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	L Suaud, Y Hemimou, P Formstecher, B Laine
Journal	Diabetes (Diabetes) Vol. 48 Issue 5 Pg. 1162-7 (May 1999) ISSN: 0012-1797 [Print] United States
PMID	10331424 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors COUP Transcription Factor II COUP Transcription Factors DNA-Binding Proteins HNF1A protein, human HNF1B protein, human HNF4A protein, human Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factor 4 Hnf1a protein, mouse Hnf1b protein, mouse MLX protein, human NR2F2 protein, human Nr2f2 protein, mouse Nuclear Proteins Phosphoproteins Receptors, Steroid Tcfl4 protein, mouse Transcription Factors Hepatocyte Nuclear Factor 1 Hepatocyte Nuclear Factor 1-beta DNA
Topics	Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors COS Cells COUP Transcription Factor II COUP Transcription Factors DNA (metabolism) DNA-Binding Proteins (pharmacology) Diabetes Mellitus, Type 1 (genetics) Dimerization Drug Synergism Hepatocyte Nuclear Factor 1 Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factor 1-beta Hepatocyte Nuclear Factor 4 Humans Mice Mutation Nuclear Proteins Phosphoproteins (chemistry, genetics, pharmacology) Promoter Regions, Genetic Receptors, Steroid Transcription Factors (chemistry, genetics, pharmacology) Transcriptional Activation

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