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A more recent version of this article appeared on March 1, 2003
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Submitted on July 1, 2002
Revised on November 12, 2002
Accepted on November 25, 2002
-regulated Smad3 and Smad4 proteins and the orphan nuclear receptor HNF-4
1 Department of Basic Sciences, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology of Hellas, Heraklion GR-71110, Greece
2 Ludwig Institute for Cancer Research, Box 595, S-751 24 Uppsala, Sweden
3 Department of Biology, Section of Genetics, Development and Molecular Biology, Aristotelian University of Thessaloniki, Thessaloniki GR-54006, Greece
* Corresponding author. E-mail address: kardasis{at}imbb.forth.gr.
We have shown previously that the TGF
-regulated Smad3 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 MH1 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 -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 co-activation by Smads. The findings suggest that the transcriptional cross talk between the TGF-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 TGF?and the Smads.
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