ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-β/Smad-induced growth arrest of prostate cells
ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-β/Smad-induced growth arrest of prostate cells
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DOI：
10.1038/sj.onc.1209571
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发表时间：
2006-09-14
期刊：
影响因子：
8
通讯作者：
Kato, M.
中科院分区：
文献类型：
--
作者：
Noda, D.;Itoh, S.;Kato, M.
转化生长因子-β（TGF-β）通过与特异性丝氨酸/苏氨酸激酶受体结合并激活特异性Smad蛋白而对许多正常细胞发挥有效的生长抑制作用，所述Smad蛋白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）抑制剂基因。有趣的是，癌细胞通常对TGF-β的抗促有丝分裂作用不敏感，其分子机制尚不清楚。在这项研究中，我们发现候选前列腺癌易感基因ELAC 2增强TGF-β/Smad诱导的转录反应。ELAC 2与活化的Smad 2结合; Smad 2的C-末端MH 2结构域与ELAC 2的N-末端区域相互作用。小干扰siRNA介导的前列腺细胞ELAC 2敲低抑制TGF-β诱导的生长停滞此外，ELAC 2被证明是专门与核Smad 2的合作伙伴，FAST-1，并加强激活的Smad 2与转录因子Sp1的相互作用。此外，TGF-β对p21 CDK抑制剂启动子的激活被ELAC 2增强。综上所述，我们的数据表明ELAC 2在TGF-β/Smad信号传导介导的生长停滞中具有重要的转录支架功能。
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.