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J Biol Chem. 2010 Jan 15;285(3):1879-87. doi: 10.1074/jbc.M109.055392. Epub 2009 Nov 16.

The protein kinase Cdelta catalytic fragment is critical for maintenance of the G2/M DNA damage checkpoint.

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  • 1Molecular and Cellular Biochemistry Program, Department of Cell Biology, Neurobiology, and Anatomy, Loyola University Chicago, Maywood, Illinois 60153, USA.

Abstract

Protein kinase Cdelta (PKCdelta) is an essential component of the intrinsic apoptotic program. Following DNA damage, such as exposure to UV radiation, PKCdelta is cleaved in a caspase-dependent manner, generating a constitutively active catalytic fragment (PKCdelta-cat), which is necessary and sufficient for keratinocyte apoptosis. We found that in addition to inducing apoptosis, expression of PKCdelta-cat caused a pronounced G(2)/M cell cycle arrest in both primary human keratinocytes and immortalized HaCaT cells. Consistent with a G(2)/M arrest, PKCdelta-cat induced phosphorylation of Cdk1 (Tyr(15)), a critical event in the G(2)/M checkpoint. Treatment with the ATM/ATR inhibitor caffeine was unable to prevent PKCdelta-cat-induced G(2)/M arrest, suggesting that PKCdelta-cat is functioning downstream of ATM/ATR in the G(2)/M checkpoint. To better understand the role of PKCdelta and PKCdelta-cat in the cell cycle response to DNA damage, we exposed wild-type and PKCdelta null mouse embryonic fibroblasts (MEFs) to UV radiation. Wild-type MEFs underwent a pronounced G(2)/M arrest, Cdk1 phosphorylation, and induction of apoptosis following UV exposure, whereas PKCdelta null MEFs were resistant to these effects. Expression of PKCdelta-green fluorescent protein, but not caspase-resistant or kinase-inactive PKCdelta, was able to restore G(2)/M checkpoint integrity in PKCdelta null MEFs. The function of PKCdelta in the DNA damage-induced G(2)/M cell cycle checkpoint may be a critical component of its tumor suppressor function.

PMID:
19917613
[PubMed - indexed for MEDLINE]
PMCID:
PMC2804346
Free PMC Article
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