Carcinogenesis, Vol. 24, No. 2, 317-325,
February 2003
© 2003 Oxford University Press
CARCINOGENESIS |
PKC isozyme S-cysteinylation by cystine stimulates the pro-apoptotic isozyme PKC
and inactivates the oncogenic isozyme PKC
Department of Cancer Biology, University of Texas M.D.Anderson Cancer Center, Houston, TX 77030, USA
Protein kinase C (PKC) is a family of ten isozymes that play distinct and in some cases opposing roles in cell growth and survival. We recently reported that diamide, a diazene carbonyl derivative which oxidizes thiols to disulfides through addition/displacement reactions at the diazene bond, induces potent GSH-dependent inactivation of several PKC isozymes, including the oncogenic isozyme PKC
, via S-glutathiolation. PKC
, a pro-apoptotic isozyme, was distinguished by its resistance to inactivation. In this report, we show that PKC-regulatory S-thiolation modifications produced by physiological disulfides elicit opposing effects on PKC and PKC activity. We report that PKC is stimulated 2.0–2.5 fold by GSSG, (Cys–Gly)2 and cystine, under conditions where PKC
and PKC are fully inactivated by cystine, and PKC
activity is affected marginally or not at all by the disulfides. Focusing on cystine, we show that DTT quenches cystine-induced PKC stimulation and PKC and PKC inactivation, indicative of oxidative regulation. By analyzing DTT-reversible isozyme radiolabeling by [35S]cystine, we demonstrate that PKC, PKC and PKC are each [35S] S-cysteinylated in association with the concentration-dependent regulation of isozyme activity by cystine. The restricted reactivity of cystine, together with the effects of DTT and thioredoxin on cystine-induced PKC isozyme regulation reported here, indicate that the cystine-induced PKC-regulatory effects entail isozyme S-cysteinylation. We recently hypothesized that antagonism of tumor promotion/progression by small cellular thiols may involve PKC regulation via oxidant-induced S-thiolation reactions with PKC isozymes. The findings of cystine-induced PKC isozyme regulation by S-cysteinylation reported here offer correlative support to the hypothetical model. Thus, PKC, a potent antagonist of DMBA–TPA-induced tumor promotion/progression in mouse skin, is stimulated by S-cysteinylation, PKC, an important mediator of the tumor promotion/progression response, is inactivated by S-cysteinylation, and PKC, which is not influential in DMBA–TPA-induced tumor promotion/progression, is not regulated by cystine. Furthermore, PKC has oncogenic activity, and S-cysteinylation inactivated PKC and PKC similarly. These findings provide evidence that S-cysteinyl acceptor-sites in PKC isozymes may offer attractive targets for development of novel cancer preventive agents.
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