SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-05-1585. This Article 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 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 Mansat-De Mas, V. Articles by Laurent, G. Search for Related Content PubMed PubMed Citation Articles by Mansat-De Mas, V. Articles by Laurent, G. Social Bookmarking                   What's this? Submitted June 4, 2002 Accepted October 1, 2002 Protein kinase C mediated Raf-1/extracellular-regulated kinase activation by daunorubicin Veronique Mansat-De Mas*, Helene Hernandez, Isabelle Plo, Christine Bezombes, Nicolas Maestre, Anne Quillet-Mary, Rodolphe Filomenko, Cecile Demur, Jean-Pierre Jaffrezou, and Guy Laurent INSERM, Unite 563, Institut Claudius Regaud, Toulouse, France Laboratoire d'Hematologie, Centre Hospitalier Universitaire Purpan, Toulouse, France Service d'Hematologie, Centre Hospitalier Universitaire Purpan, Toulouse, France INSERM, Unite 517, Ecole Pratique des Hautes Etudes, Dijon, France * Corresponding author; email: demas.v{at}chu-toulouse.fr. 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 (ERK) and stimulated activities of both Raf-1 and extracellular-regulated kinase 1 (ERK1) within 10 to 30 min in U937 cells. ERK1 stimulation was completely blocked by either the MEK inhibitor PD 98059 or the Raf-1 inhibitor 8-bromo-cAMP. However, only partial inhibition of Raf-1 and ERK1 stimulation was observed with the antioxidant N-acetylcysteine (N-Ac). Moreover, the xanthogenate compound D609 which inhibits DNR-induced phosphatidylcholine (PC) hydrolysis and subsequent diacylglycerol (DAG) production, as well as wortmannin which 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 which involve at least two contributors: PC-derived DAG, and PI3K products which converge towards PKC. Moreover, we show that both Raf-1 and MEK inhibitors, as well as PKC inhibition, sensitized cells to DNR-induced cytotoxicity. 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. Das Protein Kinase C{zeta} Attenuates Hypoxia-induced Proliferation of Fibroblasts by Regulating MAP Kinase Phosphatase-1 Expression Mol. Biol. Cell, April 1, 2006; 17(4): 1995 - 2008. [Abstract] [Full Text] [PDF] M. M. Belcheva, A. L. Clark, P. D. Haas, J. S. Serna, J. W. Hahn, A. Kiss, and C. J. Coscia {micro} and {kappa} Opioid Receptors Activate ERK/MAPK via Different Protein Kinase C Isoforms and Secondary Messengers in Astrocytes J. Biol. Chem., July 29, 2005; 280(30): 27662 - 27669. [Abstract] [Full Text] [PDF] F. B. Hickey, K. England, and T. G. Cotter Bcr-Abl regulates osteopontin transcription via Ras, PI-3K, aPKC, Raf-1, and MEK J. Leukoc. Biol., July 1, 2005; 78(1): 289 - 300. [Abstract] [Full Text] [PDF] L. Duca, E. Lambert, R. Debret, B. Rothhut, C. Blanchevoye, F. Delacoux, W. Hornebeck, L. Martiny, and L. Debelle Elastin Peptides Activate Extracellular Signal-Regulated Kinase 1/2 via a Ras-Independent Mechanism Requiring Both p110{gamma}/Raf-1 and Protein Kinase A/B-Raf Signaling in Human Skin Fibroblasts Mol. Pharmacol., April 1, 2005; 67(4): 1315 - 1324. [Abstract] [Full Text] [PDF] G. W. Small, S. Somasundaram, D. T. Moore, Y. Y. Shi, and R. Z. Orlowski Repression of Mitogen-Activated Protein Kinase (MAPK) Phosphatase-1 by Anthracyclines Contributes to Their Antiapoptotic Activation of p44/42-MAPK J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 861 - 869. [Abstract] [Full Text] [PDF]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020