitermination Mechanism Promoter-Proximal Pausing of Occurs in Some Rapidly Induced Genes Other Eukaryotic Transcription Systems Transcription Initiation by Pol I and Pol HI Is Analogous to That by Pol II 313 314 315 316 316 316 Processing of Eukaryotic Pre-mRNA The Transcription Initiation A Diverse Set of Proteins with Conserved RNA-Binding Domains Associate with Pre-mRNAs Splicing Occurs at Short, Conserved Sequences in Pre-mRNAs via Two Transesterification Reactions During Splicing, snRNAs Base-Pair with Pre-mRNA Spliceosomes, Assembled from snRNPs and a Pre-mRNA, Carry Out Splicing Chain Elongation by to the Presence of RNA-Processing Factors SR Proteins Contribute to Exon Definition in Long Pre-mRNAs Self-Splicing Group II Evolution of snRNAs 3' Are Tightly Coupled Nuclear Exonucleases Degrade Out of Pre-mRNAs Ц2Л Processing Alternative Splicing Is the Primary Mechanism for Regulating mRNA Processing A Cascade of Regulated Drosophila Splicing Repressors and Activators Control Splicing at Alternative Sites RNA Some Pre-mRNAs £Q Transport of mRNA Across the Nuclear Envelope Nuclear Pore Complexes Control Import and Export from the Nucleus Pre-mRNAs in Spliceosomes Are Not Exported from the Nucleus HłV Viral mRNAs CONTENTS XXI Cytoplasmic transcriptional Control Micro RNAs Repress Translation of Specific mRNAs RNA Complementary mRNAs Cytoplasmic Polyadenylation Promotes Translation of Some mRNAs Degradation of mRNAs in the Cytoplasm Occurs by Several Mechanisms Protein Synthesis Can Be Globally Regulated Sequence-Specific RNA-Binding Proteins Control Specific mRNA Translation Surveillance Mechanisms Prevent Translation of Improperly Processed mRNAs Localization of mRNAs Permits Production of Proteins at Specific Regions Within the Cytoplasm jjjjf Processing of rRNA and tRNA Pre-rRNA Genes Function as Nucleolar Organizers and Are Similar in All Eukaryotes Small Nucleolar RNAs Assist in Processing Pre-rRNAs Self-Splicing Group I Examples of Catalytic Pre-tRNAs Undergo Extensive Modification in the Nucleus Nuclear Bodies Are Functionally Specialized Nuclear Domains Part III Cell Structure and Function VISUALIZING, FRACTIONATING, AND CULTURING CELLS Organelies The Plasma Membrane Has Many Common Functions in All Cells Endosomes Take Up Soluble Macromolecules from the Cell Exterior Lysosomes Are Acidic Battery of Degradative Enzymes Peroxisomes Degrade Fatty Acids and Toxic Compounds The Endoplasmic Reticulum Is a Network of Interconnected Internal Membranes The Golgi Complex Processes and Sorts Secreted and Membrane Proteins Plant Cell to Elongate Rapidly The Nucleus Contains the Synthetic Apparatus, and a Fibrous Matrix Mitochondria Are the Principal Sites of ATP Production in Aerobic Nonphotosynthetic Cells Chloroplasts Contain Internal Compartments in Which Photosynthesis Takes Place Light Microscopy: Visualizing Cell Structure and Localizing Proteins Within Cells The Resolution of the Light Microscope Is About 0.2 381 Phase-Contrast and Differential Interference Contrast Microscopy Visualize Unstained Living Cells Fluorescence Microscopy Can Localize and Quantify Specific Molecules in Live Cells Imaging Subcellular Details Often Requires that the Samples Be Fixed, Sectioned, and Stained Immunofluorescence Microscopy Can Detect Specific Proteins in Fixed Cells Confocal and Deconvolution Microscopy Enable Visualization of Three-Dimensional Objects Graphics and Informatics Have Transformed Modern Microscopy Qfl Electron Microscopy: Methods and Applications Resolution of Transmission Electron Microscopy is Vastly Greater Than That of Light Microscopy Cryoelectron Microscopy Allows Visualization of Particles Without Fixation or Staining Electron Microscopy of Metal-Coated Specimens Can Reveal Surface Features of Cells and Their Components Purification of Cell Disruption of Cells Releases Their Organelles and Other Contents Centrifugation Can Separate Many Types of Organelles Organelle-Specific Antibodies Are Useful in Preparing Highly Purified Organelles xx» CONTENTS gşm of Metazoan Cells Flow Cytometry Separates Different Cell Types Culture of Animal Cells Requires Nutrient-Rich Media and Special Solid Surfaces Primary Cell Cultures Can Be Used to Study Cell Differentiation Primary Cell Cultures and Cell Strains Have a Finite Life Span Transformed Cells Can Grow Indefinitely in Culture Some Cell Lines Undergo Differentiation in Culture Hybrid Cells Called Monoclonal Antibodies HAT Medium Is Commonly Used to Isolate Hybrid Cells Classic Experiment 10 409 Lipid-Binding Motifs Help Target Peripheral Proteins to the Membrane Proteins Can Be Removed from Membranes by Detergents or High-Salt Solutions QQ\| Phospholipids, Sphingolipids, and Cholesterol: Synthesis and Intracellular Movement Fatty Acids Synthesis Is Mediated by Several Important Enzymes Small Cytosolic Proteins Facilitate Movement of Fatty Acids Incorporation of Fatty Acids into Membrane Lipids Takes Place on Flippases Move Phospholipids from One Membrane Leaflet to the Opposite Leaflet Cholesterol Is Synthesized by Enzymes in the Cytosol and Cholesterol and Phospholipids Are Transported Between ШШ and Phospholipids Spontaneously Form Bilayers Phospholipid Bilayers Form a Sealed Compartment Surrounding an Internal Aqueous Space Biomembranes of Lipids Most Lipids and Many Proteins Are Laterally Mobile in Lipid Properties of Membranes Lipid and Cytosolic Leaflets Cholesterol and Sphingolipids Cluster with Specific Proteins in Membrane Biomembranes: and Basic Functions Proteins Interact with Membranes in Three Different Ways Most Membrane-Spanning Multiple Membrane-Spanning "Barrels" Covalently Attached Hydrocarbon Chains Anchor Some Proteins to Membranes All Asymmetrically Oriented in the Bilayer 11 OF IONS AND SMALL MOLECULES Overview of Membrane Transport Only Small by Simple Diffusion Membrane Proteins Mediate Transport of Most Molecules and All Ions Across Biomembranes Uniport Transport of Glucose and Water Several Features Distinguish Uniport Transport from Simple Diffusion GLUT1 Uniporter Transports Glucose into Most Mammalian Cells The Human Genome Encodes a Family of Sugar- Transporting GLUT Proteins Transport Proteins Can Be Enriched Within Artificial Membranes and Cells Osmotic Pressure Causes Water to Move Across Membranes Aquaporins Increase the Water Permeability of Cell Membranes CONTENTS XXIII ATP-Powered Pumps and the Intracellular lonk Environment Different Classes of Pumps Structural and Functional Properties ATP-Powered Ion Pumps Generate and Maintain Ionic Gradients Across Cellular Membranes Muscle Relaxation Depends on Ca2+ ATPases That Pump Ca2+ from the Cytosol into the Sarcoplasmk Reticulum Calmodulin Regulates the Plasma Membrane Ca2+ Pumps That Control Cytosolic Ca2"1" Concentrations Na+/K+ ATPase Maintains the Intracellular Na+ and K+ Concentrations in Animal Cells V-Class H+ ATPases Maintain the Acidity of Lysosomes and Bacterial Permeases Are ABC Proteins That Import a Variety of Nutrients from the Environment The Approximately Play Diverse and Important Roles in Cell and Organ Physiology Certain ABC Proteins "Flip" Phospholipids and Other Lipid-Soluble Substrates from One Membrane Leaflet to the Opposite Leaflet Bacterial Symporter Structure Reveals the Mechanism of Substrate Binding Na+-Linked Ca2+ Antiporter Exports Ca2+ from Cardiac Muscle Cells Several Cotransporters Regulate Cytosolic A Putative Cation Exchange Protein Plays a Key Role in Evolution of Human Skin Pigmentation Numerous Transport Proteins Enable Plant Vacuoles Transepithelial Transport Multiple Transport Proteins Are Needed to Move Glucose and Epithelia Simple Rehydration Therapy Depends on the Osmotic Gradient Created by Absorption of Glucose and Na+ Parietal Cells Acidify the Stomach Contents While Maintaining a Neutral Cytosolic Classic Experiment Active Transport 12 479 Nongated Ion Channels and the Resting Membrane Potential Selective Movement of Ions Creates a Transmembrane Difference The Membrane Potential in Animal Cells Depends Largely on Potassium Ion Movements Through Open Resting K+ Channels Ion Channels Contain a Selectivity Filter Formed from Conserved Patch Clamps Permit Measurement of Ion Movements Through Single Channels Novel Ion Channels Can Be Characterized by a Combination of Oocyte Expression and Patch Clamping Na+ Entry into Mammalian Cells Has a Negative Change in Free Energy Cotransport by Symporters and Antiporters Na+-Linked Symporters Import Glucose into Animal Cells Against High Concentration Gradients First Steps of Glucose and Fatty Acid Catabolism: Glycolysis and the Citric Acid Cycle During Glycolysis (Stage I), Cytosolic Enzymes Convert Glucose to Pyruvate The Rate of Glycolysis Is Adjusted to Meet the Cell's Need for ATP Glucose Is Fermented Under Anaerobic Conditions Under Aerobic Conditions, Mitochondria Efficiently Oxidize Pyruvate and Generate ATP (Stages II-IV) Mitochondria Are Dynamic Structurally and Functionally Distinct Membranes In Stage II, Pyruvate Is Oxidized to CO2 and High- Energy Electrons Stored in Reduced Coenzymes Transporters in the Inner Mitochondrial Membrane Help Maintain Appropriate Cytosolic and Matrix Concentrations of NAD+ and NADH Mitochondrial Oxidation of Fatty Acids Generates ATP Peroxisomal Oxidation of Fatty Acids Generates No ATP 480 481 483 485 485 485 487 489 491 491 xxiv CONTENTS The Electron Transport Chain and Generation of the Proton-Motive Force Stepwise Electron Transport Efficiently Releases the Energy Stored in NADH and FADH2 Electron Transport in Mitochondria Is Coupled to Proton Pumping Electrons Flow from FADH2 and NADH to O2 Through Four Multiprotein Complexes Reduction Potentials of Electron Carriers Favor Electron Flow from NADH to O2 Experiments Using Purified Complexes Established the Stoichiometry of Proton Pumping The Translocated as Electrons Flow Through Complex III The Proton-Motive Force in Mitochondria Is Due Largely to a Voltage Gradient Across the Inner Membrane Toxic By-products of Electron Transport Can Damage Cells ЦЮІ Force for Energy-Requiring Processes The Mechanism of ATP Synthesis Is Shared Among Bacteria, Mitochondria, and Chloroplasts ATP Synthase Comprises Two Multiprotein Complexes Termed Fo and F1 Rotation of the F, Proton Movement Through Fo, Powers ATP Synthesis ATP-ADP Exchange Across the Inner Mitochondrial Membrane Is Powered by the Proton-Motive Force Rate of Mitochondrial Oxidation Normally Depends on ADP Levels Brown-Fat Mitochondria Use the Proton-Motive Force to Generate Heat Photosynthesis and Light-Absorbing Pigments Thylakoid Membranes in Chloroplasts Are the Sites of Photosynthesis in Plants Three of the Four Stages in Photosynthesis Occur Only During Illumination Each Photon of Light Has a Defined Amount of Energy Photosystems Associated Light-Harvesting Complexes 511 511 511 513 5Î4 Photoelectron Transport from Energized Reaction- Center Chlorophyll a Produces a Charge Separation Internal Antenna and Light-Harvesting Complexes Increase the Efficiency of Photosynthesis ЮЭ Photosystems 517 The Single Generates a Proton-Motive Force but No O2 Linear Electron Flow Through Both Plant PSII and O2, and NADPH An Oxygen-Evolving Complex Is Located on the Center Cells Use Multiple Mechanisms to Protect Against Damage from Reactive Oxygen Species During Photoelectron Cyclic Electron Flow Through Proton-Motive Force but No NADPH or O2 Relative Activities of Regulated ЮЗ Photosynthesis Rubisco Fixes CO2 in the Chloroplast Synthesis of Sucrose Using Fixed CO2 Is Completed in the Cytosol Light and Rubisco Fixation Photorespiration, Photosynthesis, Is Reduced in Plants That Fix CO2 by the C4 Pathway 13 MEMBRANES AND ORGANELLES Translocation Across the A Nascent Secretory Proteins to the Cotransiational GTP-Hydrolyzing Proteins Passage of Growing Polypeptides Through the Translocon Is Driven by Energy Released During Translation CONTENTS XXV ATP Hydrolysis Powers Post-translational Translocation Insertion of Proteins into the ER Several Topological Classes of Integral Membrane Proteins Are Synthesized on the Internal Stop-Transfer and Signal-Anchor Sequences Determine Topology of Single-Pass Proteins Multipass Proteins Have Multiple Internal Topogenic Sequences A Phospholipid Anchor Tethers Some Cell-Surface Proteins to the Membrane The Topology of a Membrane Protein Often Can Be Deduced from Its Sequence Protein Modifications, Folding, and Quality Control in the A Preformed W-Linked Oligosaccharide Is Added to Many Proteins in the Rough Oligosaccharide Side Chains May Promote Folding and Stability of Glycoproteins Disulfide Bonds Are Formed and Rearranged by Proteins in the Chaperones and Other and Assembly of Proteins Improperly Folded Proteins in the Expression of Protein-Folding Catalysts Unassembled or Misfolded Proteins in the Often Transported to the Cytosol for Degradation Sorting of Proteins to Mitochondria and Chloroplasts Amphipathic N-Terminal Signal Sequences Direct Proteins to the Mitochondrial Matrix 558 Mitochondrial Protein Import Requires Outer-Membrane Receptors and Translocons in Both Membranes Studies with Chimeric Proteins Demonstrate Important Features of Mitochondrial Import Three Energy Inputs Are Needed to Import Proteins into Mitochondria Multiple Signals and Pathways Target Proteins to Submitochondrial Compartments Targeting of Chloroplast Stromal Proteins Is Similar to Import of Mitochondrial Matrix Proteins Proteins Are Targeted to Thylakoids by Mechanisms Related to Inner Membrane Sorting of Peroxisomal Proteins Cytosolic Receptor Targets Proteins with an SKL Sequence at the C-Terminus into the Peroxisomal Matrix Peroxisomal Membrane and Matrix Proteins Are Incorporated by Different Pathways Transport into and out of the Nucleus Large and Small Molecules Enter and Leave the Nucleus via Nuclear Pore Complexes Importins Transport Proteins Containing Nuclear- Localization Signals into the Nucleus Exportins Transport Proteins Containing Nuclear-Export Signals out of the Nucleus Most mRNAs Are Exported from the Nucleus by a Ran-lndependent Mechanism 14 AND ENDOCYTOSIS Techniques for Studying the Secretory Pathway Transport of a Protein Through the Secretory Pathway Can Be Assayed in Living Cells Yeast Mutants Define Major Stages and Many Components in Vesicular Transport Cell-Free Transport Assays Allow Dissection of Individual Steps in Vesicular Transport Molecular Mechanisms of Vesicular Traffic Assembly of a Protein Coat Drives Vesicle Formation and Selection of Cargo Molecules A Conserved Set of GTPase Switch Proteins Controls Assembly of Different Vesicle Coats Targeting Sequences on Cargo Proteins Make Specific Molecular Contacts with Coat Proteins Rab Membranes Paired Sets of SNARE Proteins Mediate Fusion of Vesicles with Target Membranes Dissociation of SNARE Complexes After Membrane Fusion Is Driven by ATP Hydrolysis xxvi CONTENTS Early Stages of the Secretory Pathway 592 COPII to the Golgi COPI Vesicles Mediate Retrograde Transport within the Golgi and from the Golgi to the Anterograde Transport Through the Golgi Occurs by Cistemal Maturation Later Stages of the Secretory Pathway Vesicles Coated with Clathrin and/or Adapter Proteins Mediate Several Transport Steps Dynamin Is Required for Pinching Off of Clathrin Vesicles Mannose 6-Phosphate Residues Target Soluble Proteins to Lysosomes Study of Lysosomal Storage Diseases Revealed Key Components of the Lysosomal Sorting Pathway Protein Aggregation in the frans-Golgi May Function in Sorting Proteins to Regulated Secretory Vesicles Some Proteins Undergo Proteolytic Processing After Leaving the trans-Golgi Several Pathways Sort Membrane Proteins to the Apical or Basolateral Region of Polarized Cells ^QjU Cells Take Up Lipids from the Blood in the Form of Large, Weil-Defined Lipoprotein Complexes Receptors for Low-Density Lipoprotein and Other Ligands Contain Sorting Signals That Target Them for Endocytosis The Acidic Receptor-Ligand Complexes to Dissociate The Endocytic Pathway Delivers Iron to Cells without Dissociation of the Receptor-Transferrin Complex in Endosomes Directing Membrane Proteins and Cytosolic Materials to the Lysosome Multivesicular Endosomes Segregate Membrane Proteins Destined for the Lysosomal Membrane from Proteins Destined for Lysosomal Degradation Retroviruses Bud from the Plasma Membrane by a Process Similar to Formation of Multivesicular Endosomes 15 TRANSDUCTION AND SHORT-TERM CELLULAR RESPONSES From Extracellular Signal to Cellular Response Signaling Cells Produce and Release Signaling Molecules Signaling Molecules Can Act Locally or at a Distance Binding of Signaling Molecules Activates Receptors on Target Cells Щ5Щ Receptors Receptor Proteins Bind Ligands Specifically The Dissociation Constant Is a Measure of the Affinity of a Receptor for Its Ligand Binding Assays Are Used to Detect Receptors and Determine Their Affinities for Ligands Maximal Cellular Response to a Signaling Molecule Usually Does Not Require Activation of All Receptors Sensitivity of a Cell to External Signals Is Determined by the Number of Surface Receptors and Their Affinity for Ligand Receptors Can Be Purified by Affinity Techniques Classic Experiment Out of the Cell 621 ЮЗ of Intracellular Signal-Transduction Pathways GTP-Binding Proteins Are Frequently Used As On/Off Switches Protein Kinases and Phosphatases are Employed in Virtually All Signaling Pathways Second Messengers Carry and Amplify Signals from Many Receptors General Elements of Coupled Receptor Systems G Family with a Common Structure and Function G GTP for GDP on the Protein Different and in Turn Regulate Different Effector Proteins CONTENTS XXVII щ^З That Regulate Ion Channels Acetylcholine Receptors in the Heart Muscle Activate Light Activates G^-Coupled Rhodopsins Activation of Rhodopsin Induces Closing of cGMP-Gated Cation Channels Rod Cells Adapt to Varying Levels of Ambient Light Because of Opsin Phosphorylation and Binding of Insulin and Glucagon Work Together to Maintain a Stable Blood Glucose Level 658 Classic Experiment Transduction—GTP Stimulation of cAMP Synthesis 16 PATHWAYS THAT CONTROL GENE ACTIVITY Ц22Я Activate or Inhibit Adenylyl Cyclase Adenylyl Cyclase Is Stimulated and Inhibited by Different Receptor-Ligand Complexes Structural Studies Established How G^GTP Binds to and Activates Adenylyl Cyclase cAMP Activates Protein Kinase A by Releasing Catalytic Subunits Glycogen Metabolism Is Regulated by Hormone-Induced Activation of Protein Kinase A cAMP-Mediated Activation of Protein Kinase A Produces Diverse Responses in Different Cell Types Signal Amplification Commonly Occurs in Many Signaling Pathways Several Mechanisms Down-Regulate Signaling from Anchoring Proteins Localize Effects of cAMP to Specific Regions of the Cell QQI Activate Phospholipase Phosphorylated Derivatives of Inositol Are Important Second Messengers Calcium Ion Release from the Reticulum is Triggered by IP3 The Ca2+/Calmodulin Complex Mediates Many Cellular Responses to External Signals Diacylglycerol (DAG) Activates Protein Kinase C, Which Regulates Many Other Proteins Signal-Induced Relaxation of Vascular Smooth Muscle Is Mediated by cGMP-Activated Protein Kinase Integrating Responses of Cells to Environmental Influences Integration of Multiple Second Messengers Regulates Glycogenolysis TGFß Activation of Smads A of an Inactive Precursor Radioactive Tagging Was Used to Identify Receptors Activated Transcription Factors Negative Feedback Loops Regulate Signaling Loss of in Cancer Cytokine Receptors and the JAK/STAT Pathway Cytokines Influence Development of Many Cell Types Cytokine Receptors Have Similar Structures and Activate Similar Signaling Pathways JAK Complementation Genetics Revealed That JAK Signals Signaling from Cytokine Receptors Is Regulated by Negative Signals Mutant Erythropoietin Receptor That Cannot Be Turned Off Leads to Increased Numbers of Erythrocytes Receptor Tyrosine Kinases Ligand Binding Leads to Phosphorylation and Activation of Intrinsic Kinase in RTKs Overexpression of HER2, a Receptor Tyrosine Kinase, Occurs in Some Breast Cancers XXVIII CONTENTS Conserved Domains Are Important for Binding Signal- Transduction Proteins to Activated Receptors Down-regulation of RTK Signaling Occurs by Endocytosis and Lysosomal Degradation Activation of Pathways Ras, a and Inactive States Receptor Tyrosine Kinases Are Linked to Adapter Proteins Genetic Studies in Signal-Transducing Proteins in the Ras/MAP Kinase Pathway Binding of Conformational Change That Activates Signals Pass from Activated Protein Kinases MAP Kinase Regulates the Activity of Many Transcription Factors Controlling Early-Response Genes G MAP Kinase in Yeast Mating Pathways Scaffold Proteins Separate Multiple MAP Kinase Pathways in Eukaryotic Cells The Ras/MAP Kinase Pathway Can Induce Diverse Cellular Responses ЮЗ Transducers Phospholipase Cytokine Receptors Recruitment of PI-3 Kinase to Hormone-Stimulated Receptors Leads to Synthesis of Phosphorylated Phosphatidylinositols Accumulation of PI 3-Phosphates in the Plasma Membrane Leads to Activation of Several Kinases Activated Protein Kinase Cellular Responses The PI-3 Kinase Pathway Is Negatively Regulated by PTEN Phosphatase Hedgehog Signaling Relieves Repression of Target Genes 700 QQI Pathways That Involve Signal-Induced Protein Cleavage Degradation of an Inhibitor Protein Activates the NF-kB Transcription Factors Ligand-Activated Notch Is Cleaved Twice, Releasing a Transcription Factor Matrix Metalloproteases Catalyze Cleavage of Many Signaling Proteins from the Cell Surface Inappropriate Cleavage of Amyloid Precursor Protein Can Lead to Alzheimer's Disease Regulated Intramembrane Proteolysis of SREBP Releases a Transcription Factor That Acts to Maintain Phospholipid and Cholesterol Levels 17 MOVEMENT I: Microfilaments Structures Actin Is Ancient, Abundant, and Highly Conserved G-Actin Monomers Assemble into Long, Helical F-Actin Polymers F-Actin Has Structural and Functional Polarity Dynamics of Actin Filaments Actin Polymerization in Vitro Proceeds in Three Steps Actin Filaments Grow Faster at (-) Actin Filament Treadmilling Is Accelerated by Profilin Thymosin-ß4 Polymerization Capping Proteins Block Assembly and Disassembly at Actin Filament Ends 720 721 722 722 Activation of Gene Transcription by Seven-Spanning Cell-Surface Receptors CREB Links cAMP and Protein Kinase A to Activation of Gene Transcription GPCR-Bound Arrestin Wnt Signals Trigger Release of a Transcription Factor from Cytosolic Protein Complex Mechanisms of Actin Filament Assembly Formins Assemble Unbranched Filaments The Arp2/3 Complex Nucleates Branched Filament Assembly Intraceliular Movements Can Be Powered by Actin Polymerization CONTENTS XXIX Toxins That Perturb the Pool of Actin Monomers Are Useful for Studying Actin Dynamics 726 Chemotactic Gradients Induce Altered Phosphoinositide Levels Between the Front and Back of a Cell Organization of Actin-Based Cellular Structures Cross-Linking Proteins Organize Actin Filaments into Bundles or Networks Adaptor Proteins Link Actin Filaments to Membranes Myosins: Actin-Based Motor Proteins Myosins Have Head, Neck, and Tail Domains with Distinct Functions Myosins Make Up a Large Family of Mechanochemical Motor Proteins Conformational Changes in the Myosin Head Couple ATP Hydrolysis to Movement Myosin Heads Take Discrete Steps Along Actin Filaments Myosin V Walks Hand Over Hand Down an Actin Filament Myosin-Powered Movements Myosin Thick Filaments and Actin Thin Filaments ¡n Skeletal Muscle Slide Past One Another During Contraction Skeletal Muscle Is Structured by Stabilizing and Scaffolding Proteins Contraction of Skeletal Muscle Is Regulated by Ca2+ and Actin-Binding Proteins Actin and Myosin II Form Contractile Bundles in Nonmuscle Cells Myosin-Dependent Mechanisms Regulate Contraction in Smooth Muscle and Nonmuscle Cells Myosin-V-Bound Vesicles Are Carried Along Actin Filaments Cell Migration: Signaling and Chemotaxis 743 745 Cell Migration Coordinates Force Generation with Cell Adhesion and Membrane Recycling The Small GTP-Binding Proteins Cdc42, Control Actin Organization Cell Migration Involves the Coordinate Regulation of Cdc42, Migrating Cells Are Steered by Chemotactic Molecules Classic Experiment Contraction 755 18 MOVEMENT II: MICROTUBULES AND INTERMEDIATE FILAMENTS Microtubule Structure and Organization Microtubule Walls Are Polarized Structures Built from Microtubules Are Assembled from MTOCs to Generate Diverse Organizations ЩЮЦ Microtubules Are Dynamic Structures Due to Kinetic Differences at Their Ends Individual Microtubules Exhibit Dynamic Instability Localized Assembly and "Search-and-Capture" Help Organize Microtubules Drugs Affecting Tubulin Polymerization Are Useful Experimentally and to Treat Diseases Regulation of Microtubule Structure and Dynamics Microtubules Are Stabilized by Side- and End-Binding Proteins Microtubules Are Disassembled by End Binding and Severing Proteins Kinesins and Dyneins: Microtubule- Based Motor Proteins Organelles in Microtubules in Both Directions Kinesin-1 Powers Anterograde Transport of Vesicles Down Microtubules Kinesins Form a Large Protein Family with Diverse Functions Kinesin-1 Is a Highly Dynein Motors Transport Organelles Toward the End of Microtubules Kinesins and Dyneins Cooperate in the Transport of Organelles Throughout the Cell xxx CONTENTS QQI Cilia Based Surface Structures Eukaryotic Cilia and Microtubules Bridged by Dynein Motors Ciliary and Controlled Sliding of Outer Doublet Microtubules Intraflagellar Transport Moves Material Up and Down Cilia and Defects in Intraflagellar Transport Cause Disease by Affecting Sensory Primary Cilia ЦВДІ Mitosis Can Be Divided into Six Phases Centrosomes Duplicate Early in the Cell Cycle in Preparation for Mitosis The Mitotic Spindle Contains Three Classes of Microtubules Microtubule Dynamics Increases Dramatically in Mitosis Microtubules Treadmill During Mitosis The Kinetochore Captures and Helps Transport Chromosomes Duplicated Chromosomes Are Aligned by Motors and Treadmilling Microtubules Anaphase Microtubule Shortening Anaphase Action of Kinesins and Dynein Additional Mechanisms Contribute to Spindle Formation Cytokinesis Splits the Duplicated Cell in Two Plant Cells Reorganize Their Microtubules and Build a New Cell Wall in Mitosis ЦЦ2Л Intermediate Filaments Are Assembled from Subunit Intermediate Filaments Proteins Are Expressed in a Tissue-Specific Manner Intermediate Filaments Are Dynamic Defects in Lamins and Keratins Cause Many Diseases Microfilaments Transport Melanosomes Cdc42 Coordinates Microtubules and During Cell Migration 778 19 TISSUES 801 779 780 щущ An Overview 803 Cell-Adhesion Molecules Bind to One Another and 781 to Intracellular Proteins 803 782 The Extracellular Matrix Participates in Adhesion, Signaling, and Other Functions 805 783 The Evolution of Multifaceted Adhesion Molecules Enabled the Evolution of Diverse Animal Tissues 807 784 ЦЦ 784 and Their Adhesion Molecules 808 785 Epithelial Cells Have Distinct Apical, Lateral, and 786 Basal Surfaces 808 Three Types of Junctions Mediate Many Cell-Cell 788 and Cell-ECM Interactions 809 Cadherins Mediate Cell-Cell Adhesions in Adherens 789 Junctions and Desmosomes 810 Tight Junctions Seal Off Body Cavities and Restrict 789 Diffusion of Membrane Components 814 Integrins 816 789 Gap Junctions Composed of Connexins Allow Small 789 Molecules to Pass Directly Between Adjacent Cells 817 Ц2Л The Basal Lamina The Basal Lamina Provides a Foundation for Assembly of Cells into Tissues Laminin, a Multiadhesive Matrix Protein, Helps Cross-link Components of the Basal Lamina Sheet-Forming Type IV Collagen Is a Major Structural Component of the Basal Lamina Perlecan, a Proteoglycan, Cross-links Components of the Basal Lamina and Cell-Surface Receptors Coordination and Cooperation between Cytoskeletal Elements Intermediate Filament-Associated Proteins Contribute to Cellular Organization ЕИ Connective and Other Tissues Fibrillar in the ECM of Connective Tissues CONTENTS XXXI Fibrillar Fibrils Outside of the Cell Type I and II Collagens Proteoglycans and Their Constituent GAGs Play Diverse Roles in the ECM Hyaluronan Resists Compression, Facilitates Cell Migration, and Gives Cartilage Its Gel-like Properties Fibronectins Interconnect Cells and Matrix, Influencing Cell Shape, Differentiation, and Movement Adhesive Interactions in Motile and Nonmotile Cells Integrins Three-Dimensional Environment Regulation of Integrin-Mediated Adhesion and Signaling Controls Cell Movement Connections Between the ECM and Cytoskeleton Are Defective in Muscular Dystrophy IgCAMs Mediate Cell-Cell Adhesion in and Other Tissues Leukocyte Movement into Tissues Is Orchestrated by a Precisely Timed Sequence of Adhesive Interactions Plant Tissues The Plant Cell Wall Is a Laminate of Cellulose Fibrils in a Matrix of Glycoproteins Loosening of the Cell Wall Permits Plant Cell Growth Plasmodesmata Directly Connect the Cytosols of Adjacent Cells in Higher Plants Only a Few Adhesive Molecules Have Been Identified in Plants Part IV Cell Growth and Development 20 CELL CYCLE Overview of the Cell Cycle and Its Control The Cell Cycle Is an Ordered Series of Events Leading to Cell Replication Regulated Protein Phosphorylation and Degradation Control Passage Through the Cell Cycle Diverse Experimental Systems Have Been Used to Identify and Isolate Cell-Cycle Control Proteins Control of Mitosis by Cyclins and MPF Activity Maturation-Promoting Factor (MPF) Stimulates Meiotic Maturation in Oocytes and Mitosis in Somatic Cells Mitotic Cyclin Was First Identified in Early Sea Urchin Embryos Cyclin Promoting Factor (MPF) Change Together in Cycling Xenopus Egg Extracts Anaphase-Promoting Complex (APC/C) Controls Degradation of Mitotic Cyclins and Exit from Mitosis Cyclin-Dependent Kinase Regulation During Mitosis MPF Components Are Conserved Between Lower and Higher Eukaryotes Phosphorylation of the CDK Kinase Activity of MPF Conformational Changes Induced by Cyclin Binding and Phosphorylation Increase MPF Activity Molecular Mechanisms for Regulating Mitotic Events Phosphorylation of Nuclear Lamins and Other Proteins Promotes Early Mitotic Events Unlinking of Sister Chromatids Initiates Chromosome Decondensation and Reassembly of the Nuclear Envelope Depend on Dephosphorylation of MPF Substrates Cyclin-CDK and Ubiquitin-Protein Ligase A Cyclin-Dependent Kinase (CDK) Is Critical for S-Phase Entry in Three to Form S-Phase-Promoting Factors xxxii CONTENTS Degradation Replication Multiple Cyclins Regulate the Kinase Activity of S. cerevisiae CDK During Different Cell-Cycle Phases Replication at Each Origin Is Initiated Only Once During the Cell Cycle gţjiBSfl Cells Mammalian Restriction Point Is Analogous to START in Yeast Cells Multiple CDKs and Cyclins Regulate Passage of Mammalian Cells Through the Cell Cycle Regulated Expression of Two Classes of Genes Returns Go Mammalian Cells to the Cell Cycle Passage Through the Restriction Point Depends on Phosphorylation of the Tumor-Suppressor Rb Protein Cyclin A Is Required for for Entry into Mitosis Two Types of Cyclin-CDK Inhibitors Contribute to Cell-Cycle Control in Mammals ЕШЛ Regulation The Presence of Unreplicated into Mitosis Improper Assembly of the Mitotic Spindle Prevents the Initiation of Proper Segregation of Daughter Chromosomes Is Monitored by the Mitotic Exit Network Cell-Cycle Arrest of Cells with Damaged on Tumor Suppressors ЩЦ Division 892 892 Key Features Distinguish Meiosis from Mitosis Repression of Kinase Promote Premeiotic Recombination and a Meiosis-Specific Cohesin Are Necessary for the Specialized Chromosome Segregation in Meiosis I Special Properties of Rec8 Regulate Its Cleavage in Meiosis I and II The Kinetochores in Meiosis I Tension on Spindle Microtubules Contributes to Proper Spindle Attachment 895 896 898 898 Classic Experiment from the Sea: The Discovery of Cyclins 21 DEATH The Birth of Cells: Stem Cells, Niches, and Lineage Stem Cells Give Rise to Both Stem Cells and Differentiating Cells Cell Fates Are Progressively Restricted During Development The Complete Cell Lineage of Heterochronic Mutants Provide Clues About Control of Cell Lineage Cultured Embryonic Stem Cells Can Differentiate into Various Cell Types Adult Stem Cells for Different Animal Tissues Occupy Sustaining Niches Meristems Are Plants ЩЩ Mating-Type Transcription Factors Specify Cell Types MCM1 and Transcription аг-МСМІ Pheromones Induce Mating of Generate a Third Cell Type Specification and Differentiation of Muscle Embryonic Somites Give Rise to Myoblasts Myogenic Genes Were First Identified in Studies with Cultured Two Classes of Regulatory Factors Act in Concert to Guide Production of Muscle Cells Differentiation of Myoblasts Is Under Positive and Negative Control Cell-Cell Signals Are Crucial for Determination and Migration of Myoblasts bHLH Regulatory Proteins Function in Creation of Other Tissues Regulation of Asymmetric Cell Division Yeast Mating-Type Switching Depends upon Asymmetric Cell Division CONTENTS XXXIII Proteins Opposite Ends of Dividing Neuroblasts in Cell Death and Its Regulation Programmed Cell Death Occurs Through Apoptosis Neurotrophins Promote Survival of Neurons A Cascade of Caspase Proteins Functions in One Apoptotic Pathway Pro-Apoptotic Regulators Permit Caspase Activation in the Absence of Trophic Factors Some Trophic Factors Induce Inactivation of a Pro-Apoptotic Regulator Tumor Necrosis Factor and Related Death Signals Promote Cell Murder by Activating Caspases 22 OF DEVELOPMENT Highlights of Development (ЩЩ Germ-line Cells Are All That We Inherit Fertilization Unifies the Genome Genomic Imprinting Controls Gene Activation According to Maternal or Paternal Chromosome Origin Too Much of a Good Thing: The X Chromosome Is Regulated by Dosage Compensation in Early Vertebrate Embryos Cleavage Leads to the First Differentiation Events The Genomes of Most Somatic Cells Are Complete Gastrulation Creates Multiple Tissue Layers, Which Become Polarized Signal Gradients May Induce Different Cell Fates Signal Antagonists Influence Cell Fates and Tissue Induction A Cascade of Signals Distinguishes Left from Right 950 Development Progresses from Egg and Sperm to an Early Embryo As the Embryo Develops, Cell Layers Become Tissues and Organs Genes That Regulate Development Are at the Heart of Evolution 952 953 953 955 958 958 959 960 961 961 963 965 966 Control of Body Segmentation: Themes and Variations in Insects and Vertebrates Early Transcriptional Control Specifies the Embryo's Anterior and Posterior Translation Inhibitors Reinforce Anterior-Posterior Patterning Insect Segmentation Is Controlled by a Cascade of Transcription Factors Vertebrate Segmentation Is Controlled by Cyclical Expression of Regulatory Genes Differences Between Segments Are Controlled by Hox Genes Hox-Gene Expression Is Maintained by a Variety of Mechanisms Flower Development Requires Spatially Regulated Production of Transcription Factors Cell-Type Specification in Early Neural Development Neurulation Begins Formation of the Brain and Spinal Cord Signal Gradients and Transcription Factors Specify Cell Types in the Neural Tube and Somites Most Neurons in the Brain Arise in the Innermost Neural Tube and Migrate Outward Lateral Inhibition Mediated by Notch Signaling Causes Early Neural Cells to Become Different Growth and Patterning of Limbs Hox Genes Determine the Right Places for Limbs to Grow Limb Development Depends on Integration of Multiple Extracellular Signal Gradients Hox Genes Also Control Fine Patterning of Limb Structures So Far, So Good Classic Experiment Mutations to Study Development 990 991 992 994 999 23 949 Neurons and Blocks of the Nervous System Information Flows Through Neurons from to xxxiv CONTENTS Information Moves as Pulses of Ion Flow Called Action Potentials Information Flows Between Neurons via Synapses The Nervous System Uses Signaling Circuits Composed of Multiple Neurons Q29 Voltage-Gated Ion Channels and the Propagation of Action Potentials in Nerve Cells The Magnitude of the Action Potential Is Close to £Na Sequential Opening and Closing of Voltage- Gated Na+ and K+ Channels Generate Action Potentials Action Potentials Are Propagated Unidirectionally Without Diminution Nerve Cells Can Conduct Many Action Potentials in the Absence of ATP All Voltage-Gated Ion Channels Have Similar Structures Voltage-Sensing S4 to Membrane Depolarization Movement of the Channel-Inactivating Segment into the Open Pore Blocks Ion Flow Myelination Increases the Velocity of Impulse Conduction Action Potentials "Jump" from Node to Node in Myelinated Glia QQI Communication at Synapses Formation of Synapses Requires Assembly of Presynaptic and Postsynaptic Structures Neurotransmitters Vesicles by H^Linked Antiport Proteins Synaptic Vesicles Loaded with Are Localized near the Plasma Membrane Influx of Ca2+ Triggers Release of Neurotransmitters A Calcium-Binding Protein Regulates Fusion of Synaptic Vesicles with the Plasma Membrane Signaling at Synapses Is Terminated by Degradation or Reuptake of Fly Mutants Lacking Dynamin Cannot Recycle Synaptic Vesicles Opening of Acetylcholine-Gated Cation Channels Leads to Muscle Contraction All Five Subunits in the Nicotinic Acetylcholine Receptor Contribute to the Ion Channel Nerve Cells Make an All-or-None Decision to Generate an Action Potential Gap Junctions Also Allow Neurons to Communicate ЕЭД Hearing, Tasting, and Smelling The Eye Features Light-Sensitive Nerve Cells Eyes Reflect Evolutionary History Integrated Information from Multiple Ganglion Cells Forms Images of the World Mechanosensory Cells Detect Pain, Heat, Cold, Touch, and Pressure Inner Ear Cells Detect Sound and Motion Five Primary Tastes Are Sensed by Subsets of Cells in Each Taste Bud A Plethora of Receptors Detect Odors The Path to Success: Controlling Axon Growth and Targeting The Growth Cone Is a Motorized Sensory Guidance Structure The Retinotectal Map Revealed an Ordered System of Axon Connections There Are Four Families of Axon Guidance Molecules Developmental Regulators Also Guide Axon Guidance Molecules Cause the Growth Cone to Turn 24 1055 ОЛ Pathogens Enter the Body Through Different Routes and Replicate at Different Sites Leukocytes Circulate Throughout the Body and Take Up Residence in Tissues and Lymph Nodes Mechanical and Chemical Boundaries Form a First Layer of Defense Against Pathogens Innate Immunity Provides a Second Line of Defense After Mechanical and Chemical Barriers Are Crossed Inflammation Is a Complex Response to Injury That Encompasses Both Innate and Adaptive Immunity Adaptive Immunity, the Third Line of Defense, Exhibits Specificity CONTENTS XXXV QQI Immunoglobulins: and Function Immunoglobulins Have a Conserved Structure Consisting of Heavy and Light Chains Multiple Immunoglobulin Each with Different Functions Each Immunoglobulin Immunoglobulin Domains Have a Characteristic Fold Composed of Two by a Disulfide Bond The Three-Dimensional Structure of Antibody Molecules Accounts for Their Exquisite Specificity An Immunoglobulin's Constant Region Determines Its Functional Properties Generation of Antibody Diversity and B-Cell Development A Functional Light-Chain Gene Requires Assembly of V and Rearrangement of the Heavy-Chain Locus Involves V, D, and Somatic Hypermutation Allows the Generation and Selection of Antibodies with Improved Affinities B-Cell Development Requires Input from a Pre-B Cell Receptor During an Adaptive Response, from Making Membrane-Bound Secreted В They Make The MHC and Antigen Presentation The MHC Determines the Ability of Two Unrelated Individuals of the Same Species to Accept or Reject Grafts The Killing Activity of Cytotoxic Specific and MHC Restricted T Guided by Two Distinct Classes of MHC Molecules MHC Molecules Bind and Interact with the Antigen Presentation Is the Process by Which Protein Fragments Are Complexed with MHC Products and Posted to the Cell Surface Class I MHC Pathway Presents Cytosolic Antigens Class II MHC Pathway Presents Antigens Delivered to the Endocytic Pathway 1082 1082 1084 T and The Structure of the the F(ab) Portion of an Immunoglobulin TCR Genes Are Rearranged in a Manner Similar to Immunoglobulin Genes Т of Their Variable Residues Encoded in the Junctions between V, D, and Signaling via Antigen-Specific Receptors Triggers Proliferation and Differentiation of T Develop Through a Process of Positive and Negative Selection T for Full Activation Cytotoxic and Are Specialized for Killing T Signals to Other Immune Cells CD4 Based on Their Cytokine Production and Expression of Surface Markers Leukocytes Move in Response to Chemotactic Cues Provided by Chemokines Collaboration of Immune-System Cells in the Adaptive Response Toll-Like Receptors Perceive a Variety of Pathogen-Derived Macromolecular Patterns Engagement of Toll-Like Receptors Leads to Activation of Antigen-Presenting Cells Production of High-Affinity Antibodies Requires Collaboration Between Vaccines Elicit Protective Immunity Against a Variety of Pathogens Classic Experiment Somatic Rearrangement of Immunoglobulin Genes 25 1107 Tumor Cells and the Onset of Cancer 1109 Metastatic Tumor Cells Are Invasive and Can Spread Cancers Usually Originate in Proliferating Cells Cancer Stem Cells Can Be a Minority Population Tumor Growth Requires Formation of New Blood Vessels 1111 xxxvi CONTENTS Specific into Tumor Cells A Multi-hit Model of Cancer Induction Is Supported by Several Lines of Evidence Successive Oncogenic Mutations Can Be Traced in Colon Cancers DNA Microarray Reveal Subtle Differences Between Tumor Cells ££2Ш Gain-of-Function Mutations Convert Proto-oncogenes into Oncogenes Cancer-Causing Viruses Contain Oncogenes or Activate Cellular Proto-oncogenes Loss-of-Function Mutations in Tumor-Suppressor Genes Are Oncogenic Inherited Mutations in Tumor-Suppressor Genes Increase Cancer Risk Aberrations in Signaling Pathways That Control Development Are Associated with Many Cancers ^Ц£\| Promoting Proteins Oncogenic Receptors Can Promote Proliferation in the Absence of External Growth Factors Viral Activators of Growth-Factor Receptors Act as Oncoproteins Many Oncogenes Encode Constitutively Active Signal-Transduction Proteins Inappropriate Production of Nuclear Transcription Factors Can Induce Transformation Molecular Cell Biology Is Changing How Cancer Is Treated О2Я Growth-Inhibiting and Cell-Cycle Controls Mutations That Promote Unregulated Passage from G, to Loss-of-Function Mutations Affecting Chromatin- Remodeling Proteins Contribute to Tumors Loss of p53 Abolishes the DNA-Damage Checkpoint Apoptotic Genes Can Function as Proto-oncogenes or Tumor-Suppressor Genes Failure of Cell-Cycle Checkpoints Often Leads to Aneuploidy in Tumor Cells Carcinogens and Caretaker Genes in Cancer Carcinogens Induce Cancer by Damaging Some Carcinogens Have Been Linked to Specific Cancers Loss of DNA-Repair Systems Can Lead to Cancer Telomerase Expression Contributes to Immortalization of Cancer Cells GLOSSARY G-1 INDEX CONTENTS XXXVII
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genre	1\p (DE-588)4006432-3 Bibliografie gnd-content 2\p (DE-588)4123623-3 Lehrbuch gnd-content
genre_facet	Bibliografie Lehrbuch
id	DE-604.BV022496802
illustrated	Illustrated
index_date	2024-07-02T17:53:42Z
indexdate	2024-11-25T17:26:05Z
institution	BVB
isbn	9781429203142 9780716776017 0716776014
language	English
oai_aleph_id	oai:aleph.bib-bvb.de:BVB01-015703921
oclc_num	318399428
open_access_boolean
owner	DE-20 DE-355 DE-BY-UBR DE-703 DE-19 DE-BY-UBM DE-29T DE-M49 DE-BY-TUM DE-634 DE-11 DE-188 DE-91G DE-BY-TUM
owner_facet	DE-20 DE-355 DE-BY-UBR DE-703 DE-19 DE-BY-UBM DE-29T DE-M49 DE-BY-TUM DE-634 DE-11 DE-188 DE-91G DE-BY-TUM
physical	Getr. Zählung Ill., graph. Darst.
publishDate	2008
publishDateSearch	2008
publishDateSort	2008
publisher	Freeman
record_format	marc
spellingShingle	Molecular cell biology Cells cabt Molecular Biology cabt Cellular Biology cabt Biología molecular Citología Molekularbiologie (DE-588)4039983-7 gnd Cytologie (DE-588)4070177-3 gnd Zelle (DE-588)4067537-3 gnd CD-ROM (DE-588)4139307-7 gnd
subject_GND	(DE-588)4039983-7 (DE-588)4070177-3 (DE-588)4067537-3 (DE-588)4139307-7 (DE-588)4006432-3 (DE-588)4123623-3
title	Molecular cell biology
title_alt	Molekulare Zellbiologie
title_auth	Molecular cell biology
title_exact_search	Molecular cell biology
title_exact_search_txtP	Molecular cell biology
title_full	Molecular cell biology Harvey Lodish ...
title_fullStr	Molecular cell biology Harvey Lodish ...
title_full_unstemmed	Molecular cell biology Harvey Lodish ...
title_short	Molecular cell biology
title_sort	molecular cell biology
topic	Cells cabt Molecular Biology cabt Cellular Biology cabt Biología molecular Citología Molekularbiologie (DE-588)4039983-7 gnd Cytologie (DE-588)4070177-3 gnd Zelle (DE-588)4067537-3 gnd CD-ROM (DE-588)4139307-7 gnd
topic_facet	Cells Molecular Biology Cellular Biology Biología molecular Citología Molekularbiologie Cytologie Zelle CD-ROM Bibliografie Lehrbuch
url	http://www.whfreeman.com/lodish6e http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=015703921&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
work_keys_str_mv	UT molekularezellbiologie AT lodishharvey molecularcellbiology

Molecular cell biology

MARC

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