Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2
Smad3 reduces susceptibility to hepatocarcinoma by sensitizing hepatocytes to apoptosis through downregulation of Bcl-2
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DOI：
10.1016/j.ccr.2006.04.025
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发表时间：
2006-06-01
期刊：
影响因子：
50.3
通讯作者：
Zhang, Ying E.
中科院分区：
文献类型：
--
作者：
Yang, Yu-An;Zhang, Gen-Mu;Zhang, Ying E.
在肝脏中，TGF-β信号的紊乱与肝细胞癌（HCC）的发病率增加有关，但其机制尚不清楚。我们在此报道，在化学诱导的小鼠模型中，一个主要的TGF-β信号转导子Smad 3的强制表达降低了对HCC的易感性。这种保护作用是由Smad 3通过Bcl-2启动子中富含GC的元件抑制体内Bcl-2转录来促进细胞凋亡的能力所赋予的。我们还表明，Smad 3的促凋亡活性需要输入TGF-β信号和激活p38 MAPK，这选择性地发生在肝肿瘤细胞。因此，Smad 3通过充当TGF-β诱导的细胞凋亡的生理介质来实现TGF-β的肿瘤抑制功能。
In the liver, derangement of TGF-beta signaling is associated with an increased incidence of hepatocellular carcinoma (HCC), but the mechanism is not clear. We report here that forced expression of a major TGF-beta signaling transducer, Smad3, reduces susceptibility to HCC in a chemically induced murine model. This protection is conferred by Smad3's ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter. We also show that the proapoptotic activity of Smad3 requires both input from TGF-beta signaling and activation of p38 MAPK, which occurs selectively in the liver tumor cells. Thus, Smad3 enables the tumor suppression function of TGF-beta by serving as a physiological mediator of TGF-beta-induced apoptosis.