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

Article Details

Citation

LaGory EL, Sitailo LA, Denning MF

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

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

PubMed ID
19917613 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Cyclin-dependent kinase 1P06493Details