Transcriptional Regulation of Cytochrome P450 Genes by the Nuclear Receptor Hepatocyte Nuclear Factor 4-Alpha

2009 ◽  
Vol 10 (5) ◽  
pp. 508-519 ◽  
Author(s):  
Ramiro Jover ◽  
Marta Moya ◽  
M. Gomez-Lechon
Keyword(s):  
Transcriptional Regulation ◽  
Cytochrome P450 ◽  
Nuclear Receptor ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Cytochrome P450 Genes ◽  
Hepatocyte Nuclear Factor 4

scholarly journals Mechanism of a Transcriptional Cross Talk between Transforming Growth Factor-β–regulated Smad3 and Smad4 Proteins and Orphan Nuclear Receptor Hepatocyte Nuclear Factor-4

2003 ◽  
Vol 14 (3) ◽  
pp. 1279-1294 ◽  
Author(s):  
Wan-Chih Chou ◽  
Vassiliki Prokova ◽  
Keiko Shiraishi ◽  
Ulrich Valcourt ◽  
Aristidis Moustakas ◽  
...  
Keyword(s):  
Growth Factor ◽  
Nuclear Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor ◽  
Dna Binding Domain ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4 ◽  
Target Promoters

We have shown previously that the transforming growth factor-β (TGFβ)-regulated Sma-Mad (Smad) protein 3 and Smad4 proteins transactivate the apolipoprotein C-III promoter in hepatic cells via a hormone response element that binds the nuclear receptor hepatocyte nuclear factor 4 (HNF-4). In the present study, we show that Smad3 and Smad4 but not Smad2 physically interact with HNF-4 via their Mad homology 1 domains both in vitro and in vivo.The synergistic transactivation of target promoters by Smads and HNF-4 was shown to depend on the specific promoter context and did not require an intact β-hairpin/DNA binding domain of the Smads. Using glutathione S-transferase interaction assays, we established that two regions of HNF-4, the N-terminal activation function 1 (AF-1) domain (aa 1–24) and the C-terminal F domain (aa 388–455) can mediate physical Smad3/HNF-4 interactions in vitro. In vivo, Smad3 and Smad4 proteins enhanced the transactivation function of various GAL4-HNF-4 fusion proteins via the AF-1 and the adjacent DNA binding domain, whereas a single tyrosine to alanine substitution in AF-1 abolished coactivation by Smads. The findings suggest that the transcriptional cross talk between the TGFβ-regulated Smads and HNF-4 is mediated by specific functional domains in the two types of transcription factors. Furthermore, the specificity of this interaction for certain target promoters may play an important role in various hepatocyte functions, which are regulated by TGFβ and the Smads.

scholarly journals Functional Domains of the Nuclear Receptor Hepatocyte Nuclear Factor 4

1997 ◽  
Vol 272 (1) ◽  
pp. 539-550 ◽  
Author(s):  
Margarita Hadzopoulou-Cladaras ◽  
Elena Kistanova ◽  
Catherine Evagelopoulou ◽  
Shengyou Zeng ◽  
Christos Cladaras ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Functional Domains ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4

scholarly journals TRAP/SMCC/Mediator-Dependent Transcriptional Activation from DNA and Chromatin Templates by Orphan Nuclear Receptor Hepatocyte Nuclear Factor 4

2002 ◽  
Vol 22 (15) ◽  
pp. 5626-5637 ◽  
Author(s):  
Sohail Malik ◽  
Annika E. Wallberg ◽  
Yun Kyoung Kang ◽  
Robert G. Roeder
Keyword(s):  
Nuclear Receptor ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Strong Dependence ◽  
Physical Interaction ◽  
Nuclear Factor ◽  
Orphan Nuclear Receptor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4

ABSTRACT The orphan nuclear receptor hepatocyte nuclear factor 4 (HNF-4) regulates the expression of many liver-specific genes both during development and in the adult animal. Towards understanding the molecular mechanisms by which HNF-4 functions, we have established in vitro transcription systems that faithfully recapitulate HNF-4 activity. Here we have focused on the coactivator requirements for HNF-4, especially for the multicomponent TRAP/SMCC/Mediator complex that has emerged as the central regulatory module of the transcription apparatus. Using a system that has been reconstituted from purified transcription factors, as well as one consisting of unfractionated nuclear extract from which TRAP/SMCC/Mediator has been depleted by specific antibodies, we demonstrate a strong dependence of HNF-4 function on this coactivator. Importantly, we further show a TRAP/SMCC/Mediator-dependence for HNF-4 transcriptional activation from chromatin templates. The latter involves cooperation with the histone acetyltransferase-containing coactivator p300, in accord with a synergistic mode of action of the two divergent coactivators. We also show that HNF-4 and TRAP/SMCC/Mediator can interact physically. This interaction likely involves primary HNF-4 activation function 2 (AF-2)-dependent interactions with the TRAP220 subunit of TRAP/SMCC/Mediator and secondary (AF-2-independent) interactions with TRAP170/RGR1. Finally, recruitment experiments using immobilized templates strongly suggest that the functional consequences of the physical interaction probably are manifested at a postrecruitment step in the activation pathway.

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