Erk1/2 MAP kinases are required for epidermal G2/M progression
Erk1/2 mitogen-activated protein kinases (MAPKs) are often hyperactivated in human cancers, where they affect multiple processes, including proliferation. However, the effects of Erk1/2 loss in normal epithelial tissue, the setting of most extracellular signal-regulated kinase (Erk)-associated neopl...
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| Veröffentlicht in: | The Journal of cell biology 2009-05, Vol.185 (3), p.409-422 |
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| creator | Dumesic, Phillip A Scholl, Florence A Barragan, Deborah I Khavari, Paul A |
| description | Erk1/2 mitogen-activated protein kinases (MAPKs) are often hyperactivated in human cancers, where they affect multiple processes, including proliferation. However, the effects of Erk1/2 loss in normal epithelial tissue, the setting of most extracellular signal-regulated kinase (Erk)-associated neoplasms, are unknown. In epidermis, loss of Erk1 or Erk2 individually has no effect, whereas simultaneous Erk1/2 depletion inhibits cell division, demonstrating that these MAPKs are necessary for normal tissue self-renewal. Growth inhibition caused by Erk1/2 loss is rescued by reintroducing Erk2, but not by activating Erk effectors that promote G1 cell cycle progression. Unlike fibroblasts, in which Erk1/2 loss decreases cyclin D1 expression and induces G1/S arrest, Erk1/2 loss in epithelial cells reduces cyclin B1 and c-Fos expression and induces G2/M arrest while disrupting a gene regulatory network centered on cyclin B1-Cdc2. Thus, the cell cycle stages at which Erk1/2 activity is required vary by cell type, with Erk1/2 functioning in epithelial cells to enable progression through G2/M. |
| doi_str_mv | 10.1083/jcb.200804038 |
| format | Article |
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However, the effects of Erk1/2 loss in normal epithelial tissue, the setting of most extracellular signal-regulated kinase (Erk)-associated neoplasms, are unknown. In epidermis, loss of Erk1 or Erk2 individually has no effect, whereas simultaneous Erk1/2 depletion inhibits cell division, demonstrating that these MAPKs are necessary for normal tissue self-renewal. Growth inhibition caused by Erk1/2 loss is rescued by reintroducing Erk2, but not by activating Erk effectors that promote G1 cell cycle progression. Unlike fibroblasts, in which Erk1/2 loss decreases cyclin D1 expression and induces G1/S arrest, Erk1/2 loss in epithelial cells reduces cyclin B1 and c-Fos expression and induces G2/M arrest while disrupting a gene regulatory network centered on cyclin B1-Cdc2. 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However, the effects of Erk1/2 loss in normal epithelial tissue, the setting of most extracellular signal-regulated kinase (Erk)-associated neoplasms, are unknown. In epidermis, loss of Erk1 or Erk2 individually has no effect, whereas simultaneous Erk1/2 depletion inhibits cell division, demonstrating that these MAPKs are necessary for normal tissue self-renewal. Growth inhibition caused by Erk1/2 loss is rescued by reintroducing Erk2, but not by activating Erk effectors that promote G1 cell cycle progression. Unlike fibroblasts, in which Erk1/2 loss decreases cyclin D1 expression and induces G1/S arrest, Erk1/2 loss in epithelial cells reduces cyclin B1 and c-Fos expression and induces G2/M arrest while disrupting a gene regulatory network centered on cyclin B1-Cdc2. Thus, the cell cycle stages at which Erk1/2 activity is required vary by cell type, with Erk1/2 functioning in epithelial cells to enable progression through G2/M.</description><subject>Animals</subject><subject>Antibodies</subject><subject>Biochemistry</subject><subject>Cancer</subject><subject>CDC2 Protein Kinase - genetics</subject><subject>Cell cycle</subject><subject>Cell Cycle - physiology</subject><subject>Cell division</subject><subject>Cell Division - physiology</subject><subject>Cyclin B - genetics</subject><subject>Cyclin B1</subject><subject>Cyclins</subject><subject>Enzyme Activation</subject><subject>Epidermal Cells</subject><subject>Epidermis</subject><subject>Epidermis - physiology</subject><subject>Epithelial Cells - cytology</subject><subject>Epithelial Cells - enzymology</subject><subject>Fibroblasts</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - enzymology</subject><subject>Fibroblasts - physiology</subject><subject>G2 Phase - physiology</subject><subject>Gene Expression Regulation</subject><subject>Humans</subject><subject>Keratinocytes</subject><subject>Keratinocytes - cytology</subject><subject>Keratinocytes - physiology</subject><subject>Keratinocytes - transplantation</subject><subject>Kinases</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>Neoplasms - enzymology</subject><subject>Neoplasms - pathology</subject><subject>RNA, Small Interfering - genetics</subject><subject>Skin</subject><subject>Skin grafts</subject><subject>Small interfering RNA</subject><subject>Tissues</subject><subject>Transplantation, Heterologous</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1v1DAQxS0EokvhyBGIOHBLd8YfSXypVFWlILUCCXq2HGe8eJuNt_YGif8ew66Wj9Mc3k9P781j7CXCGUInlmvXn3GADiSI7hFboJJQdyjhMVsAcKy14uqEPct5DQCyleIpO0EtUTbQLtj5VbrHJa9uLz5X92GymXJlE1WJHuaQaKh8TBVtw0BpY8fqmi9vq22Kq0Q5hzg9Z0-8HTO9ONxTdvf-6uvlh_rm0_XHy4ub2ikud_UgyDsLjSbne-SN7Z3W6O3gBJeiU4q4963lg3UdaeU1QtMP2IKyCKBRnLLzve927jc0OJp2yY5mm8LGph8m2mD-Vabwzazid8NbAPHb4N3BIMWHmfLObEJ2NI52ojhn07Tliai6Ar79D1zHOU2lnOHYIiLXskD1HnIp5pzIH5MgmF-zmDKLOc5S-Nd_x_9DH3YowKs9sM67mI46ByXaUqHob_a6t9HYVQrZ3H3hgAKw4R0ILn4Clk-aDQ</recordid><startdate>20090504</startdate><enddate>20090504</enddate><creator>Dumesic, Phillip A</creator><creator>Scholl, Florence A</creator><creator>Barragan, Deborah I</creator><creator>Khavari, Paul A</creator><general>The Rockefeller University Press</general><general>Rockefeller University Press</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20090504</creationdate><title>Erk1/2 MAP kinases are required for epidermal G2/M progression</title><author>Dumesic, Phillip A ; Scholl, Florence A ; Barragan, Deborah I ; Khavari, Paul A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c524t-d3efca069ecfb126abc991fadc3243855e2ff7a2dac8e95f9106bd1705a100913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Antibodies</topic><topic>Biochemistry</topic><topic>Cancer</topic><topic>CDC2 Protein Kinase - genetics</topic><topic>Cell cycle</topic><topic>Cell Cycle - physiology</topic><topic>Cell division</topic><topic>Cell Division - physiology</topic><topic>Cyclin B - genetics</topic><topic>Cyclin B1</topic><topic>Cyclins</topic><topic>Enzyme Activation</topic><topic>Epidermal Cells</topic><topic>Epidermis</topic><topic>Epidermis - physiology</topic><topic>Epithelial Cells - cytology</topic><topic>Epithelial Cells - enzymology</topic><topic>Fibroblasts</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - enzymology</topic><topic>Fibroblasts - physiology</topic><topic>G2 Phase - physiology</topic><topic>Gene Expression Regulation</topic><topic>Humans</topic><topic>Keratinocytes</topic><topic>Keratinocytes - cytology</topic><topic>Keratinocytes - physiology</topic><topic>Keratinocytes - transplantation</topic><topic>Kinases</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Mitogen-Activated Protein Kinase 1 - metabolism</topic><topic>Mitogen-Activated Protein Kinase 3 - metabolism</topic><topic>Neoplasms - enzymology</topic><topic>Neoplasms - pathology</topic><topic>RNA, Small Interfering - genetics</topic><topic>Skin</topic><topic>Skin grafts</topic><topic>Small interfering RNA</topic><topic>Tissues</topic><topic>Transplantation, Heterologous</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dumesic, Phillip A</creatorcontrib><creatorcontrib>Scholl, Florence A</creatorcontrib><creatorcontrib>Barragan, Deborah I</creatorcontrib><creatorcontrib>Khavari, Paul A</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dumesic, Phillip A</au><au>Scholl, Florence A</au><au>Barragan, Deborah I</au><au>Khavari, Paul A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Erk1/2 MAP kinases are required for epidermal G2/M progression</atitle><jtitle>The Journal of cell biology</jtitle><addtitle>J Cell Biol</addtitle><date>2009-05-04</date><risdate>2009</risdate><volume>185</volume><issue>3</issue><spage>409</spage><epage>422</epage><pages>409-422</pages><issn>0021-9525</issn><eissn>1540-8140</eissn><coden>JCLBA3</coden><abstract>Erk1/2 mitogen-activated protein kinases (MAPKs) are often hyperactivated in human cancers, where they affect multiple processes, including proliferation. However, the effects of Erk1/2 loss in normal epithelial tissue, the setting of most extracellular signal-regulated kinase (Erk)-associated neoplasms, are unknown. In epidermis, loss of Erk1 or Erk2 individually has no effect, whereas simultaneous Erk1/2 depletion inhibits cell division, demonstrating that these MAPKs are necessary for normal tissue self-renewal. Growth inhibition caused by Erk1/2 loss is rescued by reintroducing Erk2, but not by activating Erk effectors that promote G1 cell cycle progression. Unlike fibroblasts, in which Erk1/2 loss decreases cyclin D1 expression and induces G1/S arrest, Erk1/2 loss in epithelial cells reduces cyclin B1 and c-Fos expression and induces G2/M arrest while disrupting a gene regulatory network centered on cyclin B1-Cdc2. Thus, the cell cycle stages at which Erk1/2 activity is required vary by cell type, with Erk1/2 functioning in epithelial cells to enable progression through G2/M.</abstract><cop>United States</cop><pub>The Rockefeller University Press</pub><pmid>19414607</pmid><doi>10.1083/jcb.200804038</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antibodies Biochemistry Cancer CDC2 Protein Kinase - genetics Cell cycle Cell Cycle - physiology Cell division Cell Division - physiology Cyclin B - genetics Cyclin B1 Cyclins Enzyme Activation Epidermal Cells Epidermis Epidermis - physiology Epithelial Cells - cytology Epithelial Cells - enzymology Fibroblasts Fibroblasts - cytology Fibroblasts - enzymology Fibroblasts - physiology G2 Phase - physiology Gene Expression Regulation Humans Keratinocytes Keratinocytes - cytology Keratinocytes - physiology Keratinocytes - transplantation Kinases Mice Mice, SCID Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Neoplasms - enzymology Neoplasms - pathology RNA, Small Interfering - genetics Skin Skin grafts Small interfering RNA Tissues Transplantation, Heterologous |
| title | Erk1/2 MAP kinases are required for epidermal G2/M progression |
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