Transcriptional activation by hepatocyte nuclear factor-1 requires synergism between multiple coactivator proteins.
Hepatocyte nuclear factor-1 (HNF-1) plays an important role in the regulation of a large number of genes expressed in the liver, kidney, and pancreatic beta-cells. In exploring the molecular mechanism involved in HNF-1-dependent gene activation in the in vivo chromatin context, we found that HNF-1 can physically interact with the histone acetyltransferases (HATs) CREB-binding protein (CBP), p300/CBP-associated factor (P/CAF), Src-1, and RAC3. The transcriptional activation potential of HNF-1 on a genome integrated promoter was strictly dependent on the synergistic action of CBP and P/CAF, which can independently interact with the N-terminal and C-terminal domain of HNF-1, respectively. Moreover, the HAT activity of both coactivators was important, as opposed to the selective requirement for the HAT activity of P/CAF in activation from a transiently transfected reporter. Interaction of CBP with the N-terminal domain of HNF-1 greatly increased the binding affinity for P/CAF with the C-terminal activation domain, which may represent the molecular basis for the observed functional synergism. The results support a model that involves the combined action of multiple coactivators recruited by HNF-1, which activate transcription by coupling nucleosome modification and recruitment of the general transcription machinery.
Soutoglou
E
E
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, 711 10 Herakleion Crete, Greece.
Papafotiou
G
G
Katrakili
N
N
Talianidis
I
I
D016475:3T3 Cells; D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051548:Histone Acetyltransferases; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D010957:Plasmids; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051548:Histone Acetyltransferases; D009687:Nuclear Proteins; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; C494364:Crebbp protein, mouse; C538861:Ncoa1 protein, mouse