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.
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.
Gupta
Pawan
P
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Park
Sung Wook
SW
Farooqui
Mariya
M
Wei
L-N
LN
D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D051958:Nuclear Receptor Coactivator 2 / Q000737:chemistry / Q000378:metabolism; D000078723:Nuclear Receptor Interacting Protein 1; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; D000078723:Nuclear Receptor Interacting Protein 1; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D014157:Transcription Factors; D014212:Tretinoin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C539823:Nr2c1 protein, mouse