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Molecular and Cellular Biology, March 2002, p. 1626-1638, Vol. 22, No. 6
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.6.1626-1638.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Competitive Cofactor Recruitment by Orphan Receptor Hepatocyte Nuclear Factor 4{alpha}1: Modulation by the F Domain

Michael D. Ruse, Jr.,1 Martin L. Privalsky,2 and Frances M. Sladek3*

Biochemistry and Molecular Biology Graduate Program,1 Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521,3 Section of Microbiology, Division of Biological Sciences, University of California, Davis, California 956162

Received 14 June 2001/ Returned for modification 20 July 2001/ Accepted 21 December 2001

For most ligand-dependent nuclear receptors, the status of endogenous ligand modulates the relative affinities for corepressor and coactivator complexes. It is less clear what parameters modulate the switch between corepressor and coactivator for the orphan receptors. Our previous work demonstrated that hepatocyte nuclear factor 4{alpha}1 (HNF4{alpha}1, NR2A1) interacts with the p160 coactivator GRIP1 and the cointegrators CBP and p300 in the absence of exogenously added ligand and that removal of the F domain enhances these interactions. Here, we utilized transient-transfection analysis to demonstrate repression of HNF4{alpha}1 activity by the corepressor silencing mediator of retinoid and thyroid receptors (SMRT) in several cell lines and on several HNF4{alpha}-responsive promoter elements. Glutathione S-transferase pulldown assays confirmed a direct interaction between HNF4{alpha}1 and receptor interaction domain 2 of SMRT. Loss of the F domain resulted in marked reduction of the ability of SMRT to interact with HNF4{alpha}1 in vitro and repress HNF4{alpha}1 activity in vivo, although the isolated F domain itself failed to interact with SMRT. Surprisingly, loss of both the A/B and F domains restored full repression by SMRT, suggesting involvement of both domains in the SMRT interaction. Finally, we show that when coexpressed along with HNF4{alpha}1 and GRIP1, CBP, or p300, SMRT can titer out HNF4{alpha}1-mediated transactivation in a dose-dependent manner and that this competition derives from mutually exclusive binding. Collectively, these results suggest that HNF4{alpha} can functionally interact with both a coactivator and a corepressor without altering the status of any putative ligand and that the presence of the F domain may play a role in discriminating between the different coregulators.

* Corresponding author. Mailing address: Department of Cell Biology and Neuroscience, 5429 Boyce Hall, University of California, Riverside, Riverside, CA 92521. Phone: (909) 787-2264. Fax: (909)787-3087. E-mail: frances.sladek{at}ucr.edu.

Molecular and Cellular Biology, March 2002, p. 1626-1638, Vol. 22, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.6.1626-1638.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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