Activation of peroxisome proliferator-activated receptor γ bypasses the function of the retinoblastoma protein in adipocyte differentiation
Activation of peroxisome proliferator-activated receptor γ bypasses the function of the retinoblastoma protein in adipocyte differentiation
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DOI：
10.1074/jbc.274.4.2386
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发表时间：
1999-01-22
影响因子：
4.8
通讯作者：
Kristiansen, K
中科院分区：
文献类型：
--
作者：
Hansen, JB;Petersen, RK;Kristiansen, K
视网膜母细胞瘤蛋白(PRB)是发育、增殖和细胞分化的重要调节因子。最近发现pRb在脂肪细胞分化中起关键作用，与成脂CCAAT/增强子结合蛋白(C/EBPs)相互作用，并通过C/EBPβ正向调节反式激活。我们证明了PPAR-γ介导的反式激活是非依赖于pRb的，并且存在于Rb+/+和Rb-/-小鼠胚胎成纤维细胞中的PPAR-γ1通过配体诱导的反式激活足以绕过由于缺乏pRb而引起的分化障碍。分化的RB-/-细胞积累脂肪并表达脂肪细胞标志物，包括C/EBPα和PPARγ2。有趣的是，在没有其他PRB家族成员p107和p130代偿性上调的情况下，pRb缺陷细胞的脂肪转化发生。RB+/+以及RB-/-细胞有效地退出。成脂诱导剂刺激后完成克隆扩增后的细胞周期。我们的结论是，配体诱导小鼠胚胎成纤维细胞内源性PPARγ1的激活足以启动转录级联反应，导致PPARγ2和C/EBPα的表达诱导，退出细胞周期，并在缺乏功能性pRB的情况下发生终末分化。
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/EBP beta. We show that PPAR gamma-mediated transactivation is pRB-independent, and that ligand-induced transactivation by PPAR gamma 1 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/EBP alpha and PPAR gamma 2, 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 PPAR gamma 1 in mouse embryo fibroblasts is sufficient to initiate a transcriptional cascade resulting in induction of PPAR gamma 2 and C/EBP alpha expression, withdrawal from the cell cycle, and terminal differentiation in the absence of a functional pRB.