Abstract
Keratinocyte apoptosis induced by UV radiation is a major protective mechanism from skin photocarcinogenesis. The induction of apoptosis by UV radiation, as well as a variety of genotoxic stimuli, involves the activation of PKC-δ by caspase-3-mediated cleavage in its hinge region, thus generating a constitutively active catalytic fragment. To determine the role of PKC-δ cleavage in UV apoptosis signaling, we introduced a caspase-resistant PKC-δ mutant (D330A) into human keratinocytes by retrovirus transduction. Overexpression of PKC-δ(D330A) protected keratinocytes from UV-induced apoptosis and enhanced long-term survival. PKC-δ(D330A) partially prevented the release of cytochrome c from the mitochondria and the loss of Mcl-1, a key antiapoptotic protein downregulated during UV apoptosis. Thus, the cleavage and activation of PKC-δ are critical components of UV-induced apoptosis in human keratinocytes, and the inactivation of PKC-δ can promote the survival of keratinocytes exposed to UV radiation.
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Abbreviations
- UV:
-
ultraviolet
- PKC:
-
protein kinase C
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Acknowledgements
We thank all members of the Skin Cancer Research Program for their input into this project, especially Shalini S Tibudan and Drs. Leonid A Sitailo, Jian-Zhong Qin, and Brian J Nickoloff. This work was supported in part by NIH Grant CA83784 (MF Denning).
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D'Costa, A., Denning, M. A caspase-resistant mutant of PKC-δ protects keratinocytes from UV-induced apoptosis. Cell Death Differ 12, 224–232 (2005). https://doi.org/10.1038/sj.cdd.4401558
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DOI: https://doi.org/10.1038/sj.cdd.4401558
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