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J. Biol. Chem., Vol. 282, Issue 31, 22993-23004, August 3, 2007

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NFBD1/MDC1 Associates with p53 and Regulates Its Function at the Crossroad between Cell Survival and Death in Response to DNA Damage^*

Mitsuru Nakanishi¹, Toshinori Ozaki¹, Hideki Yamamoto, Takayuki Hanamoto, Hironobu Kikuchi, Kazushige Furuya, Masahiro Asaka, Domenico Delia^¶, and Akira Nakagawara²

From the Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan, the Department of Gastroenterology, Hokkaido University School of Medicine, Sapporo 060-8638, Japan, and the ^¶Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy

NFBD1/MDC1, which belongs to the BRCT superfamily, has an anti-apoptotic activity and contributes to the early cellular responses to DNA damage. Here we found that NFBD1 protects cells from apoptotic cell death by inhibiting phosphorylation of p53 at Ser-15 under steady state as well as early phase of DNA damage, thereby blocking its transcriptional and pro-apoptotic activities. During late phase of DNA damage, a remarkable reduction of NFBD1 was observed in dying but not in surviving A549 cells bearing wild-type p53. Small interference RNA-mediated knockdown of the endogenous NFBD1 resulted in an increase in sensitivity to adriamycin in A549 cells but not in p53-deficient H1299 cells. Immunoprecipitation and luciferase reporter analyses demonstrated that NFBD1 binds to the NH₂-terminal region of p53 and strongly inhibits its transcriptional activity. Additionally, BRCT domains, which can interact with p53, reduced the adriamycin-induced phosphorylation levels of p53 at Ser-15 and also suppressed the transcriptional activity of p53. Thus, our present findings strongly suggest that NFBD1 plays an important role in the decision of cell survival and death after DNA damage through the regulation of p53.

Received for publication, December 13, 2006 , and in revised form, May 2, 2007.

^* This work was supported in part by a grant-in-aid from the Ministry of Health, Labor, and Welfare for Third Term Comprehensive Control Research for Cancer, a grant-in-aid for Cancer Research from the Ministry of Health, Labor, and Welfare of Japan, a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and a grant from Uehara Memorial Foundation. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 81-43-264-5431; Fax: 81-43-265-4459; E-mail: akiranak{at}chiba-cc.jp.

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