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This Article Full Text Full Text (PDF) 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 Maddens, S. Articles by Jaffrézou, J.-P. Search for Related Content PubMed PubMed Citation Articles by Maddens, S. Articles by Jaffrézou, J.-P. Related Collections Hematopoiesis and Stem Cells Apoptosis Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 August 2002, Vol. 100, No. 4, pp. 1294-1301 HEMATOPOIESIS Kit signaling inhibits the sphingomyelin-ceramide pathway through PLC1: implication in stem cell factor radioprotective effect Stéphane Maddens, Alexandra Charruyer, Isabelle Plo, Patrice Dubreuil, Stuart Berger, Bernard Salles, Guy Laurent, and Jean-Pierre Jaffrézou From the Institut Nationale de la Santé et de la Recherche Médicale E9910, Institut Claudius Régaud, Institut de Pharmacologie et de Biologie Structurale, Service d'Hématologie, and Centre Hospitalier Universitaire Purpan, Toulouse, France; Laboratoire de Cancérologie Expérimentale, Institut National de la Santé et de la Recherche Médicale U119, Institut Paoli Calmettes, Marseille, France; and Arthritis and Immune Disorder Research Centre, Toronto, Ontario, Canada. Previous studies demonstrated that Kit activation confers radioprotection. However, the mechanism by which Kit signaling interferes with cellular response to ionizing radiation (IR) has not been firmly established. Based on the role of the sphingomyelin (SM) cycle apoptotic pathway in IR-induced apoptosis, we hypothesized that one of the Kit signaling components might inhibit IR-induced ceramide production or ceramide-induced apoptosis. Results show that, in both Ba/F3 and 32D murine cell lines transfected with wild-type c-kit, stem cell factor (SCF) stimulation resulted in a significant reduction of IR-induced apoptosis and cytotoxicity, whereas DNA repair remained unaffected. Moreover, SCF stimulation inhibited IR-induced neutral sphingomyelinase (N-SMase) stimulation and ceramide production. The SCF inhibitory effect on SM cycle was not influenced by wortmannin, a phosphoinositide-3 kinase (PI3K) inhibitor. The SCF protective effect was maintained in 32D-KitYF719 cells in which the PI3K/Akt signaling pathway is abolished due to mutation in Kit docking site for PI3K. In contrast, phospholipase C  (PLC) inhibition by U73122 totally restored IR-induced N-SMase stimulation, ceramide production, and apoptosis in Kit-activated cells. Moreover, SCF did not protect 32D-KitYF728 cells (lacking a functional docking site for PLC1), from IR-induced SM cycle. Finally, SCF-induced radioprotection of human CD34+ bone marrow cells was also inhibited by U73122. Altogether, these results suggest that SCF radioprotection is due to PLC1-dependent negative regulation of IR-induced N-SMase stimulation. Beyond the scope of Kit-expressing cells, it suggests that PLC1 status could greatly influence the post-DNA damage cellular response to IR, and perhaps, to other genotoxic agents. © 2002 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: S. W. Redding Cancer Therapy-Related Oral Mucositis J Dent Educ., August 1, 2005; 69(8): 919 - 929. [Abstract] [Full Text] [PDF] J. Lennartsson, T. Jelacic, D. Linnekin, and R. Shivakrupa Normal and Oncogenic Forms of the Receptor Tyrosine Kinase Kit Stem Cells, January 1, 2005; 23(1): 16 - 43. [Abstract] [Full Text] [PDF] L. Hong, V. Munugalavadla, and R. Kapur c-Kit-Mediated Overlapping and Unique Functional and Biochemical Outcomes via Diverse Signaling Pathways Mol. Cell. Biol., February 1, 2004; 24(3): 1401 - 1410. [Abstract] [Full Text] [PDF]

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