Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa
Details
Publication Year 2007-02-12, Volume 176, Issue #4, Page 415-424
Journal Title
JOURNAL OF CELL BIOLOGY
Publication Type
Journal Article
Abstract
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 Ill 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.
Publisher
ROCKEFELLER UNIV PRESS
Keywords
CELL-DEATH INDUCTION; P53-MEDIATED APOPTOSIS; LYMPHOCYTE APOPTOSIS; DNA-DAMAGE; PUMA; MICE; CANCER; BCL-2; P53; RESPONSES
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Creation Date: 2007-02-12 12:00:00
Last Modified: 0001-01-01 12:00:00
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