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J Biol Chem. 2004 Sep 17;279(38):39431-7. Epub 2004 Jul 19.

Regulation of Bax activation and apoptotic response to microtubule-damaging agents by p53 transcription-dependent and -independent pathways.

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Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, Florida 33612, USA.


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 DeltaProAE, 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.

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