NDLI: Overexpression of the Atypical Protein Kinase C ζ Reduces Topoisomerase II Catalytic Activity, Cleavable Complexes Formation, and Drug-induced Cytotoxicity in Monocytic U937 Leukemia Cells

Content Provider	Journal of Biological Chemistry (JBC)
Author	Plo, Isabelle Hernandez, Hélène Kohlhagen, Glenda Lautier, Dominique Pommier, Yves Laurent, Guy
Abstract	In this study, we evaluated the influence of protein kinase Cζ (PKCζ) on topoisomerase II inhibitor-induced cytotoxicity in monocytic U937 cells. In U937-ζJ and U937-ζB cells, enforced PKCζ expression, conferred by stable transfection of PKCζ cDNA, resulted in total inhibition of VP-16- and mitoxantrone-induced apoptosis and decreased drug-induced cytotoxicity, compared with U937-neo control cells. In PKCζ-overexpressing cells, drug resistance correlated with decreased VP-16-induced DNA strand breaks and DNA protein cross-links measured by alkaline elution. Kinetoplast decatenation assay revealed that PKCζ overexpression resulted in reduced global topoisomerase II activity. Moreover, in PKCζ-overexpressing cells, we found that PKCζ interacted with both α and β isoforms of topoisomerase II, and these two enzymes were constitutively phosphorylated. However, when human recombinant PKCζ (rH-PKCζ) was incubated with purified topoisomerase II isoforms, rH-PKCζ interacted with topoisomerase IIβ but not with topoisomerase IIα. PKCζ/topoisomerase IIβ interaction resulted in phosphorylation of this enzyme and in decrease of its catalytic activity. Finally, this report shows for the first time that topoisomerase IIβ is a substrate for PKCζ, and that PKCζ may significantly influence topoisomerase II inhibitor-induced cytotoxicity by altering topoisomerase IIβ activity through its kinase function.
Related Links	http://www.jbc.org/content/277/35/31407.abstract
Ending Page	31415
Starting Page	31407
Page Count	9
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	35
Volume Number	277
DOI	10.1074/jbc.M204654200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2002-08-30
Access Restriction	Open
Subject Keyword	Double-strand breaks (DSB) 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) Atypical multidrug resistant phenotype (at-MDR) DNA protein cross-links (DPC) Etoposide (VP-16) Recombinant human PKCζ (rH-PKCζ) Myelin basic protein (MBP) Protein kinase Cζ (PKCζ) Phenylmethylsulfonyl fluoride (PMSF) Dithiothreitol (DTT) Mitogen-activated protein kinase (MAPK) DNA: REPLICATION REPAIR AND RECOMBINATION
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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