Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-β-mediated induction of the CDK inhibitor p15Ink4B
Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-β-mediated induction of the CDK inhibitor p15Ink4B
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DOI：
10.1016/s1097-2765(01)00430-0
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发表时间：
2002-01-01
期刊：
影响因子：
16
通讯作者：
Lin, X
中科院分区：
文献类型：
--
作者：
Feng, XH;Liang, YY;Lin, X
c-Myc癌基因与多种人类肿瘤的发生有关。培养的上皮细胞中c-Myc基因的异位表达导致对tgf - β的抗增殖作用产生抗性。然而，对c- myc介导的tgf - β耐药的确切机制知之甚少。在这项研究中，我们揭示了c-Myc与Smad2和Smad3这两个参与tgf - β信号传导的特定信号转导相互作用。通过与Smads的直接相互作用，c-Myc与p15（Ink4B）基因启动子上的Sp1-Smad复合物结合，从而抑制tgf - β诱导的Sp1转录活性和p15（Ink4B）基因的Smad/Sp1依赖性转录。这些结果表明，致癌基因c-Myc部分通过抑制Smads的生长抑制功能来促进细胞生长和癌症发展。
The c-Myc oncogene has been implicated in the genesis of diverse human tumors. Ectopic expression of the c-Myc gene in cultured epithelial cells causes resistance to the antiproliferative effects of TGF-beta. However, little is known about the precise mechanisms of c-Myc-mediated TGF-beta resistance. In this study, we reveal that c-Myc physically interacts with Smad2 and Smad3, two specific signal transducers involved in TGF-beta signaling. Through its direct interaction with Smads, c-Myc binds to the Sp1-Smad complex on the promoter of the p15(Ink4B) gene, thereby inhibiting the TGF-beta-induced transcriptional activity of Sp1 and Smad/Sp1-dependent transcription of the p15(Ink4B) gene. These results suggest that oncogenic c-Myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of Smads.