Transforming growth factor-β inhibits adipocyte differentiation by Smad3 interacting with CCAAT/enhancer-binding protein (C/EBP) and repressing C/EBP transactivation function
Transforming growth factor-β inhibits adipocyte differentiation by Smad3 interacting with CCAAT/enhancer-binding protein (C/EBP) and repressing C/EBP transactivation function
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DOI：
10.1074/jbc.m212259200
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发表时间：
2003-03-14
影响因子：
4.8
通讯作者：
Derynck, R
中科院分区：
文献类型：
--
作者：
Choy, L;Derynck, R
转化生长因子(TGF)- β是一种有效的脂肪细胞分化抑制剂。为了确定哪些脂肪细胞转录因子可能被tgf - β靶向，我们在NIH3T3细胞中过表达关键的脂肪生成转录因子，C/EBPbeta， C/EBPdelta或过氧化物酶体增殖物激活受体(PPAR) γ，并测试tgf - β阻断脂肪生成的能力。我们发现tgf - β抑制由C/EBPbeta或C/EBPdelta驱动的脂肪细胞分化，而不影响C/EBP蛋白表达水平，这表明这些C/EBP是tgf - β作用的直接靶点。由于tgf - β通过信号传导Smad3抑制脂肪形成，我们研究了Smad3和Smad4与C/EBPbeta、C/EBPdelta和PPARgamma2之间的物理和功能相互作用。发现C/EBPbeta和C/EBPdelta与Smad3和Smad4存在物理相互作用，Smad3与Smad4和tgf - β信号共同抑制C/ ebp的转录活性。因此，Smad3/4在C/EBP结合位点抑制C/EBP活性抑制了PPARgamma2和瘦素启动子的转录。相比之下，PPARgamma与Smad3的相互作用非常弱，其转录活性不受Smad3/4或tgf - β的抑制。Smad3/4并没有降低C/EBP与其同源DNA序列的结合能力，而是通过抑制C/EBP的反激活功能来抑制转录。
Transforming growth factor (TGF)-beta is a potent inhibitor of adipocyte differentiation. To identify which adipocyte transcription factors might be targeted by TGF-beta, we overexpressed key adipogenic transcription factors, C/EBPbeta, C/EBPdelta, or peroxisome proliferator-activated receptor (PPAR) gamma in NIH3T3 cells and tested the ability of TGF-beta to block adipogenesis. We show that TGF-beta inhibits adipocyte differentiation driven by either C/EBPbeta or C/EBPdelta without affecting C/EBP protein expression levels, suggesting that these C/EBPs are a direct target of TGF-beta action. Because TGF-beta inhibits adipogenesis by signaling through Smad3, we examined physical and functional interactions of Smad3 and Smad4 with C/EBPbeta, C/EBPdelta, and PPARgamma2. C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs. Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPARgamma2 and leptin promoters. In contrast, PPARgamma interacted only very weakly with Smad3 and its transcriptional activity was not repressed by Smad3/4 or in response to TGF-beta. Smad3/4 did not reduce the ability of C/EBP to bind to its cognate DNA sequence, but repressed transcription by inhibiting the transactivation function of C/EBP.