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J. Biol. Chem., Vol. 280, Issue 44, 37169-37177, November 4, 2005
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1
From the
Institute of Molecular Medicine, University of Düsseldorf, 40225 Düsseldorf, Germany and the Department of Hematology, Oncology and Tumor Immunology, Charite, Humboldt University, 13125 Berlin, Germany
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.
Received for publication, February 23, 2005 , and in revised form, August 9, 2005.
* This work was supported by the Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft Grants SFB 503 and SFB 575. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Universitätsstrasse 1, 40225 Düsseldorf, Germany. Tel.: 49-211-811-5973; Fax: 49-211-811-5892; E-mail: janicke{at}uni-duesseldorf.de.
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