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Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes

Oncogene volume 21, pages 2991–3002 (2002)Cite this article

Abstract

The carcinogenic effects of sunlight in human epidermis may be thwarted by either: transient growth arrest and repair of DNA photodamage in keratinocytes (KCs); elimination of KCs with damaged DNA via apoptosis; or by stimulating a senescence switch whereby KCs become irreversibly growth arrested. Using normal human skin organ cultures and living epidermal equivalents, we demonstrate that in the proliferative basal layer, removal of KCs via apoptosis had a rapid onset (beginning within 2 h) following UV-light exposure generating progressively greater numbers of KCs with thymine dimers as the dose of UV-light was increased; involved induction of Apaf-1, activation of caspase-3, and was dependent on p53 activation as addition of a p53 chemical inhibitor blocked the apoptotic response. Suprabasal layer KCs underwent apoptosis at much later time points (>8 h). KCs in the basal layer repaired DNA damage more rapidly than KCs in suprabasal layers. Steady state levels of p53 increased in irradiated cells, and the increase was accompanied by phosphorylation of serine 9 and serine 15, but not serine 6 residues. By contrast, cultured KCs undergoing spontaneous replicative senescence were resistant to UV-induced apoptosis. Senescent KCs constitutively contained low levels of p53, which were neither increased nor phosphorylated or acetylated after UV-exposure and possessed minimal DNA binding activity, indicative of functional inactivation. Furthermore, treatment of senescent KCs with DNA damaging agent adriamycin did not result in activation of latent p53 or apoptosis. When KCs within psoriatic plaques were examined, they resembled senescent KCs in that they expressed p53, which was not phosphorylated or acetylated. Thus, UV-light induces DNA damage in human epidermal KCs triggering p53 activation, and subsequent apoptosis involving distinct cell layers and kinetics. However, the lack of p53 activation as seen in senescent KCs and psoriatic plaques, is associated with a relative resistance of KCs to UV-induced apoptosis. In conclusion, the sensitivity and resistance of KCs to apoptosis depends not only on the location within various layers of epidermis and levels of p53, but may also involve p53 activation via post-translational modifications.

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Acknowledgements

The authors thank Stephanie Russo and Jodie Carroll for manuscript preparation. This work was supported by NIH grants AR 40065 and AR 47307 (BJ Nickoloff).

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  1. Jian-Zhong Qin and Vijaya Chaturvedi: J Qin and V Chaturvedi contributed equally to this work

Authors and Affiliations

  1. Department of Pathology, Loyola University Medical Center, Illinois, USA

    Jian-Zhong Qin, Vijaya Chaturvedi, Mitchell F Denning, Patricia Bacon, Jeffry Panella & Brian J Nickoloff

  2. Department of Radiation Oncology, Loyola University Medical Center, Illinois, USA

    Divaker Choubey

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  1. Jian-Zhong Qin
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Correspondence to Brian J Nickoloff.

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Qin, JZ., Chaturvedi, V., Denning, M. et al. Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes. Oncogene 21, 2991–3002 (2002). https://doi.org/10.1038/sj.onc.1205404

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