Activation of peroxisome proliferator-activated receptor γ bypasses the function of the retinoblastoma protein in adipocyte differentiation

Abstract

The retinoblastoma protein (pRB) is an important regulator of development, proliferation, and cellular differentiation, pRB was recently shown to play a pivotal role in adipocyte differentiation, to interact physically with adipogenic CCAAT/enhancer-binding proteins (C/EBPs), and to positively regulate transactivation by C/EBPβ. We show that PPARγ-mediated transactivation is pRB-independent, and that ligand-induced transactivation by PPARγ1 present in RB(+/+) and RB(-/-) mouse embryo fibroblasts is sufficient to bypass the differentiation block imposed by the absence of pRB. The differentiated RB(-/-) cells accumulate lipid and express adipocyte markers, including C/EBPα and PPARγ2. Interestingly, adipose conversion of pRB-deficient cells occurs in the absence of compensatory up-regulations of the other pRB family members p107 and p130. RB(+/+) as well as RB(-/-) cells efficiently exit from the cell cycle after completion of clonal expansion following stimulation with adipogenic inducers. We conclude that ligand- induced activation of endogenous PPARγ1 in mouse embryo fibroblasts is sufficient to initiate a transcriptional cascade resulting in induction of PPARγ2 and C/EBPα expression, withdrawal from the cell cycle, and terminal differentiation in the absence of a functional pRB.