Feng Xin-Hua, Liang Yao-Yun, Liang Min, Zhai Weiguo, Lin Xia
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Mol Cell. 2002 Jan;9(1):133-43. doi: 10.1016/s1097-2765(01)00430-0.
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.
c-Myc癌基因与多种人类肿瘤的发生有关。c-Myc基因在培养的上皮细胞中的异位表达导致对TGF-β抗增殖作用的抗性。然而，关于c-Myc介导的TGF-β抗性的确切机制知之甚少。在本研究中，我们发现c-Myc与Smad2和Smad3发生物理相互作用，这是参与TGF-β信号传导的两个特定信号转导分子。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转录活性以及p15(Ink4B)基因的Smad/Sp1依赖性转录。这些结果表明，致癌性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。
