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Molecular and Cellular Biology, October 1999, p. 6509-6522, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Modulation of Transcriptional Activation and Coactivator Interaction by a Splicing Variation in the F Domain of Nuclear Receptor Hepatocyte Nuclear Factor 4alpha 1

Frances M. Sladek,1,* Michael D. Ruse Jr.,2 Luviminda Nepomuceno,1 Shih-Ming Huang,3 and Michael R. Stallcup3

Environmental Toxicology1 and Biochemistry2 Graduate Programs, University of California, Riverside, California 92521, and Departments of Pathology and of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 900333

Received 24 November 1998/Returned for modification 22 January 1999/Accepted 25 June 1999

Transcription factors, such as nuclear receptors, often exist in various forms that are generated by highly conserved splicing events. Whereas the functional significance of these splicing variants is often not known, it is known that nuclear receptors activate transcription through interaction with coactivators. The parameters, other than ligands, that might modulate those interactions, however, are not well characterized, nor is the role of splicing variants. In this study, transient transfection, yeast two-hybrid, and GST pulldown assays are used to show not only that nuclear receptor hepatocyte nuclear factor 4 alpha 1 (HNF4alpha 1, NR2A1) interacts with GRIP1, and other coactivators, in the absence of ligand but also that the uncommonly large F domain in the C terminus of the receptor inhibits that interaction. In vitro, the F domain was found to obscure an AF-2-independent binding site for GRIP1 that did not map to nuclear receptor boxes II or III. The results also show that a natural splicing variant containing a 10-amino-acid insert in the middle of the F domain (HNF4alpha 2) abrogates that inhibition in vivo and in vitro. A series of protease digestion assays indicates that there may be structural differences between HNF4alpha 1 and HNF4alpha 2 in the F domain as well as in the ligand binding domain (LBD). The data also suggest that there is a direct physical contact between the F domain and the LBD of HNF4alpha 1 and -alpha 2 and that that contact is different in the HNF4alpha 1 and HNF4alpha 2 isoforms. Finally, we propose a model in which the F domain of HNF4alpha 1 acts as a negative regulatory region for transactivation and in which the alpha 2 insert ameliorates the negative effect of the F domain. A conserved repressor sequence in the F domains of HNF4alpha 1 and -alpha 2 suggests that this model may be relevant to other nuclear receptors as well.

* Corresponding author. Mailing address: Environmental Toxicology Graduate Program, 5419 Boyce Hall, University of California, Riverside, CA 92521. Phone: (909) 787-2264. Fax: (909) 787-3087. E-mail: frances.sladek{at}ucr.edu.

Molecular and Cellular Biology, October 1999, p. 6509-6522, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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