Mutated p21WAF1/CIP1/SDI1 lacking CDK-inhibitory activity fails to prevent apoptosis in human colorectal carcinoma cells
Mutated p21WAF1/CIP1/SDI1 lacking CDK-inhibitory activity fails to prevent apoptosis in human colorectal carcinoma cells
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DOI：
10.1038/sj.onc.1201585
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发表时间：
1998-02-12
期刊：
影响因子：
8
通讯作者：
Takebe, H
中科院分区：
文献类型：
--
作者：
Lu, YJ;Yamagishi, N;Takebe, H
建立了人结直肠肿瘤细胞系，其在 IPTG 处理 (LacSwitch) 下表达野生型 p21 或在密码子 46 (Cys) 或 140 (Gly) 处有突变的 p21。 IPTG诱导的windtype p21与CDK2和PCNA结合，抑制细胞内CDK活性，降低细胞生长速度；然而，两种IPTG诱导的突变p21蛋白既不与CDK2结合也不影响CDK活性，但与PCNA结合，并且不影响细胞生长速率，野生型p21抑制细胞凋亡并增强X射线照射或阿霉素处理的细胞的存活率；但是，突变的 p21 既不抑制细胞凋亡，也不影响细胞存活。当用含羞草（一种不依赖于 p53 的 p21 诱导剂）或丁内酯 I（一种 CDK 特异性抑制剂）处理细胞时，细胞内源性 p21 被诱导，并且 X 射线或阿霉素诱导的细胞凋亡被阻断。这些结果表明，需要 p21 的 CDK 结合或 CDK 抑制活性来防止细胞凋亡，即需要 CDK用于人类肿瘤细胞的凋亡。
Human colorectal tumor cell lines were established which express wildtype p21 or p21 with a mutation at codon 46 (Cys) or 140 (Gly) on IPTG treatment (LacSwitch). The IPTG-induced windtype p21 bound to CDK2 and PCNA and inhibited CDK activity in the cells and reduced cell growth rate; whereas, both IPTG-induced mutated p21 proteins neither bound to CDK2 nor affected the CDK activity but did bind to PCNA, and they did not affect the cell growth rate, Wildtype p21 suppressed apoptosis and enhanced survival of X-ray-irradiated or adriamycin-treated cells; but, mutated p21 neither suppressed apoptosis nor affected cell survival, When cells were treated with mimosine, a p53-independent p21-inducer, or butyrolactone I, a specific inhibitor of CDK, cellular endogenous p21 was induced and X-ray or adriamycin-induced apoptosis was blocked, These results suggest that CDK-binding or CDK-inhibitory activity of p21 is required to prevent apoptosis, i.,e.,, CDK is required for apoptosis in human tumor cells.