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Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-xL reduction thereby enhancing UV-light induced apoptosis

Oncogene volume 24, pages 5299–5312 (2005)Cite this article

Abstract

Ultraviolet (UV) light exposure is a common cause of epithelial-derived skin cancers, and the epidermal response to UV-light has been extensively studied using both mouse models and cultured human keratinocytes (KCs). Elimination of cells with UV-induced DNA damage via apoptosis provides a powerful mechanism to minimize retention or expansion of genetically abnormal cells. This cell editing function has largely been ascribed to the biological role of the p53 tumor suppressor gene, as mutations or deletions involving p53 have been linked to skin cancer development. Rather than introducing mutations, or using cells with complete loss of wild-type p53, we used an siRNA-based approach to knockdown, but not eliminate, p53 levels in primary cultures of human KCs followed by UV-irradiation. Surprisingly, when p53 levels were reduced by 50–80% the apoptosis induced by exposure to UV-light was accelerated and markedly enhanced (two- to three- fold) compared to control siRNA treated KCs. The p53 siRNA treated KCs were characterized by elevated E2F-1 levels accompanied by accelerated elimination of the Mcl-1 and Bcl-xL antiapoptotic proteins, as well as enhanced Bax oligomerization. Forced overexpression of either Mcl-1 or Bcl-xL reduced the UV-light enhanced apoptotic response in p53 siRNA treated KCs. We conclude that p53 not only can provide proapoptotic signals but also regulates a survival pathway influencing Mcl-1 and Bcl-xL levels. This overlooked survival function of p53 may explain previous paradoxical responses noted by investigators using p53 heterozygous and knockout mouse models, and opens up the possibility that not all liaisons within the cell involving p53 necessarily represent fatal attractions.

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Acknowledgements

We thank Drs Divaker Choubey and Brian Bonish for their valuable assistance with this work, and Ms Lynn Walter for preparing the text and figures. This work was supported by NIH grants CA 83784 (MFD) and AR 47814 and AR 47307 (BJN).

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Authors and Affiliations

  1. Department of Pathology, Oncology Institute, Loyola University Medical Center, USA

    Vijaya Chaturvedi, Leonid A Sitailo, Jian-Zhong Qin, Barbara Bodner, Mitchell F Denning, Jonathan Curry & Brian J Nickoloff

  2. Department of Radiation Oncology, Yale University Medical School, USA

    Wengeng Zhang & Douglas Brash

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  1. Vijaya Chaturvedi
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  2. Leonid A Sitailo
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Correspondence to Brian J Nickoloff.

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Chaturvedi, V., Sitailo, L., Qin, JZ. et al. Knockdown of p53 levels in human keratinocytes accelerates Mcl-1 and Bcl-xL reduction thereby enhancing UV-light induced apoptosis. Oncogene 24, 5299–5312 (2005). https://doi.org/10.1038/sj.onc.1208650

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