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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-05-1585. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-05-1585v1 101/4/1543    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mas, V. M.-D. Articles by Laurent, G. Search for Related Content PubMed PubMed Citation Articles by Mas, V. M.-D. Articles by Laurent, G. Related Collections Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 February 2003, Vol. 101, No. 4, pp. 1543-1550 NEOPLASIA Protein kinase C mediated Raf-1/extracellular-regulated kinase activation by daunorubicin Véronique Mansat-De Mas, Hélène Hernandez, Isabelle Plo, Christine Bezombes, Nicolas Maestre, Anne Quillet-Mary, Rodolphe Filomenko, Cécile Demur, Jean-Pierre Jaffrézou, and Guy Laurent From the Institut National de la Santé et de la Recherche Médicale U563, Institut Claudius Régaud, Toulouse, France; the Laboratoire d'Hématologie, the Service d'Hématologie, Centre Hospitalier Universitaire Purpan, Toulouse, France; and the Institut National de la Santé et de la Recherche Médicale U517, Ecole pratique des Hautes Etudes, Dijon, France. In light of the emerging concept of a protective function of the mitogen-activated protein kinase (MAPK) pathway under stress conditions, we investigated the influence of the anthracycline daunorubicin (DNR) on MAPK signaling and its possible contribution to DNR-induced cytotoxicity. We show that DNR increased phosphorylation of extracellular-regulated kinases (ERKs) and stimulated activities of both Raf-1 and extracellular-regulated kinase 1 (ERK1) within 10 to 30 minutes in U937 cells. ERK1 stimulation was completely blocked by either the mitogen-induced extracellular kinase (MEK) inhibitor PD98059 or the Raf-1 inhibitor 8-bromo-cAMP (cyclic adenosine monophosphate). However, only partial inhibition of Raf-1 and ERK1 stimulation was observed with the antioxidant N-acetylcysteine (N-Ac). Moreover, the xanthogenate compound D609 that inhibits DNR-induced phosphatidylcholine (PC) hydrolysis and subsequent diacylglycerol (DAG) production, as well as wortmannin that blocks phosphoinositide-3 kinase (PI3K) stimulation, only partially inhibited Raf-1 and ERK1 stimulation. We also observed that DNR stimulated protein kinase C  (PKC), an atypical PKC isoform, and that both D609 and wortmannin significantly inhibited DNR-triggered PKC activation. Finally, we found that the expression of PKC kinase-defective mutant resulted in the abrogation of DNR-induced ERK phosphorylation. Altogether, these results demonstrate that DNR activates the classical Raf-1/MEK/ERK pathway and that Raf-1 activation is mediated through complex signaling pathways that involve at least 2 contributors: PC-derived DAG and PI3K products that converge toward PKC. Moreover, we show that both Raf-1 and MEK inhibitors, as well as PKC inhibition, sensitized cells to DNR-induced cytotoxicity. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Leseux, G. Laurent, C. Laurent, M. Rigo, A. Blanc, D. Olive, and C. Bezombes PKC {zeta} mTOR pathway: a new target for rituximab therapy in follicular lymphoma Blood, January 1, 2008; 111(1): 285 - 291. [Abstract] [Full Text] [PDF] J. Tan, P. P. Dwivedi, P. Anderson, B. K. Nutchey, P. O'Loughlin, H. A. Morris, B. K. May, A. Ferrante, and C. S. Hii Antineoplastic agents target the 25-hydroxyvitamin D3 24-hydroxylase messenger RNA for degradation: implications in anticancer activity Mol. Cancer Ther., December 1, 2007; 6(12): 3131 - 3138. [Abstract] [Full Text] [PDF] M. D. Short, S. M. Fox, C. F. Lam, K. R. Stenmark, and M. 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