Essmann Frank, Pohlmann Stephan, Gillissen Bernhard, Daniel Peter T, Schulze-Osthoff Klaus, Jänicke Reiner U
Institute of Molecular Medicine, University of Düsseldorf, 40225 Düsseldorf, Germany.
J Biol Chem. 2005 Nov 4;280(44):37169-77. doi: 10.1074/jbc.M502052200. Epub 2005 Sep 7.
The tumor suppressor protein p53 promotes apoptosis in response to death stimuli by transactivation of target genes and by transcription-independent mechanisms. Recently, it was shown that during apoptosis p53 can specifically translocate to mitochondria, where it physically interacts with and inactivates prosurvival Bcl-2 proteins. In the present study, we therefore investigated the role of mitochondrial translocation of p53 for the stress response of tumor cells. In various cell lines, DNA damage induced by either ionizing irradiation or topoisomerase inhibitors triggered a robust translocation of a fraction of p53 to mitochondria to a similar extent. Nevertheless, the cells succumbed to apoptosis only in response to topoisomerase inhibitors, but remained resistant to apoptosis induced by ionizing radiation. Irradiated cells became senescent, although irradiation triggered a functional p53 response and induced expression of p21, Bax, and Puma. Interestingly, even the targeted expression of p53 to mitochondria was insufficient to launch apoptosis, whereas overexpression of wild-type p53 induced Bax activation and apoptotic alterations. Together, these results suggest that, in contrast to previous reports, mitochondrial translocation of p53 does not per se lead to cell death and that this might constitute a mechanism that contributes to the resistance of tumor cells to ionizing radiation-induced apoptosis.
肿瘤抑制蛋白p53通过激活靶基因的转录以及转录非依赖机制，对死亡刺激作出反应，从而促进细胞凋亡。最近有研究表明，在细胞凋亡过程中，p53能够特异性地转位至线粒体，在那里它与促生存Bcl-2蛋白发生物理相互作用并使其失活。因此，在本研究中，我们探讨了p53的线粒体转位在肿瘤细胞应激反应中的作用。在多种细胞系中，电离辐射或拓扑异构酶抑制剂诱导的DNA损伤均能引发一部分p53向线粒体的强烈转位，且程度相似。然而，细胞仅在对拓扑异构酶抑制剂作出反应时才会发生凋亡，而对电离辐射诱导的凋亡仍具有抗性。尽管辐射引发了功能性的p53反应并诱导了p21、Bax和Puma的表达，但受辐射的细胞会发生衰老。有趣的是，即使将p53靶向定位于线粒体也不足以引发凋亡，而野生型p53的过表达则会诱导Bax激活和凋亡改变。总之，这些结果表明，与先前的报道相反，p53的线粒体转位本身并不会导致细胞死亡，这可能构成了一种导致肿瘤细胞对电离辐射诱导的凋亡产生抗性的机制。
