COOH-terminal domain of p53 modulates p53-mediated transcriptional transactivation, cell growth, and apoptosis.
COOH-terminal domain of p53 modulates p53-mediated transcriptional transactivation, cell growth, and apoptosis.
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发表时间：
1999-02
期刊：
影响因子：
11.2
通讯作者：
Xiaoling Zhou;X. W. Wang;Lixin Xu;Koichi Hagiwara;M. Nagashima;R. Wolkowicz;Irit Zurer;V. Rotter;Curtis C. Harris
中科院分区：
文献类型：
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作者：
Xiaoling Zhou;X. W. Wang;Lixin Xu;Koichi Hagiwara;M. Nagashima;R. Wolkowicz;Irit Zurer;V. Rotter;Curtis C. Harris
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，并且在许多不同类型的人类癌症中经常发生突变。 p53 的 COOH 末端调节蛋白质的转录和细胞凋亡活性。尽管p53的COOH末端突变体并不常见，但我们提出这些p53突变体仍然有助于癌细胞的选择性克隆扩张。因此，我们分析了肿瘤来源的 p53 COOH 末端结构域 (CTD) 突变体（352D/H、356G/W、342-stop、360-del 和 387-del）的功能。结果表明，与野生型p53相比，所有突变体的细胞凋亡活性均受损。然而，其中一些突变体仍然转录激活 p21Waf/Cip1 并抑制细胞生长。有趣的是，在肿瘤来源的 CTD 突变体中，寡聚缺陷突变体 342-stop 是唯一一种不表现出序列特异性 DNA 结合或无法转录激活 p21Waf1/Cip1、Bax 和 IGF-BP3 的突变体。这种肿瘤来源的 CTD 突变体未能抑制细胞生长，这支持了这样的假设：p53 序列特异性的 p21Waf1/Cip1 转录反式活性与细胞周期停滞的诱导相关，并且 p53 转录反式活性需要 p53 蛋白的寡聚化。这些和其他数据表明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，并且细胞凋亡功能的失活而不是生长的抑制是人类肿瘤发生过程中的重要步骤。
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.