INHIBITION OF ADIPOGENESIS BY THE STRESS-INDUCED PROTEIN CHOP (GADD153)
INHIBITION OF ADIPOGENESIS BY THE STRESS-INDUCED PROTEIN CHOP (GADD153)
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DOI：
10.1002/j.1460-2075.1995.tb00147.x
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发表时间：
1995-10-02
期刊：
影响因子：
11.4
通讯作者：
RON, D
中科院分区：
文献类型：
--
作者：
BATCHVAROVA, N;WANG, XZ;RON, D
3 T3-L1细胞的脂肪细胞转化依赖于来自C/EBP家族的转录因子的诱导，所述转录因子激活脂肪形成基因的启动子。我们发现，CHOP（一种与C/EBP同种型α和β强烈二聚化并指导所得异源二聚体远离经典C/EBP结合位点的核蛋白）的表达显著抑制该分化过程。在分化过程早期CHOP的存在抑制C/EBP α和β基因表达。C/EBP α的异位表达绕过了CHOP对分化的抑制作用，进一步证明CHOP作用是通过抑制C/EBP α基因表达介导的，而不仅仅是抑制编码蛋白的DNA结合活性。在低葡萄糖浓度培养基中诱导分化的细胞中也观察到C/EBP α和β表达减弱的类似模式。这种应激培养条件与内源性CHOP的诱导和分化过程的显著减弱有关。我们的数据表明，CHOP功能作为一种诱导型抑制剂的脂肪细胞分化的代谢应激反应。它通过干扰成脂C/EBP亚型的积累来实现这一目的。
Adipocytic conversion of 3T3-L1 cells is dependent on induction of transcription factors from the C/EBP family that activate promoters of adipogenic genes, We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process, Surprisingly, the presence of CHOP early in the differentiation process inhibits C/EBP alpha and beta gene expression. Ectopic expression of C/EBP alpha bypasses the inhibitory effect of CHOP on differentiation, providing further evidence that CHOP action is mediated by inhibition of C/EBP alpha gene expression rather than merely inhibiting the encoded protein's DNA-binding activity. A similar pattern of attenuated expression of C/EBP alpha and beta is also observed in cells induced to differentiate in media with low glucose concentration. This stressed culture condition is associated with induction of endogenous CHOP and marked attenuation of the differentiation process. Our data suggest that CHOP functions as an inducible inhibitor of adipocytic differentiation in response to metabolic stress. It does so by interfering with the accumulation of adipogenic C/EBP isoforms.