HNF-1alpha and endodermal transcription factors cooperatively activate Fabpl: MODY3 mutations abrogate cooperativity.
Hepatocyte nuclear factor (HNF)-1alpha plays a central role in intestinal and hepatic gene regulation and is required for hepatic expression of the liver fatty acid binding protein gene (Fabpl). An Fabpl transgene was directly activated through cognate sites by HNF-1alpha and HNF-1beta, as well as five other endodermal factors: CDX-1, C/EBPbeta, GATA-4, FoxA2, and HNF-4alpha. HNF-1alpha activated the Fabpl transgene by as much as 60-fold greater in the presence of the other five endodermal factors than in their absence, accounting for up to one-half the total transgene activation by the group of six factors. This degree of synergistic interaction suggests that multifactor cooperativity is a critical determinant of endodermal gene activation by HNF-1alpha. Mutations in HNF-1alpha that result in maturity onset diabetes of the young (MODY3) provide evidence for the in vivo significance of these synergistic interactions. An R131Q HNF-1alpha MODY3 mutant exhibits complete loss of synergistic activation in concert with the other endodermal transcription factors despite wild-type transactivation ability in their absence. Furthermore, whereas wild-type HNF-1alpha exhibited pairwise cooperative synergy with each of the other five factors, the R131Q mutant could synergize only with GATA-4 and C/EBPbeta. Selective loss of synergy with other endodermal transcription factors accompanied by retention of native transactivation ability in an HNF-1alpha MODY mutant suggests in vivo significance for cooperative synergy.
Divine
Joyce K
JK
Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
McCaul
Sean P
SP
Simon
Theodore C
TC
D000818:Animals; D001483:Base Sequence; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004707:Endoderm / Q000378:metabolism; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000502:physiology; D051381:Rats; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D019076:Transgenes / Q000502:physiology; D025521:Tumor Suppressor Proteins
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C107608:FABP7 protein, human; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496489:Hnf1a protein, rat; C496496:Hnf1b protein, mouse; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta