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Published online February 5, 2007
doi:10.1083/jcb.200608070
The Journal of Cell Biology, Vol. 176, No. 4, 415-424
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Naik et al.
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Article

 Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa

Edwina Naik1, Ewa M. Michalak1, Andreas Villunger2, Jerry M. Adams1, and Andreas Strasser1

1 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
2 Division of Developmental Immunology, Biocenter, Innsbruck Medical University, 6020 Innsbruck, Austria

Correspondence to Andreas Strasser: strasser{at}wehi.edu.au

To identify the mechanisms of ultraviolet radiation (UVR)–induced cell death, for which the tumor suppressor p53 is essential, we have analyzed mouse embryonic fibroblasts (MEFs) and keratinocytes in mouse skin that have specific apoptotic pathways blocked genetically. Blocking the death receptor pathway provided no protection to MEFs, whereas UVR-induced apoptosis was potently inhibited by Bcl-2 overexpression, implicating the mitochondrial pathway. Indeed, Bcl-2 overexpression boosted cell survival more than p53 loss, revealing a p53-independent pathway controlled by the Bcl-2 family. Analysis of primary MEFs lacking individual members of its BH3-only subfamily identified major initiating roles for the p53 targets Noxa and Puma. In the transformed derivatives, where Puma, unexpectedly, was not induced by UVR, Noxa had the dominant role and Bim a minor role. Furthermore, loss of Noxa suppressed the formation of apoptotic keratinocytes in the skin of UV-irradiated mice. Collectively, these results demonstrate that UVR activates the Bcl-2–regulated apoptotic pathway predominantly through activation of Noxa and, depending on cellular context, Puma.

Abbreviations used in this paper: FADD, Fas-associated death domain; ICAD, inhibitor of caspase-activated DNase; MEF, mouse embryonic fibroblast; PI, propidium iodide; SBC, sunburn cell; UVR, UV radiation; wt, wild-type.


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