HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 38, 39431-39437, September 17, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/38/39431    most recent M401530200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamaguchi, H. Articles by Wang, H.-G. Search for Related Content PubMed PubMed Citation Articles by Yamaguchi, H. Articles by Wang, H.-G. Social Bookmarking                      What's this?

Regulation of Bax Activation and Apoptotic Response to Microtubule-damaging Agents by p53 Transcription-dependent and -independent Pathways^*

Hirohito Yamaguchi, Jiandong Chen¶, Kapil Bhalla||, and Hong-Gang Wang**

From the Drug Discovery Program, ^¶Molecular Oncology Program, and ^||Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, and the Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida 33612

Microtubule-damaging agents (MDA) are potent antineoplastic drugs that are widely used in clinical treatment for a variety of cancers. However, the precise mechanisms underlying MDA-induced cell death are largely unknown. Here, we report that both p53 and Bax are central participants in the MDA-mediated cell death machinery in HCT116 human colon cancer cells. MDA, including epothilone B analogue (BMS-247550) and vinblastine, induced apoptosis of Bax-positive HCT116 cells in a p53-dependent manner; p53 was required for MDA-induced Bax conformational change. In response to MDA treatment, the BH3-only proapoptotic protein PUMA was up-regulated in p53-positive but not in p53 knockout HCT116 cells. Moreover, PUMA knockout HCT116 cells were resistant to MDA-induced Bax conformational change and apoptosis. In addition, introducing p53 plasmid DNA into p53-deficient HCT116 cells restored PUMA expression and apoptotic response to MDA treatment. However, ectopic expression of the p53 point mutation L22Q/W23S, but not the proline-rich domain deletion mutants 83-393 and ProAE, could also sensitize p53 knockout HCT116 cells to MDA-induced Bax activation and apoptosis, although all mutants failed to restore PUMA expression. Together, these findings suggest that p53 acts upstream of Bax to promote MDA-mediated cell death in a proline-rich domain-dependent manner through both transcription-dependent (by up-regulating PUMA expression) and -independent mechanisms in human colon cancer HCT116 cells.

Received for publication, February 11, 2004 , and in revised form, June 23, 2004.

^* This work was supported by National Institutes of Health grants. 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. E-mail: wanghg{at}moffitt.usf.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Upreti, R. Chu, E. Galitovskaya, S. K. Smart, and T. C. Chambers Key role for Bak activation and Bak-Bax interaction in the apoptotic response to vinblastine Mol. Cancer Ther., July 1, 2008; 7(7): 2224 - 2232. [Abstract] [Full Text] [PDF]

				L. Vahdat Ixabepilone: A Novel Antineoplastic Agent with Low Susceptibility to Multiple Tumor Resistance Mechanisms Oncologist, March 1, 2008; 13(3): 214 - 221. [Abstract] [Full Text] [PDF]

				T. Uo, Y. Kinoshita, and R. S. Morrison Apoptotic Actions of p53 Require Transcriptional Activation of PUMA and Do Not Involve a Direct Mitochondrial/Cytoplasmic Site of Action in Postnatal Cortical Neurons J. Neurosci., November 7, 2007; 27(45): 12198 - 12210. [Abstract] [Full Text] [PDF]

				I. Irminger-Finger Science of Cancer and Aging J. Clin. Oncol., May 10, 2007; 25(14): 1844 - 1851. [Abstract] [Full Text] [PDF]

				J. Cheng, R. Cui, C.-H. Chen, and J. Du Oxidized Low-Density Lipoprotein Stimulates p53-Dependent Activation of Proapoptotic Bax Leading to Apoptosis of Differentiated Endothelial Progenitor Cells Endocrinology, May 1, 2007; 148(5): 2085 - 2094. [Abstract] [Full Text] [PDF]

				Y.-A. Kim, D. Xiao, H. Xiao, A. A. Powolny, K. L. Lew, M. L. Reilly, Y. Zeng, Z. Wang, and S. V. Singh Mitochondria-mediated apoptosis by diallyl trisulfide in human prostate cancer cells is associated with generation of reactive oxygen species and regulated by Bax/Bak Mol. Cancer Ther., May 1, 2007; 6(5): 1599 - 1609. [Abstract] [Full Text] [PDF]

				C. Vogel, C. Hager, and H. Bastians Mechanisms of Mitotic Cell Death Induced by Chemotherapy-Mediated G2 Checkpoint Abrogation Cancer Res., January 1, 2007; 67(1): 339 - 345. [Abstract] [Full Text] [PDF]

				S Mani, H. McDaid, A Grossman, F Muggia, S Goel, T Griffin, D Colevas, S. Horwitz, and M. Egorin Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone Ann. Onc., January 1, 2007; 18(1): 190 - 195. [Abstract] [Full Text] [PDF]

				M. Upreti, C. S. Lyle, B. Skaug, L. Du, and T. C. Chambers Vinblastine-induced Apoptosis Is Mediated by Discrete Alterations in Subcellular Location, Oligomeric Structure, and Activation Status of Specific Bcl-2 Family Members J. Biol. Chem., June 9, 2006; 281(23): 15941 - 15950. [Abstract] [Full Text] [PDF]

				H. Yamaguchi and H.-G. Wang Tissue Transglutaminase Serves as an Inhibitor of Apoptosis by Cross-Linking Caspase 3 in Thapsigargin-Treated Cells Mol. Cell. Biol., January 15, 2006; 26(2): 569 - 579. [Abstract] [Full Text] [PDF]

				Y. Takahashi, M. Karbowski, H. Yamaguchi, A. Kazi, J. Wu, S. M. Sebti, R. J. Youle, and H.-G. Wang Loss of Bif-1 Suppresses Bax/Bak Conformational Change and Mitochondrial Apoptosis Mol. Cell. Biol., November 1, 2005; 25(21): 9369 - 9382. [Abstract] [Full Text] [PDF]

				K. Tsuchihara, V. Lapin, C. Bakal, H. Okada, L. Brown, M. Hirota-Tsuchihara, K. Zaugg, A. Ho, A. Itie-YouTen, M. Harris-Brandts, et al. Ckap2 Regulates Aneuploidy, Cell Cycling, and Cell Death in a p53-Dependent Manner Cancer Res., August 1, 2005; 65(15): 6685 - 6691. [Abstract] [Full Text] [PDF]

				K. Iskander, A. Gaikwad, M. Paquet, D. J. Long II, C. Brayton, R. Barrios, and A. K. Jaiswal Lower Induction of p53 and Decreased Apoptosis in NQO1-Null Mice Lead to Increased Sensitivity to Chemical-Induced Skin Carcinogenesis Cancer Res., March 15, 2005; 65(6): 2054 - 2058. [Abstract] [Full Text] [PDF]

				S. Choi and S. V. Singh Bax and Bak Are Required for Apoptosis Induction by Sulforaphane, a Cruciferous Vegetable-Derived Cancer Chemopreventive Agent Cancer Res., March 1, 2005; 65(5): 2035 - 2043. [Abstract] [Full Text] [PDF]