Zhou X, Wang X W, Xu L, Hagiwara K, Nagashima M, Wolkowicz R, Zurer I, Rotter V, Harris C C
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cancer Res. 1999 Feb 15;59(4):843-8.
The tumor suppressor protein p53 contributes to the control of cell cycle checkpoints and stress-induced apoptosis and is frequently mutated in many different types of human cancers. The COOH terminus of p53 modulates the transcriptional and apoptotic activities of the protein. Although COOH-terminal mutants of p53 are uncommon, we proposed that these p53 mutants nevertheless contributed to the selective clonal expansion of the cancer cells. Therefore, we analyzed the tumor-derived p53 COOH-terminal domain (CTD) mutants (352D/H, 356G/W, 342-stop, 360-del, and 387-del) functionally. The results have revealed that all mutants have impaired apoptotic activity when compared with wild-type p53. However, some of these mutants still transcriptionally transactivate p21Waf/Cip1 and inhibit cell growth. Interestingly, of the tumor-derived CTD mutants, oligomerization-defective mutant 342-stop was the only one that did not exhibit sequence-specific DNA binding or failed to transactivate p21Waf1/Cip1, Bax, and IGF-BP3 transcriptionally. The failure to inhibit cell growth by this tumor-derived CTD mutant supports the hypothesis that p53 sequence-specific transcriptional transactivity to p21Waf1/Cip1 is correlated with induction of cell cycle arrest and that the p53 transcriptional transactivity requires oligomerization of the p53 protein. These and other data indicate that the CTD of p53 is an important component of p53-mediated apoptosis and cell growth arrest and that inactivation of the apoptotic function, but not the inhibition of growth, is an important step during human tumorigenesis.
肿瘤抑制蛋白p53有助于控制细胞周期检查点和应激诱导的细胞凋亡，且在许多不同类型的人类癌症中经常发生突变。p53的羧基末端调节该蛋白的转录和凋亡活性。尽管p53的羧基末端突变体并不常见，但我们提出这些p53突变体仍有助于癌细胞的选择性克隆扩增。因此，我们对肿瘤来源的p53羧基末端结构域（CTD）突变体（352D/H、356G/W、342-stop、360-del和387-del）进行了功能分析。结果显示，与野生型p53相比，所有突变体的凋亡活性均受损。然而，其中一些突变体仍能转录激活p21Waf/Cip1并抑制细胞生长。有趣的是，在肿瘤来源的CTD突变体中，寡聚化缺陷突变体342-stop是唯一一个既不表现出序列特异性DNA结合，也不能转录激活p21Waf1/Cip1、Bax和IGF-BP3的突变体。这种肿瘤来源的CTD突变体无法抑制细胞生长，支持了以下假设：p53对p21Waf1/Cip1的序列特异性转录活性与细胞周期停滞的诱导相关，且p53转录活性需要p53蛋白的寡聚化。这些及其他数据表明，p53的CTD是p53介导的细胞凋亡和细胞生长停滞的重要组成部分，且凋亡功能的失活而非生长抑制是人类肿瘤发生过程中的重要步骤。
