{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:54:57Z","timestamp":1790146497139,"version":"4.0.1"},"reference-count":49,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,11,1]]},"abstract":"<jats:p>HNF4\u03b1 (hepatocyte nuclear factor 4\u03b1) belongs to a complex transcription factor network that is crucial for the function of hepatocytes and pancreatic \u03b2-cells. In these cells, it activates the expression of a very large number of genes, including genes involved in the transport and metabolism of glucose and lipids. Mutations in the HNF4\u03b1 gene correlate with MODY1 (maturity-onset diabetes of the young 1), a form of type II diabetes characterized by an impaired glucose-induced insulin secretion. The MODY1 G115S (Gly115\u2192Ser) HNF4\u03b1 mutation is located in the DNA-binding domain of this nuclear receptor. We show here that the G115S mutation failed to affect HNF4\u03b1-mediated transcription on apolipoprotein promoters in HepG2 cells. Conversely, in pancreatic \u03b2-cell lines, this mutation resulted in strong impairments of HNF4\u03b1 transcriptional activity on the promoters of LPK (liver pyruvate kinase) and HNF1\u03b1, with this transcription factor playing a key role in endocrine pancreas. We show as well that the G115S mutation creates a PKA (protein kinase A) phosphorylation site, and that PKA-mediated phosphorylation results in a decreased transcriptional activity of the mutant. Moreover, the G115E (Gly115\u2192Glu) mutation mimicking phosphorylation reduced HNF4\u03b1 DNA-binding and transcriptional activities. Our results may account for the 100% penetrance of diabetes in human carriers of this mutation. In addition, they suggest that introduction of a phosphorylation site in the DNA-binding domain may represent a new mechanism by which a MODY1 mutation leads to loss of HNF4\u03b1 function.<\/jats:p>","DOI":"10.1042\/bj20040473","type":"journal-article","created":{"date-parts":[[2004,10,26]],"date-time":"2004-10-26T10:23:11Z","timestamp":1098786191000},"page":"573-580","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The G115S mutation associated with maturity-onset diabetes of the young impairs hepatocyte nuclear factor 4\u03b1 activities and introduces a PKA phosphorylation site in its DNA-binding domain"],"prefix":"10.1042","volume":"383","author":[{"given":"B\u00e9n\u00e9dicte","family":"OXOMBRE","sequence":"first","affiliation":[{"name":"INSERM U459, Facult\u00e9 de M\u00e9decine Henri Warembourg, 1 Place de Verdun, 59045 Lille Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa","family":"KOUACH","sequence":"additional","affiliation":[{"name":"Laboratoire de Spectrom\u00e9trie de masse, Facult\u00e9 de M\u00e9decine Henri Warembourg, 1 Place de Verdun, 59045 Lille Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ericka","family":"MOERMAN","sequence":"additional","affiliation":[{"name":"INSERM U459, Facult\u00e9 de M\u00e9decine Henri Warembourg, 1 Place de Verdun, 59045 Lille Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"FORMSTECHER","sequence":"additional","affiliation":[{"name":"INSERM U459, Facult\u00e9 de M\u00e9decine Henri Warembourg, 1 Place de Verdun, 59045 Lille Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"LAINE","sequence":"additional","affiliation":[{"name":"INSERM U459, Facult\u00e9 de M\u00e9decine Henri Warembourg, 1 Place de Verdun, 59045 Lille Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2004,10,26]]},"reference":[{"key":"2021112217420846000_B1","first-page":"309","article-title":"Hepatocyte nuclear factor 4\u03b1","volume-title":"Nuclear Receptors and Genetic Diseases","author":"Sladek","year":"2001"},{"key":"2021112217420846000_B2","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1096\/fasebj.10.2.8641560","article-title":"Liver-enriched transcription factors and hepatocyte differentiation","volume":"10","author":"Cereghini","year":"1996","journal-title":"FASEB J."},{"key":"2021112217420846000_B3","doi-asserted-by":"crossref","first-page":"14189","DOI":"10.1073\/pnas.251558998","article-title":"Dissecting the transcriptional network of pancreatic islets during development and differentiation","volume":"98","author":"Shih","year":"2001","journal-title":"Proc. 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