{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T13:12:48Z","timestamp":1777468368084,"version":"3.51.4"},"reference-count":45,"publisher":"The Endocrine Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Pancreatic \u03b2-cell survival remains poorly understood despite decades of research. GATA transcription factors broadly regulate embryogenesis and influence survival of several cell types, but their role in adult \u03b2-cells remains undefined. To investigate the role of GATA factors in adult \u03b2-cells, we derived \u03b2-cell-inducible Gata4- and Gata6-knockout mice, along with whole-body inducible Gata4 knockouts. \u03b2-Cell Gata4 deletion modestly increased the proportion of dying \u03b2-cells in situ with ultrastructural abnormalities suggesting endoplasmic reticulum (ER) stress. Notably, glucose homeostasis was not grossly altered in Gata4- and Gata6-knockout mice, suggesting that GATA factors do not have essential roles in \u03b2-cells. Several ER stress signals were up-regulated in Gata4 and Gata6 knockouts, most notably CHOP, a known regulator of ER stress-induced apoptosis. However, ER stress signals were not elevated to levels observed after acute thapsigargin administration, suggesting that GATA deficiency only caused mild ER stress. Simultaneous deletion of Gata4 and CHOP partially restored \u03b2-cell survival. In contrast, whole-body inducible Gata4 knockouts displayed no evidence of ER stress in other GATA4-enriched tissues, such as heart. Indeed, distinct GATA transcriptional targets were differentially expressed in islets compared with heart. Such \u03b2-cell-specific findings prompted study of a large meta-analysis dataset to investigate single nucleotide polymorphisms harbored within the human GATA4 locus, revealing several variants significantly associated with type 1 diabetes mellitus. We conclude that GATA factors have important but nonessential roles to promote ER integrity and \u03b2-cell survival in a tissue-specific manner and that GATA factors likely contribute to type 1 diabetes mellitus pathogenesis.<\/jats:p>","DOI":"10.1210\/me.2013-1265","type":"journal-article","created":{"date-parts":[[2013,11,28]],"date-time":"2013-11-28T04:52:18Z","timestamp":1385614338000},"page":"28-39","source":"Crossref","is-referenced-by-count":19,"title":["GATA Factors Promote ER Integrity and \u03b2-Cell Survival and Contribute to Type 1 Diabetes Risk"],"prefix":"10.1210","volume":"28","author":[{"given":"Daniel J.","family":"Sartori","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Diabetes (D.J.S., C.J.W., S.Y.L., M.M.R., C.L.), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher J.","family":"Wilbur","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes (D.J.S., C.J.W., S.Y.L., M.M.R., C.L.), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon Y.","family":"Long","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes (D.J.S., C.J.W., S.Y.L., M.M.R., C.L.), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew M.","family":"Rankin","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes (D.J.S., C.J.W., S.Y.L., M.M.R., C.L.), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changhong","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes (D.J.S., C.J.W., S.Y.L., M.M.R., C.L.), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan P.","family":"Bradfield","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, Center for Applied Genomics (J.P.B., H.H., S.F.A.G.), Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hakon","family":"Hakonarson","sequence":"additional","affiliation":[{"name":"Children's Hospital of Philadelphia, Department of Pediatrics (H.H., S.F.A.G.), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104"},{"name":"Perelman School of Medicine, Center for Applied Genomics (J.P.B., H.H., S.F.A.G.), Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Struan F. A.","family":"Grant","sequence":"additional","affiliation":[{"name":"Children's Hospital of Philadelphia, Department of Pediatrics (H.H., S.F.A.G.), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104"},{"name":"Perelman School of Medicine, Center for Applied Genomics (J.P.B., H.H., S.F.A.G.), Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William T.","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Cardiology (W.T.P.), Children's Hospital, Boston, Harvard Medical School, Boston, Massachusetts 02115"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jake A.","family":"Kushner","sequence":"additional","affiliation":[{"name":"Section of Pediatric Diabetes and Endocrinology (J.A.K.), Baylor College of Medicine, Houston, Texas 77030"},{"name":"Diabetes and Endocrinology Service (J.A.K.), Texas Children's Hospital, Houston, Texas 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"issue":"9","key":"2020071613323196800_B1","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.2337\/db06-1771","article-title":"Distinct in vivo roles of caspase-8 in \u03b2-cells in physiological and diabetes models","volume":"56","author":"Liadis","year":"2007","journal-title":"Diabetes"},{"issue":"9","key":"2020071613323196800_B2","doi-asserted-by":"crossref","first-page":"3620","DOI":"10.1128\/MCB.25.9.3620-3629.2005","article-title":"Caspase-3-dependent \u03b2-cell apoptosis in the initiation of autoimmune diabetes mellitus","volume":"25","author":"Liadis","year":"2005","journal-title":"Mol Cell Biol"},{"issue":"2","key":"2020071613323196800_B3","doi-asserted-by":"crossref","first-page":"E340","DOI":"10.1152\/ajpendo.2000.278.2.E340","article-title":"Overexpression of Bcl-x(L) in \u03b2-cells prevents cell death but impairs mitochondrial signal for insulin secretion","volume":"278","author":"Zhou","year":"2000","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"1","key":"2020071613323196800_B4","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1096\/fj.00-0414fje","article-title":"The common Arg972 polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets","volume":"15","author":"Federici","year":"2001","journal-title":"FASEB J"},{"issue":"9","key":"2020071613323196800_B5","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.2337\/diabetes.54.9.2557","article-title":"Very slow turnover of \u03b2-cells in aged adult mice","volume":"54","author":"Teta","year":"2005","journal-title":"Diabetes"},{"issue":"6865","key":"2020071613323196800_B6","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1038\/414792a","article-title":"\u03b2-Cell death during progression to diabetes","volume":"414","author":"Mathis","year":"2001","journal-title":"Nature"},{"issue":"3","key":"2020071613323196800_B7","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1210\/er.2007-0039","article-title":"The unfolded protein response: a pathway that links insulin demand with \u03b2-cell failure and diabetes","volume":"29","author":"Scheuner","year":"2008","journal-title":"Endocr Rev"},{"issue":"110","key":"2020071613323196800_B8","doi-asserted-by":"crossref","first-page":"pe7","DOI":"10.1126\/scisignal.3110pe7","article-title":"ER stress in pancreatic \u03b2 cells: the thin red line between adaptation and failure","volume":"3","author":"Eizirik","year":"2010","journal-title":"Sci Signal"},{"issue":"10","key":"2020071613323196800_B9","doi-asserted-by":"crossref","first-page":"3378","DOI":"10.1172\/JCI34587","article-title":"Chop deletion reduces oxidative stress, improves \u03b2 cell function, and promotes cell survival in multiple mouse models of diabetes","volume":"118","author":"Song","year":"2008","journal-title":"J Clin Invest"},{"issue":"4","key":"2020071613323196800_B10","doi-asserted-by":"crossref","first-page":"818","DOI":"10.2337\/db11-1293","article-title":"Islet \u03b2-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model","volume":"61","author":"Tersey","year":"2012","journal-title":"Diabetes"},{"issue":"45","key":"2020071613323196800_B11","doi-asserted-by":"crossref","first-page":"19090","DOI":"10.1073\/pnas.0904849106","article-title":"Pdx1 (MODY4) regulates pancreatic \u03b2 cell susceptibility to ER stress","volume":"106","author":"Sachdeva","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"issue":"8","key":"2020071613323196800_B12","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1172\/JCI200316537","article-title":"Increased islet apoptosis in Pdx1+\/\u2212 mice","volume":"111","author":"Johnson","year":"2003","journal-title":"J Clin Invest"},{"issue":"1\u20132","key":"2020071613323196800_B13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.mce.2004.06.007","article-title":"Transcription factor GATA-6 is expressed in the endocrine and GATA-4 in the exocrine pancreas","volume":"226","author":"Ketola","year":"2004","journal-title":"Mol Cell Endocrinol"},{"issue":"2","key":"2020071613323196800_B14","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.ydbio.2006.06.046","article-title":"Gata6 is an important regulator of mouse pancreas development","volume":"298","author":"Decker","year":"2006","journal-title":"Dev Biol"},{"issue":"10","key":"2020071613323196800_B15","doi-asserted-by":"crossref","first-page":"3504","DOI":"10.1172\/JCI63240","article-title":"GATA4 and GATA6 control mouse pancreas organogenesis","volume":"122","author":"Carrasco","year":"2012","journal-title":"J Clin Invest"},{"issue":"10","key":"2020071613323196800_B16","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1136\/gutjnl-2012-303328","article-title":"Gata6 is required for complete acinar differentiation and maintenance of the exocrine pancreas in adult mice","volume":"62","author":"Martinelli","year":"2013","journal-title":"Gut"},{"issue":"10","key":"2020071613323196800_B17","doi-asserted-by":"crossref","first-page":"3469","DOI":"10.1172\/JCI65751","article-title":"GATA believe it: new essential regulators of pancreas development","volume":"122","author":"Rodr\u00edguez-Segu\u00ed","year":"2012","journal-title":"J Clin Invest"},{"issue":"10","key":"2020071613323196800_B18","doi-asserted-by":"crossref","first-page":"3516","DOI":"10.1172\/JCI63352","article-title":"Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis","volume":"122","author":"Xuan","year":"2012","journal-title":"J Clin Invest"},{"issue":"1","key":"2020071613323196800_B19","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.ydbio.2004.08.008","article-title":"GATA4 is a dosage-sensitive regulator of cardiac morphogenesis","volume":"275","author":"Pu","year":"2004","journal-title":"Dev Biol"},{"issue":"6987","key":"2020071613323196800_B20","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nature02520","article-title":"Adult pancreatic \u03b2-cells are formed by self-duplication rather than stem-cell differentiation","volume":"429","author":"Dor","year":"2004","journal-title":"Nature"},{"key":"2020071613323196800_B21","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1471-213X-6-19","article-title":"Generation of mice harbouring a conditional loss-of-function allele of Gata6","volume":"6","author":"Sodhi","year":"2006","journal-title":"BMC Dev Biol"},{"issue":"1","key":"2020071613323196800_B22","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.stem.2007.03.002","article-title":"Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss","volume":"1","author":"Ruzankina","year":"2007","journal-title":"Cell Stem Cell"},{"issue":"5","key":"2020071613323196800_B23","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.2337\/db12-0848","article-title":"\u03b2 Cells are not generated in pancreatic duct ligation induced injury in adult mice","volume":"62","author":"Rankin","year":"2013","journal-title":"Diabetes"},{"issue":"46","key":"2020071613323196800_B24","first-page":"2166","article-title":"Immunofluorescent detection of two thymidine analogues (CldU and IdU) in primary tissue","volume":"pii","author":"Tuttle","year":"2010","journal-title":"J Vis Exp"},{"issue":"7","key":"2020071613323196800_B25","doi-asserted-by":"crossref","first-page":"4223","DOI":"10.1128\/MCB.13.7.4223","article-title":"Pancreatic \u03b2 cells cultured from individual preneoplastic foci in a multistage tumorigenesis pathway: a potentially general technique for isolating physiologically representative cell lines","volume":"13","author":"Radvanyi","year":"1993","journal-title":"Mol Cell Biol"},{"issue":"5 Pt 1","key":"2020071613323196800_B26","first-page":"E846","article-title":"Glucose metabolism and insulin release in mouse \u03b2 HC9 cells, as model for wild-type pancreatic \u03b2-cells","volume":"270","author":"Liang","year":"1996","journal-title":"Am J Physiol"},{"issue":"11","key":"2020071613323196800_B27","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1210\/me.2009-0057","article-title":"Cyclin D2 protein stability is regulated in pancreatic \u03b2-cells","volume":"23","author":"He","year":"2009","journal-title":"Mol Endocrinol"},{"issue":"9","key":"2020071613323196800_B28","doi-asserted-by":"crossref","first-page":"3752","DOI":"10.1128\/MCB.25.9.3752-3762.2005","article-title":"Cyclins D2 and D1 are essential for postnatal pancreatic \u03b2-cell growth","volume":"25","author":"Kushner","year":"2005","journal-title":"Mol Cell Biol"},{"issue":"3","key":"2020071613323196800_B29","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1210\/me.2004-0051","article-title":"The zinc finger-containing transcription factor Gata-4 is expressed in the developing endocrine pancreas and activates glucagon gene expression","volume":"19","author":"Ritz-Laser","year":"2005","journal-title":"Mol Endocrinol"},{"issue":"4","key":"2020071613323196800_B30","doi-asserted-by":"crossref","first-page":"906","DOI":"10.2337\/db08-1464","article-title":"Successful versus failed adaptation to high-fat diet-induced insulin resistance: the role of IAPP-induced \u03b2-cell endoplasmic reticulum stress","volume":"58","author":"Matveyenko","year":"2009","journal-title":"Diabetes"},{"issue":"18","key":"2020071613323196800_B31","doi-asserted-by":"crossref","first-page":"6975","DOI":"10.1073\/pnas.0401833101","article-title":"Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity","volume":"101","author":"Aries","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"issue":"6","key":"2020071613323196800_B32","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1165\/rcmb.2006-0359OC","article-title":"Regulation of Bcl-xL expression in lung vascular smooth muscle","volume":"36","author":"Suzuki","year":"2007","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"11","key":"2020071613323196800_B33","doi-asserted-by":"crossref","first-page":"5635","DOI":"10.1210\/en.2008-0148","article-title":"GATA-4 regulates Bcl-2 expression in ovarian granulosa cell tumors","volume":"149","author":"Kyr\u00f6nlahti","year":"2008","journal-title":"Endocrinology"},{"issue":"1","key":"2020071613323196800_B34","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.cmet.2009.06.002","article-title":"Translation attenuation through eIF2\u03b1 phosphorylation prevents oxidative stress and maintains the differentiated state in \u03b2 cells","volume":"10","author":"Back","year":"2009","journal-title":"Cell Metab"},{"issue":"27","key":"2020071613323196800_B35","doi-asserted-by":"crossref","first-page":"24390","DOI":"10.1074\/jbc.M202490200","article-title":"The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism","volume":"277","author":"Dai","year":"2002","journal-title":"J Biol Chem"},{"issue":"2","key":"2020071613323196800_B36","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/dvdy.20552","article-title":"GATA-4:FOG interactions regulate gastric epithelial development in the mouse","volume":"234","author":"Jacobsen","year":"2005","journal-title":"Dev Dyn"},{"issue":"7145","key":"2020071613323196800_B37","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/nature05911","article-title":"Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls","volume":"447","author":"Wellcome Trust Case Control Consortium","year":"2007","journal-title":"Nature"},{"issue":"9","key":"2020071613323196800_B38","doi-asserted-by":"crossref","first-page":"e1002293","DOI":"10.1371\/journal.pgen.1002293","article-title":"A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci","volume":"7","author":"Bradfield","year":"2011","journal-title":"PLoS Genet"},{"issue":"4","key":"2020071613323196800_B39","doi-asserted-by":"crossref","first-page":"E735","DOI":"10.1152\/ajpendo.00696.2009","article-title":"Executioners of apoptosis in pancreatic \u03b2-cells: not just for cell death","volume":"298","author":"Choi","year":"2010","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"6","key":"2020071613323196800_B40","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.2337\/db08-1198","article-title":"Adaptive \u03b2-cell proliferation is severely restricted with advanced age","volume":"58","author":"Rankin","year":"2009","journal-title":"Diabetes"},{"issue":"9","key":"2020071613323196800_B41","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/sj.embor.7400779","article-title":"Mediators of endoplasmic reticulum stress-induced apoptosis","volume":"7","author":"Szegezdi","year":"2006","journal-title":"EMBO Rep"},{"issue":"15","key":"2020071613323196800_B42","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1016\/j.lfs.2003.10.002","article-title":"Regulation of cardiac myocyte apoptosis by the GATA-4 transcription factor","volume":"74","author":"Suzuki","year":"2004","journal-title":"Life Sci"},{"issue":"34","key":"2020071613323196800_B43","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1038\/onc.2009.159","article-title":"GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system","volume":"28","author":"Agnihotri","year":"2009","journal-title":"Oncogene"},{"issue":"20","key":"2020071613323196800_B44","doi-asserted-by":"crossref","first-page":"7583","DOI":"10.1128\/MCB.20.20.7583-7590.2000","article-title":"Functional conservation of regulatory elements in the pdx-1 gene: PDX-1 and hepatocyte nuclear factor 3\u03b2 transcription factors mediate \u03b2-cell-specific expression","volume":"20","author":"Marshak","year":"2000","journal-title":"Mol Cell Biol"},{"issue":"2","key":"2020071613323196800_B45","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S1097-2765(02)00459-8","article-title":"Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4","volume":"9","author":"Cirillo","year":"2002","journal-title":"Mol Cell"}],"container-title":["Molecular Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/28\/1\/28\/8903028\/mend0028.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/28\/1\/28\/8903028\/mend0028.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T00:05:17Z","timestamp":1594944317000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mend\/article\/28\/1\/28\/2556226"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,1]]},"references-count":45,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2014,1,1]]}},"URL":"https:\/\/doi.org\/10.1210\/me.2013-1265","relation":{},"ISSN":["0888-8809","1944-9917"],"issn-type":[{"value":"0888-8809","type":"print"},{"value":"1944-9917","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,1,1]]}}}