title: Functional study of the E276Q mutant hepatocyte nuclear factor-4alpha found in type 1 maturity-onset diabetes of the young: impaired synergy with chicken ovalbumin upstream promoter transcription factor II on the hepatocyte nuclear factor-1 promoter.
abstract: Seven mutations in the hepatocyte nuclear factor (HNF)-4alpha gene have been shown to correlate with type 1 maturity-onset diabetes of the young (MODY 1), a monogenic form of type 2 diabetes. Up to now, only the functional properties of two MODY 1 HNF-4alpha mutants, Q268X and V393I, have been investigated to address how the mutations in the HNF-4alpha gene, found by genetic studies, can give rise to impaired activities of mutated HNF-4alpha proteins and can cause this disease. The E276Q mutation results in a nonconservative substitution occurring in the HNF-4alpha E domain, which is involved in dimerization and transactivation activities as well as in protein-protein interactions with other transcription factors or coactivators. Using the mutated human HNF-4alpha2, we have found that, in the absence of chicken ovalbumin upstream promoter transcription factor II (COUP TFII), the E276Q substitution does not significantly affect the dimerization and transactivating activities of HNF-4alpha, at least on the promoters studied herein. On the other hand, in the presence of COUP TFII, the substitution impairs the enhancement of HNF-4-mediated activation of HNF-1 promoter. The impaired synergy between COUP TFII and HNF-4 on the HNF-1 promoter results from an alteration of their interaction. HNF-1 expression plays a crucial role in transactivation of insulin promoter and of numerous genes coding for enzymes involved in glucose homeostasis. Therefore, its downregulation resulting from the E276Q mutation in HNF-4alpha gene most probably impairs the function of pancreatic beta-cells.
authors.affiliation: Unité 459 INSERM, Laboratory of Cell Biology, University of Medicine H. Warembourg, Lille, France.
authors.forename: L
authors.initials: L
authors.lastname: Suaud
authors.forename: Y
authors.initials: Y
authors.lastname: Hemimou
authors.forename: P
authors.initials: P
authors.lastname: Formstecher
authors.forename: B
authors.initials: B
authors.lastname: Laine
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D019556:COS Cells; D051837:COUP Transcription Factor II; D051836:COUP Transcription Factors; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D019281:Dimerization; D004357:Drug Synergism; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011987:Receptors, Steroid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology*; D015533:Transcriptional Activation
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051837:COUP Transcription Factor II; D051836:COUP Transcription Factors; D004247:DNA; D004268:DNA-Binding Proteins; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011987:Receptors, Steroid; D014157:Transcription Factors; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; C403128:MLX protein, human; C497587:Nr2f2 protein, mouse; C501970:Tcfl4 protein, mouse; C095569:NR2F2 protein, human