Welcker M, Lukas J, Strauss M, Bartek J
Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
Cancer Res. 1998 Nov 15;58(22):5053-6.
The cyclin-dependent kinase (CDK) inhibitor p21WAF1/CIP1 is a multidomain, multifunctional protein and a candidate tumor suppressor. Here, we show that, among rationally designed and tumor-associated mutants of human p21 ectopically expressed in U-2-OS cells, those that are selectively deficient in binding to either cyclin or CDK are partially impaired in inhibiting endogenous CDK activities but efficiently promote assembly of active cyclin D/CDK4(6) complexes. These results provide mechanistic insights into the p21-cyclin/CDK interplay in vivo and suggest a functional subclassification of tumor-specific aberrations of p21. Intriguingly, the subclass exemplified by the melanoma-derived N50S mutant may promote tumorigenesis, by both attenuating CDK-inhibitory function and concomitantly activating the proto-oncogenic cyclin D-dependent kinases.
细胞周期蛋白依赖性激酶（CDK）抑制剂p21WAF1/CIP1是一种多结构域、多功能蛋白，也是一种候选肿瘤抑制因子。在此，我们表明，在U-2-OS细胞中异位表达的人p21的合理设计且与肿瘤相关的突变体中，那些选择性缺乏与细胞周期蛋白或CDK结合能力的突变体在抑制内源性CDK活性方面部分受损，但能有效促进活性细胞周期蛋白D/CDK4（6）复合物的组装。这些结果为体内p21-细胞周期蛋白/CDK相互作用提供了机制性见解，并提示了p21肿瘤特异性异常的功能亚分类。有趣的是，以黑色素瘤来源的N50S突变体为例的亚类可能通过减弱CDK抑制功能并同时激活原癌基因细胞周期蛋白D依赖性激酶来促进肿瘤发生。
