Noda D, Itoh S, Watanabe Y, Inamitsu M, Dennler S, Itoh F, Koike S, Danielpour D, ten Dijke P, Kato M
Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Oncogene. 2006 Sep 14;25(41):5591-600. doi: 10.1038/sj.onc.1209571. Epub 2006 Apr 24.
Transforming growth factor-beta (TGF-beta) elicits a potent growth inhibitory effect on many normal cells by binding to specific serine/threonine kinase receptors and activating specific Smad proteins, which regulate the expression of cell cycle genes, including the p21 cyclin-dependent kinase (CDK) inhibitor gene. Interestingly, cancer cells are often insensitive to the anti-mitogenic effects of TGF-beta for which the molecular mechanisms are not well understood. In this study, we found that the candidate prostate cancer susceptibility gene ELAC2 potentiates TGF-beta/Smad-induced transcriptional responses. ELAC2 associates with activated Smad2; the C-terminal MH2 domain of Smad2 interacts with the N-terminal region of ELAC2. Small interfering siRNA-mediated knock-down of ELAC2 in prostate cells suppressed TGF-beta-induced growth arrest. Moreover, ELAC2 was shown to specifically associate with the nuclear Smad2 partner, FAST-1 and to potentiate the interaction of activated Smad2 with transcription factor Sp1. Furthermore, activation of the p21 CDK inhibitor promoter by TGF-beta is potentiated by ELAC2. Taken together our data indicate an important transcriptional scaffold function for ELAC2 in TGF-beta/Smad signaling mediated growth arrest.
转化生长因子-β（TGF-β）通过与特定的丝氨酸/苏氨酸激酶受体结合并激活特定的Smad蛋白，从而对许多正常细胞产生强大的生长抑制作用，这些Smad蛋白可调节细胞周期基因的表达，包括p21细胞周期蛋白依赖性激酶（CDK）抑制基因。有趣的是，癌细胞通常对TGF-β的抗有丝分裂作用不敏感，其分子机制尚不清楚。在本研究中，我们发现候选前列腺癌易感基因ELAC2可增强TGF-β/Smad诱导的转录反应。ELAC2与激活的Smad2相关联；Smad2的C末端MH2结构域与ELAC2的N末端区域相互作用。前列腺细胞中通过小干扰RNA介导的ELAC2敲低抑制了TGF-β诱导的生长停滞。此外，ELAC2被证明与核Smad2伴侣FAST-1特异性相关，并增强激活的Smad2与转录因子Sp1的相互作用。此外，ELAC2增强了TGF-β对p21 CDK抑制基因启动子的激活作用。综上所述，我们的数据表明ELAC2在TGF-β/Smad信号介导的生长停滞中具有重要的转录支架功能。
