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pubmed-article:12435813pubmed:abstractTextInduction of apoptosis by chemotherapeutic drugs involves the sphingomyelin-ceramide (SM-CER) pathway. This signaling is critically dependent on reactive oxygen species (ROS) generation and p53/p56 Lyn activation. In this study, we have investigated the influence of protein kinase C (PKC) zeta overexpression on the SM-CER pathway in U937 human leukemia cell line. We show that PKCzeta overexpression resulted in delayed apoptosis and significant resistance to both 1-beta-D-arabinofuranosylcytosine (ara-C) and daunorubicin (DNR), but there was no significant protection against cell-permeant C(6)-CER. Moreover, PKCzeta overexpression abrogated drug-induced neutral sphingomyelinase stimulation and CER generation by inhibiting ROS production. We further investigated p53/p56 Lyn activation in PKCzeta-overexpressing U937 cells treated with ara-C or DNR. We demonstrate that PKCzeta inhibited p53/p56 Lyn phosphorylation and stimulation in drug- or H(2)O(2)-treated cells, suggesting that p53/p56 Lyn redox regulation is altered in PKCzeta-overexpressing cells. Finally, we show that PKCzeta-overexpressing U937 cells displayed accelerated H(2)O(2) detoxification. Altogether, our study provides evidence for the role of PKCzeta in the negative regulation of drug-induced SM-CER pathway.lld:pubmed
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pubmed-article:12435813pubmed:authorpubmed-author:GuyLaurentLlld:pubmed
pubmed-article:12435813pubmed:authorpubmed-author:JaffrézouJean...lld:pubmed
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pubmed-article:12435813pubmed:authorpubmed-author:LouatThierryTlld:pubmed
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pubmed-article:12435813pubmed:pagination1446-55lld:pubmed
pubmed-article:12435813pubmed:dateRevised2011-11-2lld:pubmed
pubmed-article:12435813pubmed:articleTitleOverexpression of protein kinase Czeta confers protection against antileukemic drugs by inhibiting the redox-dependent sphingomyelinase activation.lld:pubmed
pubmed-article:12435813pubmed:affiliationInstitut National de la Santé et de la Recherche Médicale U563, Institut Claudius Regaud, Toulouse, France. christinebezombes@yahoo.comlld:pubmed
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