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Cell proliferation control mediated by reguktion of cdk inhibitor p27^<kip1>

cdk 抑制剂 p27^<kip1> 调节介导的细胞增殖控制

基本信息

批准号：
08458231
负责人：
KATO Jun-ya
金额：
$ 5.5万
依托单位：
Nara Institute of Science and Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08458231/
关键词：
Cyclin Cdk Cdk inhibitor Cell Cycle

项目摘要

The cyclin-dependent kinase inhibitor p27^<Kip1> plays an essential role in control of mammalian cell proliferation both in vitro and in vivo. Although p27^<Kip1> mutations are rare in human tumors, reduced expression of the protein correlates well with poor survival among breast and colorectal carcinoma patients, suggesting that disturbance of p27^<Kip1> regulatory mechanisms contributes to neoplasia. Cellular abundance of p27^<Kip1> is controlled translationally or by multiple posttranslational mechanisms including phosphorylation by cyclin E/cdk2 complexes, degradation by the ubiquitin/proteasome pathway, and sequestration by unknown Myc-inducible proteins, cyclin D/cdk4 complexes, or the viral ElA oncoprotein. Here we show that a mouse 38kDa protein encoded by the Jab1 genephysically and specifically interacted with p27^<Kip1>. We demonstrate that overexpression of p38 in mammalian cells specifically translocated p2^<Kip1> from the nucleus to the cytoplasm in a proteasome-dependent manner, and decreased intracellular levels of p27^<Kip1> protein by accelerating its degradation. Furthermore, ectopic p38 expression in mouse fibroblasts partially overcame p27^<Kip1>-mediated Gi arrest, and markedly reduced their serum dependency. Our findings suggest that p38 functions as a negative regulator of p27^<Kip1> by targeting it for degradation.

细胞周期蛋白依赖性激酶抑制剂p27^<Kip1>在体外和体内控制哺乳动物细胞增殖中起重要作用。尽管p27^<Kip1>突变在人类肿瘤中很少见，但该蛋白的表达降低与乳腺癌和结直肠癌患者的低生存率密切相关，这表明p27^<Kip1>调节机制的紊乱有助于肿瘤的发生。p27^<Kip1>的细胞丰度是通过翻译或多种翻译后机制控制的，包括细胞周期蛋白E/cdk2复合物的磷酸化、泛素/蛋白酶体途径的降解、未知的myc诱导蛋白、细胞周期蛋白D/cdk4复合物或病毒ElA癌蛋白的隔离。在这里，我们证明了由Jab1编码的小鼠38kDa蛋白与p27^<Kip1>的遗传物理和特异性相互作用。我们证明，哺乳动物细胞中p38的过表达以蛋白酶体依赖的方式特异性地将p2^<Kip1>从细胞核转移到细胞质，并通过加速其降解来降低细胞内p27^<Kip1>蛋白的水平。此外，小鼠成纤维细胞中的异位p38表达部分克服了p27^<Kip1>介导的Gi停滞，并显着降低了它们的血清依赖性。我们的研究结果表明，p38作为p27^<Kip1>的负调节因子，通过靶向p27^<Kip1>降解。