Hes1 directly controls cell proliferation through the transcriptional repression of p27Kip1
Hes1 directly controls cell proliferation through the transcriptional repression of p27Kip1
复制标题
DOI：
10.1128/mcb.25.10.4262-4271.2005
复制
发表时间：
2005-05-01
影响因子：
5.3
通讯作者：
Minato, N
中科院分区：
文献类型：
--
作者：
Murata, K;Hattori, M;Minato, N
转录调节因子Hes1在发育过程中对神经元、内分泌和T淋巴细胞祖细胞的分化和增殖起着至关重要的作用。然而，Hes1调控细胞增殖的机制仍有待验证。在胚胎癌细胞中，内源性Hes1表达被视黄酸抑制，与增强的p27（Kip1）表达和细胞周期阻滞一致。相反，条件表达的一个温和的，但不是最大水平的Hes1在HeLa细胞中的四环素诱导系统导致p27（Kip1）的表达减少，这是由于减少基础转录，而不是增强蛋白酶体降解，伴随着增长率和饱和密度的增加。Hes（1）诱导抑制了p27（Kip 1）基因5'侧翼基础增强子区的启动子活性，其方式依赖于Hes 1表达水平，这是通过其与启动子区中的C类位点的结合介导的。最后，发育不良的胎儿胸腺，以及肝脏和大脑的Hes1缺陷小鼠，显示出显着增加p27（Kip1）的转录与对照组相比。这些结果表明，Hes1直接有助于促进祖细胞增殖，通过转录抑制细胞周期蛋白依赖性激酶抑制剂，p27（Kip1）。
A transcriptional regulator, Hes1, plays crucial roles in the control of differentiation and proliferation of neuronal, endocrine, and T-lymphocyte progenitors during development. Mechanisms for the regulation of cell proliferation by Hes1, however, remain to be verified. In embryonic carcinoma cells, endogenous Hes1 expression was repressed by retinoic acid in concord with enhanced p27(Kip1) expression and cell cycle arrest. Conversely, conditional expression of a moderate but not maximal level of Hes1 in HeLa cells by a tetracycline-inducible system resulted in reduced p27(Kip1) expression, which was attributed to decreased basal transcript rather than enhanced proteasomal degradation, with concomitant increases in the growth rate and saturation density. Hes(1) induction repressed the promoter activity of a 5' flanking basal enhancer region of p27(Kip1) gene in a manner dependent on Hesl expression levels, and this was mediated by its binding to class C sites in the promoter region. Finally, hypoplastic fetal thymi, as well as livers and brains of Hes1-deficient mice, showed significantly increased p27(Kip1) transcripts compared with those of control littermates. These results have suggested that Hes1 directly contributes to the promotion of progenitor cell proliferation through transcriptional repression of a cyclin-dependent kinase inhibitor, p27(Kip1).