Abstract
Nuclear receptor coactivator PRIP (peroxisome proliferators-activated receptor (PPARgamma)-interacting protein) appears to serve as a linker between cAMP response element-binding protein-binding protein (CBP/p300)anchored and PBP (PPARgamma-binding protein)-anchored coactivator complexes involved in the transcriptional activity of nuclear receptors. Disruption of PRIP and PBP genes results in embryonic lethality between embryonic day 11.5 and 12.5 (postcoitum), indicating that PRIP and PBP are essential and nonredundant coactivators. Both PRIP and PBP were initially identified as PPARgamma coactivators, suggesting a role for these molecules in PPARgamma-induced adipogenesis. PBP-/- mouse embryonic fibroblasts fail to exhibit PPARgamma-stimulated adipogenesis indicating that PBP is a downstream regulator of PPARgamma-mediated adipogenesis. We now show that PRIP-/- mouse embryonic fibroblasts are also refractory to PPARgamma-stimulated adipogenesis and fail to express adipogenic marker aP2, a PPARgamma-responsive gene. Chromatin immunoprecipitation assays reveal reduced association in PRIP-/- cells of PIMT (PRIP-binding protein) and PBP with aP2 gene promoter, suggesting that PRIP is required for the linking of CBP/p300-anchored cofactor complex with PBP-anchored mediator complex. These data indicate that PRIP, like PBP, is a downstream regulator of PPARgamma-mediated adipogenesis and that both these coactivators are required for the successful completion of adipogenic program.
Highlights
On Northern blotting, Peroxisome proliferator-activated receptor (PPAR)␥1 mRNA level in PRIPϪ/Ϫ mouse embryonic fibroblasts (MEFs) were at a higher level than that noted in the wild type MEFs showing the differentiated morphology (Fig. 2A)
We have examined the role of nuclear receptor coactivator PRIP in the PPAR␥1-directed adipogenesis using wild type and PRIPϪ/Ϫ MEFs
The refractoriness of PRIPϪ/Ϫ MEFs to PPAR␥-stimulated adipogenesis is similar to that described for PPAR␥-binding protein (PBP)/TRAP220Ϫ/Ϫ MEFs [27], suggesting that both PRIP and PBP play important roles in mediating the adipocyte differentiating effects of PPAR␥
Summary
Chromatin immunoprecipitation assays reveal reduced association in PRIP؊/؊ cells of PIMT (PRIP-binding protein) and PBP with aP2 gene promoter, suggesting that PRIP is required for the linking of CBP/p300-anchored cofactor complex with PBP-anchored mediator complex These data indicate that PRIP, like PBP, is a downstream regulator of PPAR␥-mediated adipogenesis and that both these coactivators are required for the successful completion of adipogenic program. Either sequentially or combinatorially, manifests as a second multiprotein complex, variously referred to as TRAP-DRIP-ARC mediator complex, which facilitates interaction with RNA polymerase II complexes of the basal transcription machinery (10 –12) This second complex, devoid of histone acetyltransferase activity, is anchored by PPAR␥-binding protein (PBP), which was initially cloned as PPAR␥-binding nuclear receptor coactivator [13]. Evidence obtained from gene knock-out studies has established that both PBP and PRIP null mutations lead to embryonic lethality, implying that these coactivators influence the physio-
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