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Polyamines Modulate the Interaction between Nuclear Receptors and Vitamin D Receptor-Interacting Protein 205

Environmental Toxicology Graduate Program (Y.M.), Departments of Cell Biology and Neuroscience (F.M.S.) and Biomedical Sciences (L.H., C.V.B.), University of California, Riverside, California 92521; and Cell Biology Program (C.R., L.P.F.), Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Address all correspondence and requests for reprints to: Frances M. Sladek, Ph.D., Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, California 92521. E-mail: frances.sladek{at}ucr.edu.

Nuclear receptors (NR) activate transcription by interacting with several different coactivator complexes, primarily via LXXLL motifs (NR boxes) of the coactivator that bind a common region in the ligand binding domain of nuclear receptors (activation function-2, AF–2) in a ligand-dependent fashion. However, how nuclear receptors distinguish between different sets of coactivators remains a mystery, as does the mechanism by which orphan receptors such as hepatocyte nuclear factor 4 (HNF4) activate transcription. In this study, we show that HNF4 interacts with a complex containing vitamin D receptor (VDR)-interacting proteins (DRIPs) in the absence of exogenously added ligand. However, whereas a full-length DRIP205 construct enhanced the activation by HNF4 in vivo, it did not interact well with the HNF4 ligand binding domain in vitro. In investigating this discrepancy, we found that the polyamine spermine significantly enhanced the interaction between HNF4 and full-length DRIP205 in an AF-2, NR-box-dependent manner. Spermine also enhanced the interaction of DRIP205 with the VDR even in the presence of its ligand, but decreased the interaction of both HNF4 and VDR with the p160 coactivator glucocorticoid receptor interacting protein 1 (GR1P1). We also found that GR1P1 and DRIP205 synergistically activated HNF4-mediated transcription and that a specific inhibitor of polyamine biosynthesis, -difluoromethylornithine (DFMO), decreased the ability of HNF4 to activate transcription in vivo. These results lead us to propose a model in which polyamines may facilitate the switch between different coactivator complexes binding to NRs.

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