In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute
In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute
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DOI：
10.1038/cdd.2008.16
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发表时间：
2008-06-01
影响因子：
12.4
通讯作者：
Strasser, A.
中科院分区：
文献类型：
--
作者：
Michalak, E. M.;Villunger, A.;Strasser, A.
p53 诱导 DNA 受损细胞凋亡的能力被认为对其肿瘤抑制功能有很大贡献。 P53 已被提议通过众多转录靶标甚至通过直接细胞质作用来诱导细胞凋亡。在多种细胞类型中，两个转录靶标可介导其凋亡作用，它们编码 Noxa 和 Puma，它们是 Bcl-2 家族中仅包含 BH3 的成员。为了测试它们在 p53 依赖性细胞凋亡中的功能是否重叠，我们生成了两者都缺乏的小鼠。这些小鼠发育正常，尚未出现肿瘤。在胚胎成纤维细胞中，Noxa 和 Puma 的缺失阻止了依托泊苷诱导细胞凋亡。此外，在全身伽马射线照射后，两种蛋白质的缺失比单独缺失 Puma 能更好地保护胸腺细胞。事实上，它们的联合缺陷对胸腺细胞的保护作用与 p53 本身的缺失一样强大。这些结果表明，至少在成纤维细胞和胸腺细胞中，p53 诱导的细胞凋亡主要通过 Noxa 和 Puma 进行，其中 Puma 在多种细胞类型中起主导作用。小鼠体内没有肿瘤表明，除了诱导细胞凋亡之外，p53 抑制肿瘤还需要其他功能。
The ability of p53 to induce apoptosis in cells with damaged DNA is thought to contribute greatly to its tumour suppressor function. P53 has been proposed to induce apoptosis via numerous transcriptional targets or even by direct cytoplasmic action. Two transcriptional targets shown to mediate its apoptotic role in several cell types encode Noxa and Puma, BH3-only members of the Bcl-2 family. To test if their functions in p53-dependent apoptosis overlap, we generated mice lacking both. These mice develop normally and no tumours have yet arisen. In embryonic fibroblasts, the absence of both Noxa and Puma prevented induction of apoptosis by etoposide. Moreover, following whole body gamma-irradiation, the loss of both proteins protected thymocytes better than loss of Puma alone. Indeed, their combined deficiency protected thymocytes as strongly as loss of p53 itself. These results indicate that, at least in fibroblasts and thymocytes, p53-induced apoptosis proceeds principally via Noxa and Puma, with Puma having the predominant role in diverse cell types. The absence of tumours in the mice suggests that tumour suppression by p53 requires functions in addition to induction of apoptosis.