Translational Control Is Required for the Unfolded Protein Response and In Vivo Glucose Homeostasis
The accumulation of unfolded protein in the endoplasmic reticulum (ER) attenuates protein synthesis initiation through phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at Ser51. Subsequently, transcription of genes encoding adaptive functions including the gluco...
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| Veröffentlicht in: | Molecular cell 2001-06, Vol.7 (6), p.1165-1176 |
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| creator | Scheuner, Donalyn Song, Benbo McEwen, Edward Liu, Chuan Laybutt, Ross Gillespie, Patrick Saunders, Thom Bonner-Weir, Susan Kaufman, Randal J |
| description | The accumulation of unfolded protein in the endoplasmic reticulum (ER) attenuates protein synthesis initiation through phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at Ser51. Subsequently, transcription of genes encoding adaptive functions including the glucose-regulated proteins is induced. We show that eIF2α phosphorylation is required for translation attenuation, transcriptional induction, and survival in response to ER stress. Mice with a homozygous mutation at the eIF2α phosphorylation site (Ser51Ala) died within 18 hr after birth due to hypoglycemia associated with defective gluconeogenesis. In addition, homozygous mutant embryos and neonates displayed a deficiency in pancreatic β cells. The results demonstrate that regulation of translation through eIF2α phosphorylation is essential for the ER stress response and in vivo glucose homeostasis. |
| doi_str_mv | 10.1016/S1097-2765(01)00265-9 |
| format | Article |
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Subsequently, transcription of genes encoding adaptive functions including the glucose-regulated proteins is induced. We show that eIF2α phosphorylation is required for translation attenuation, transcriptional induction, and survival in response to ER stress. Mice with a homozygous mutation at the eIF2α phosphorylation site (Ser51Ala) died within 18 hr after birth due to hypoglycemia associated with defective gluconeogenesis. In addition, homozygous mutant embryos and neonates displayed a deficiency in pancreatic β cells. The results demonstrate that regulation of translation through eIF2α phosphorylation is essential for the ER stress response and in vivo glucose homeostasis.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/S1097-2765(01)00265-9</identifier><identifier>PMID: 11430820</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Activating Transcription Factors ; Animals ; Animals, Newborn ; Blood Proteins - genetics ; Blood Proteins - metabolism ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; CCAAT-Enhancer-Binding Proteins - genetics ; CCAAT-Enhancer-Binding Proteins - metabolism ; Cell Survival - physiology ; DNA-Binding Proteins - chemistry ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Endoplasmic Reticulum - metabolism ; Gene Expression - physiology ; Germ-Line Mutation ; Gluconeogenesis - physiology ; glucose ; Glucose - metabolism ; Heat-Shock Proteins ; Homeostasis - physiology ; Homozygote ; Hypoglycemia - genetics ; Hypoglycemia - metabolism ; initiation factor eIF-2 ; Islets of Langerhans - cytology ; Islets of Langerhans - metabolism ; Mice ; Mice, Mutant Strains ; Molecular Chaperones - genetics ; Molecular Chaperones - metabolism ; Mutagenesis - physiology ; Phosphorylation ; Protein Biosynthesis - physiology ; Protein Folding ; RNA, Messenger - analysis ; Transcription Factor CHOP ; Transcription Factors - chemistry ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcriptional Activation - physiology ; unfolded protein response</subject><ispartof>Molecular cell, 2001-06, Vol.7 (6), p.1165-1176</ispartof><rights>2001 Cell Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c557t-eb9389143033a8329135f9069b37eeb2dd6e3e81704f8e15dee8e0dd334cdabd3</citedby><cites>FETCH-LOGICAL-c557t-eb9389143033a8329135f9069b37eeb2dd6e3e81704f8e15dee8e0dd334cdabd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1097276501002659$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11430820$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Scheuner, Donalyn</creatorcontrib><creatorcontrib>Song, Benbo</creatorcontrib><creatorcontrib>McEwen, Edward</creatorcontrib><creatorcontrib>Liu, Chuan</creatorcontrib><creatorcontrib>Laybutt, Ross</creatorcontrib><creatorcontrib>Gillespie, Patrick</creatorcontrib><creatorcontrib>Saunders, Thom</creatorcontrib><creatorcontrib>Bonner-Weir, Susan</creatorcontrib><creatorcontrib>Kaufman, Randal J</creatorcontrib><title>Translational Control Is Required for the Unfolded Protein Response and In Vivo Glucose Homeostasis</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>The accumulation of unfolded protein in the endoplasmic reticulum (ER) attenuates protein synthesis initiation through phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at Ser51. Subsequently, transcription of genes encoding adaptive functions including the glucose-regulated proteins is induced. We show that eIF2α phosphorylation is required for translation attenuation, transcriptional induction, and survival in response to ER stress. Mice with a homozygous mutation at the eIF2α phosphorylation site (Ser51Ala) died within 18 hr after birth due to hypoglycemia associated with defective gluconeogenesis. In addition, homozygous mutant embryos and neonates displayed a deficiency in pancreatic β cells. 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Song, Benbo ; McEwen, Edward ; Liu, Chuan ; Laybutt, Ross ; Gillespie, Patrick ; Saunders, Thom ; Bonner-Weir, Susan ; Kaufman, Randal J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c557t-eb9389143033a8329135f9069b37eeb2dd6e3e81704f8e15dee8e0dd334cdabd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Activating Transcription Factors</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Blood Proteins - genetics</topic><topic>Blood Proteins - metabolism</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>CCAAT-Enhancer-Binding Proteins - genetics</topic><topic>CCAAT-Enhancer-Binding Proteins - metabolism</topic><topic>Cell Survival - physiology</topic><topic>DNA-Binding Proteins - chemistry</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Endoplasmic Reticulum - metabolism</topic><topic>Gene Expression - physiology</topic><topic>Germ-Line Mutation</topic><topic>Gluconeogenesis - physiology</topic><topic>glucose</topic><topic>Glucose - metabolism</topic><topic>Heat-Shock Proteins</topic><topic>Homeostasis - physiology</topic><topic>Homozygote</topic><topic>Hypoglycemia - genetics</topic><topic>Hypoglycemia - metabolism</topic><topic>initiation factor eIF-2</topic><topic>Islets of Langerhans - cytology</topic><topic>Islets of Langerhans - metabolism</topic><topic>Mice</topic><topic>Mice, Mutant Strains</topic><topic>Molecular Chaperones - genetics</topic><topic>Molecular Chaperones - metabolism</topic><topic>Mutagenesis - physiology</topic><topic>Phosphorylation</topic><topic>Protein Biosynthesis - physiology</topic><topic>Protein Folding</topic><topic>RNA, Messenger - analysis</topic><topic>Transcription Factor CHOP</topic><topic>Transcription Factors - chemistry</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transcriptional Activation - physiology</topic><topic>unfolded protein response</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Scheuner, Donalyn</creatorcontrib><creatorcontrib>Song, Benbo</creatorcontrib><creatorcontrib>McEwen, Edward</creatorcontrib><creatorcontrib>Liu, Chuan</creatorcontrib><creatorcontrib>Laybutt, Ross</creatorcontrib><creatorcontrib>Gillespie, Patrick</creatorcontrib><creatorcontrib>Saunders, Thom</creatorcontrib><creatorcontrib>Bonner-Weir, Susan</creatorcontrib><creatorcontrib>Kaufman, Randal J</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Scheuner, Donalyn</au><au>Song, Benbo</au><au>McEwen, Edward</au><au>Liu, Chuan</au><au>Laybutt, Ross</au><au>Gillespie, Patrick</au><au>Saunders, Thom</au><au>Bonner-Weir, Susan</au><au>Kaufman, Randal J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Translational Control Is Required for the Unfolded Protein Response and In Vivo Glucose Homeostasis</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2001-06-01</date><risdate>2001</risdate><volume>7</volume><issue>6</issue><spage>1165</spage><epage>1176</epage><pages>1165-1176</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>The accumulation of unfolded protein in the endoplasmic reticulum (ER) attenuates protein synthesis initiation through phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at Ser51. Subsequently, transcription of genes encoding adaptive functions including the glucose-regulated proteins is induced. We show that eIF2α phosphorylation is required for translation attenuation, transcriptional induction, and survival in response to ER stress. Mice with a homozygous mutation at the eIF2α phosphorylation site (Ser51Ala) died within 18 hr after birth due to hypoglycemia associated with defective gluconeogenesis. In addition, homozygous mutant embryos and neonates displayed a deficiency in pancreatic β cells. The results demonstrate that regulation of translation through eIF2α phosphorylation is essential for the ER stress response and in vivo glucose homeostasis.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>11430820</pmid><doi>10.1016/S1097-2765(01)00265-9</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Activating Transcription Factors Animals Animals, Newborn Blood Proteins - genetics Blood Proteins - metabolism Carrier Proteins - genetics Carrier Proteins - metabolism CCAAT-Enhancer-Binding Proteins - genetics CCAAT-Enhancer-Binding Proteins - metabolism Cell Survival - physiology DNA-Binding Proteins - chemistry DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Endoplasmic Reticulum - metabolism Gene Expression - physiology Germ-Line Mutation Gluconeogenesis - physiology glucose Glucose - metabolism Heat-Shock Proteins Homeostasis - physiology Homozygote Hypoglycemia - genetics Hypoglycemia - metabolism initiation factor eIF-2 Islets of Langerhans - cytology Islets of Langerhans - metabolism Mice Mice, Mutant Strains Molecular Chaperones - genetics Molecular Chaperones - metabolism Mutagenesis - physiology Phosphorylation Protein Biosynthesis - physiology Protein Folding RNA, Messenger - analysis Transcription Factor CHOP Transcription Factors - chemistry Transcription Factors - genetics Transcription Factors - metabolism Transcriptional Activation - physiology unfolded protein response |
| title | Translational Control Is Required for the Unfolded Protein Response and In Vivo Glucose Homeostasis |
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