Helmholtz Zentrum München, German Research Center for Environmental Health, Marchioninistrasse 25, Munich, D-81377, Germany.
Cell Commun Signal. 2013 Apr 17;11(1):27. doi: 10.1186/1478-811X-11-27.
The p53 protein is the best studied target in human cancer. For decades, p53 has been believed to act mainly as a tumor suppressor and by transcriptional regulation. Only recently, the complex and diverse function of p53 has attracted more attention. Using several molecular approaches, we studied the impact of different p53 variants on extrinsic and intrinsic apoptosis signaling.
We reproduced the previously published results within intrinsic apoptosis induction: while wild-type p53 promoted cell death, different p53 mutations reduced apoptosis sensitivity. The prediction of the impact of the p53 status on the extrinsic cell death induction was much more complex. The presence of p53 in tumor cell lines and primary xenograft tumor cells resulted in either augmented, unchanged or reduced cell death. The substitution of wild-type p53 by mutant p53 did not affect the extrinsic apoptosis inducing capacity.
In summary, we have identified a non-expected impact of p53 on extrinsic cell death induction. We suggest that the impact of the p53 status of tumor cells on extrinsic apoptosis signaling should be studied in detail especially in the context of therapeutic approaches that aim to restore p53 function to facilitate cell death via the extrinsic apoptosis pathway.
p53 蛋白是人类癌症中研究最透彻的靶点。几十年来，人们一直认为 p53 主要作为肿瘤抑制因子发挥作用，并通过转录调控发挥作用。直到最近，p53 的复杂多样的功能才引起了更多的关注。我们使用几种分子方法研究了不同 p53 变体对外源和内源细胞凋亡信号的影响。
我们重现了先前关于内源细胞凋亡诱导的研究结果：野生型 p53 促进细胞死亡，而不同的 p53 突变则降低了细胞对凋亡的敏感性。对 p53 状态对外源细胞死亡诱导影响的预测要复杂得多。肿瘤细胞系和原代异种移植肿瘤细胞中 p53 的存在导致细胞死亡增加、不变或减少。野生型 p53 被突变型 p53 取代并不影响外源细胞凋亡的诱导能力。
总之，我们发现了 p53 对外源细胞死亡诱导的非预期影响。我们建议，特别是在旨在恢复 p53 功能以通过外源细胞凋亡途径促进细胞死亡的治疗方法的背景下，应详细研究肿瘤细胞 p53 状态对外源细胞凋亡信号的影响。
