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Regulation of PUMA-α by p53 in cisplatin-induced renal cell apoptosis

Oncogene volume 25, pages 4056–4066 (2006)Cite this article

Abstract

Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. Depending on its concentration, cisplatin induces necrosis or apoptosis of tubular cells in the kidneys, whereas the underlying injury mechanism is unclear. Our recent work has suggested a critical role for p53 in cisplatin-induced tubular cell apoptosis; nevertheless, the apoptotic events triggered by p53 remain elusive. The current study has examined Bcl-2 family proteins, critical regulators of apoptosis that may be subjected to p53 regulation. Following cisplatin treatment, the expression of Bcl-xL, an antiapoptotic molecule, was suppressed, while the expression of Bak, a proapoptotic molecule, increased slightly. Of interest, PUMA-α, a newly identified p53-responsive proapoptotic Bcl-2 family protein, was drastically induced by cisplatin. PUMA-α induction preceded or paralleled the development of apoptosis. Induced PUMA-α was localized in mitochondria and appeared to antagonize Bcl-xL via molecular interaction. PUMA-α induction during cisplatin treatment was attenuated by pifithrin-α, a pharmacological inhibitor of p53, which was accompanied by the amelioration of Bax activation, cytochrome c release and apoptosis. Moreover, PUMA-α induction was suppressed by dominant-negative p53. Importantly, cisplatin-induced apoptosis was ameliorated in PUMA-α knockout cells. In vivo, cisplatin induced PUMA-α in the kidneys, and the inductive response was abrogated in p53-deficient animals. Together, this study has demonstrated the first compelling evidence for the involvement of PUMA-α in p53-mediated renal cell apoptosis during cisplatin nephrotoxicity.

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Acknowledgements

We thank Drs Mivechi and Moskophidis at the Medical College of Georgia for providing the breeding pairs of p53-deficient mice. We also thank Dr Xiao-Ming Yin at the University of Pittsburgh for the polyclonal antibody to Bid. This study was supported in part by grants from National Institutes of Health and Department of Veterans Affairs.

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Author notes

  1. M Jiang: Man Jiang is an exchange graduate student at the Medical College of Georgia, as part of the International Cooperative Agreement between the Medical College of Georgia and Wuhan University School of Medicine in China.

Authors and Affiliations

  1. Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA, USA

    M Jiang, Q Wei, J Wang & Z Dong

  2. Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA, USA

    Q Du

  3. Departments of Pathology and Pharmacology, University of Pittsburgh Cancer institute, Pittsburgh, PA, USA

    J Yu & L Zhang

  4. Department of Veterans Affairs Medical Center, Medical Research Service, GA, Augusta, USA

    Z Dong

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Correspondence to Z Dong.

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Jiang, M., Wei, Q., Wang, J. et al. Regulation of PUMA-α by p53 in cisplatin-induced renal cell apoptosis. Oncogene 25, 4056–4066 (2006). https://doi.org/10.1038/sj.onc.1209440

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