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J. Biol. Chem., Vol. 279, Issue 26, 27549-27559, June 25, 2004

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Stabilization of p53 Is a Novel Mechanism for Proapoptotic Function of NF-B^*

Shuichi Fujioka, Christian Schmidt, Guido M. Sclabas, Zhongkui Li, Hélène Pelicano¶, Bailu Peng, Alice Yao||, Jiangong Niu**, Wei Zhang¶, Douglas B. Evans, James L. Abbruzzese, Peng Huang¶, and Paul J. Chiao**¶¶

From the Departments of Surgical Oncology, Gastrointestinal Medical Oncology, and Molecular & Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, the Visceral and Transplantation Surgery, Inselspital, University of Bern, 3010 Bern, Switzerland, the ^¶Department of Molecular Pathology and ^||Summer Student Program, The University of Texas-Houston Health Science Center, Houston, Texas 77030, and the ^**Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030

Both pro- and antiapoptotic activities of NF-B transcription factor have been observed; however, less is known about the mechanism by which NF-B induces apoptosis. To elucidate how NF-B regulates proapoptotic signaling, we performed functional analyses using wild-type, ikk1^-/-, ikk2^-/-, rela^-/- murine fibroblasts, MDAPanc-28/Puro, MDAPanc-28/IBM, and HCT116/p53^+/+ and HCT116/p53^-/- cells with investigational anticancer agent doxycycline as a superoxide inducer for generating apoptotic stimulus. In this report, we show that doxycycline increased superoxide generation and subsequently activated NF-B, which in turn up-regulated p53 expression and increased the stability and DNA binding activity of p53. Consequently, NF-B-dependent p53 activity induced the expression of p53-regulated genes PUMA and p21^waf1 as well as apoptosis. Importantly, lack of RelA, IKK, and p53 as well as expression of a dominant negative IB (IBM) inhibited NF-B-dependent p53 activation and apoptosis. The doxycycline-induced NF-B activation was not inhibited in HCT116/p53^-/- cells. Our results demonstrate that NF-B plays an essential role in activation of wild-type p53 tumor suppressor to initiate proapoptotic signaling in response to overgeneration of superoxide. Thus, these findings reveal a mechanism of NF-B-regulated proapoptotic signaling.

Received for publication, December 9, 2003 , and in revised form, March 11, 2004.

^* The work was supported by NCI, National Institutes of Health Grants CA78778-01 and PA-98-029 and by a grant from the Lockton Fund for Pancreatic Cancer Research. 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.

^¶¶ To whom correspondence should be addressed: Dept. of Surgical Oncology and Department of Molecular & Cellular Oncology, Unit 107, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. Tel.: 713-794-1030; Fax: 713-794-4830; E-mail: pjchiao{at}mail.mdanderson.org.

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