Involvement of protein kinase C-delta in DNA damage-induced apoptosis

Citation
A. Basu et al., Involvement of protein kinase C-delta in DNA damage-induced apoptosis, CELL DEAT D, 8(9), 2001, pp. 899-908
Citations number
43
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell & Developmental Biology
Journal title
CELL DEATH AND DIFFERENTIATION
ISSN journal
1350-9047 → ACNP
Volume
8
Issue
9
Year of publication
2001
Pages
899 - 908
Database
ISI
SICI code
1350-9047(200109)8:9<899:IOPKCI>2.0.ZU;2-R
Abstract
We have previously shown that the protein kinase C (PKC) signal transductio n pathway regulates cell death by the DNA damaging agent cis-diamminedichlo roplatinum(II) (cDDP). In the present study we have investigated how PKC in fluences the sequence of events that are triggered by cDDP-induced DNA dama ge. cDDP caused activation of caspases-8,-9,-3,-7 and cleavage of PKC delta . Rottlerin, a selective inhibitor of novel PKC delta, blocked activation o f caspases, proteolytic activation of PKC delta and cell death induced by c DDP. In contrast, Go 6976, an inhibitor of conventional PKC alpha and betaI , did not prevent cDDP-induced caspase activation and cDDP cytotoxicity. In HeLa cells, PKC delta was distributed both in the cytosol and heavy membra ne (HM) fraction containing mitochondria. While caspase-8 was primarily cyt osolic, a small amount of caspases-9, -7 and -3 could be detected in the HM fraction. cDDP caused a time-dependent increase in Cytochrome c release fr om the mitochondria and processing of both cytosolic and membrane-associate d caspases, as well as proteolytic cleavage of PKC delta. Rottlerin attenua ted late but not early release of Cytochrome c by cDDP. It, however, inhibi ted activation of caspases and proteolytic cleavage of PKC delta in both cy tosolic and HM fractions. The antiapoptotic effect of rottlerin was evident when it was added together with or following cDDP addition but not when ad ded after cDDP was removed from the medium. Thus, the PKC delta inhibitor a cts at an early stage of the cDDP-induced cell death pathway that precedes caspase activation.