TReP-132 controls cell proliferation by regulating the expression of the cyclin-dependent kinase inhibitors p21WAF1/Cip1 and p27Kip1
TReP-132 controls cell proliferation by regulating the expression of the cyclin-dependent kinase inhibitors p21WAF1/Cip1 and p27Kip1
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DOI：
10.1128/mcb.25.11.4335-4348.2005
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发表时间：
2005-06-01
影响因子：
5.3
通讯作者：
Hum, DW
中科院分区：
文献类型：
--
作者：
Gizard, F;Robillard, R;Hum, DW
132 kDa 的转录调节蛋白 (TReP-132) 已在类固醇生成组织中被发现，它充当类固醇生成因子 1 (SF-1) 的共激活剂。我们在此表明 TReP-132 在细胞增殖的控制中发挥作用。在人 HeLa 细胞中，使用小干扰 RNA 敲低 TReP-132 会导致 G(1)-> S 细胞周期进程加快。 TReP-132 的生长抑制作用进一步被证明是通过 G(1) 细胞周期蛋白依赖性激酶抑制剂 p21(WAF1) (p21) 和 p27(KIP1) (p27) 表达水平的诱导介导的。结果，G(1) 细胞周期蛋白/细胞周期蛋白依赖性激酶活性和 pRB 磷酸化显着降低，细胞周期进程被阻断在 G1 期。 TReP-132 对 p21 和 p27 基因转录的刺激作用涉及 TReP-132 与转录因子 Sp1 在其启动子中近端 Sp1 结合位点的相互作用。此外，在不同的乳腺肿瘤细胞系中，内源性TReP-132表达与较低的增殖率呈正相关。此外，TReP-132 敲低导致类固醇反应性和非反应性 T-47D 和 MDA-MB-231 细胞系中的细胞增殖增强，并分别降低 p21 和 p27 mRNA 水平。最后，人类乳腺肿瘤样本的统计分析强调，TReP-132 的表达与 p21 和 p27 水平相关，并且与较低的肿瘤发生率和侵袭性相关。总之，这些结果表明 TReP-132 是一种基础细胞周期调节蛋白，至少部分通过与 Sp1 相互作用来激活 p21 和 p27 基因启动子。
The transcriptional regulating protein of 132 kDa (TReP-132) has been identified in steroidogenic tissues, where it acts as a coactivator of steroidogenic factor 1 (SF-1). We show here that TReP-132 plays a role in the control of cell proliferation. In human HeLa cells, TReP-132 knockdown by using small interfering RNA resulted in increased G(1)-> S cell cycle progression. The growth-inhibitory effects of TReP-132 was further shown to be mediated by induction of G(1) cyclin-dependent kinase inhibitors p21(WAF1) (p21) and p27(KIP1) (p27) expression levels. As a consequence, G(1) cyclin/cyclin-dependent kinase activities and pRB phosphorylation were markedly reduced, and cell cycle progression was blocked in the G, phase. The stimulatory effect of TReP-132 on p21 and p27 gene transcription involved interaction of TReP-132 with the transcription factor Sp1 at proximal Sp1-binding sites in their promoters. Moreover, in different breast tumor cell lines, endogenous TReP-132 expression was positively related with a lower proliferation rate. In addition, TReP-132 knockdown resulted in enhanced cell proliferation and lowered p21 and p27 mRNA levels in the steroid-responsive and nonresponsive T-47D and MDA-MB-231 cell lines, respectively. Finally, a statistic profiling of human breast tumor samples highlighted that expression of TReP-132 is correlated with p21 and p27 levels and is associated with lower tumor incidence and aggressiveness. Together, these results identify TReP-132 as a basal cell cycle regulatory protein acting, at least in part, by interacting with Sp1 to activate the p21 and p27 gene promoters.