Orphan nuclear receptor TR2, a mediator of preadipocyte proliferation, is differentially regulated by RA through exchange of coactivator PCAF with corepressor RIP140 on a platform molecule GRIP1.

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Orphan nuclear receptor TR2 is a preadipocyte proliferator. Knockdown of TR2 in 3T3-L1 preadipocytes reduced their proliferation efficiency, whereas specific elevation of TR2 in these cells facilitated their proliferation. All-trans retinoic acid (RA) stimulates cellular proliferation in 3T3-L1 preadipocytes by activating TR2 through an IR0-type RA response element, which further activates c-Myc expression. In post-differentiated adipocytes, RA becomes a repressive signal for TR2 and rapidly down-regulates its expression. The biphasic effect of RA on TR2 expression in 3T3-L1 is mediated by differential RA-dependent coregulator recruitment to the receptor/Glucocorticoid Receptor-Interacting Protein 1 (GRIP1) complex that binds IR0 on the TR2 promoter. RA induces the recruitment of histone acetyl transferase-containing/GRIP1/p300/CBP-associated factor (PCAF) complex to the TR2 promoter in undifferentiated cells, whereas it triggers recruitment of histone deacetylase-containing/GRIP1/receptor-interacting protein 140 (RIP140) complex in differentiated cells. GRIP1 directly interacts with RIP140 through its carboxyl terminal AD2 domain. GRIP1 interacts with PCAF and RIP140 directly and differentially, functioning as a platform molecule to mediate differential RA-induced coregulator recruitment to TR2 promoter target. This results in a biphasic effect of RA on the expression of TR2 in undifferentiated and differentiated cells, which is required for RA-stimulated preadipocyte proliferation.
Mesh Terms:
3T3-L1 Cells, Adaptor Proteins, Signal Transducing, Adipocytes, Animals, Binding Sites, Cell Cycle Proteins, Cell Differentiation, Cell Proliferation, Histone Acetyltransferases, Mice, Nuclear Proteins, Nuclear Receptor Coactivator 2, Nuclear Receptor Subfamily 2, Group C, Member 1, Promoter Regions, Genetic, Protein Structure, Tertiary, Receptors, Thyroid Hormone, Repressor Proteins, Stem Cells, Transcription Factors, Tretinoin, p300-CBP Transcription Factors
Nucleic Acids Res. Mar. 29, 2007; 35(7);2269-82 [PUBMED:17389641]
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