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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2324-2331. Prepublished online as a Blood First Edition Paper on November 23, 2004; DOI 10.1182/blood-2004-08-3247. This Article Full Text (PDF) All Versions of this Article: 2004-08-3247v1 105/6/2324    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 Tanaka, A. Articles by Matsuda, H. Search for Related Content PubMed PubMed Citation Articles by Tanaka, A. Articles by Matsuda, H. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 23, 2004 Accepted October 30, 2004 A novel NF-B inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors Akane Tanaka, Masayo Konno, Susumu Muto, Naotomo Kambe, Eiichi Morii, Tatsutoshi Nakahata, Akiko Itai, and Hiroshi Matsuda* Laboratory of Molecular Pathology and Therapeutics, Division of Animal Life Science, Graduate School, Institute of Symbiotic Science and Technology, Tokyo University of Agriculture and Technology, Tokyo, Japan Institute of Medicinal Molecular Design Inc., Tokyo, Japan Department of Dermatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan Department of Pathology, Osaka University Medical School/Graduate School of Frontier Bioscience, Suita, Osaka, Japan Department of Pediatrics, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan * Corresponding author; email: hiro{at}cc.tuat.ac.jp. Constitutive phosphorylation of c-kit tyrosine kinase is the major cause of factor-independent proliferation of mast cells. Recently available tyrosine kinase inhibitors have shown marked activity against mast cell lines that carry wild-type as well as some but not other mutant c-kit. Here we clearly demonstrated that a novel NF-B inhibitor, IMD-0354, restrained factor-independent proliferation of mast cells with c-kit mutations but not normal mast cells. In HMC-1 cells with the Asp816Val and Val560Gly mutations, we found that NF-B was constitutively activated without any exogenous stimulation. When DNA binding activity of NF-B was inhibited by treatment with IMD-0354, cell proliferation was completely suppressed. We detected expression of cyclin D2, D3, and E in HMC-1 cells, and that cyclin D3 expression was dramatically decreased by treatment with IMD-0354. Abolishing protein kinase C or phosphatidylinositol 3 kinase pathways also inhibited NF-B translocation to the nucleus, indicating the involvement of these signaling cascades in NF-B activation in HMC-1 cells. Our findings indicated that auto-phosphorylated c-kit receptors induced NF-B activation, resulting in up-regulation of cyclin D3 expression and cell cycle progression. The observations from the current study suggest a therapeutic potential, in systemic mastocytosis, for compounds that interfere with NF-B signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Mutant Kit: thwarting the message down below Ayalew Tefferi Blood 2005 105: 2240-2241. [Full Text] [PDF] This article has been cited by other articles: C.-B. Xu, J.-P. Zheng, W. Zhang, Y. Zhang, and L. Edvinsson Lipid-Soluble Smoke Particles Upregulate Vascular Smooth Muscle ETB Receptors via Activation of Mitogen-Activating Protein Kinases and NF-kappaB Pathways Toxicol. Sci., December 1, 2008; 106(2): 546 - 555. [Abstract] [Full Text] [PDF] A. Yanai, S. Maeda, W. Shibata, Y. Hikiba, K. Sakamoto, H. Nakagawa, T. Ohmae, Y. Hirata, K. Ogura, S. Muto, et al. Activation of I{kappa}B Kinase and NF-{kappa}B Is Essential for Helicobacter pylori-Induced Chronic Gastritis in Mongolian Gerbils Infect. Immun., February 1, 2008; 76(2): 781 - 787. [Abstract] [Full Text] [PDF] A. Tefferi, S. Verstovsek, and A. Pardanani How we diagnose and treat WHO-defined systemic mastocytosis in adults Haematologica, January 1, 2008; 93(1): 6 - 9. [Full Text] [PDF] E. Voisset, S. Lopez, P. Dubreuil, and P. De Sepulveda The tyrosine kinase FES is an essential effector of KITD816V proliferation signal Blood, October 1, 2007; 110(7): 2593 - 2599. [Abstract] [Full Text] [PDF] Y. Onai, J.-i. Suzuki, Y. Maejima, G. Haraguchi, S. Muto, A. Itai, and M. Isobe Inhibition of NF-{kappa}B improves left ventricular remodeling and cardiac dysfunction after myocardial infarction Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H530 - H538. [Abstract] [Full Text] [PDF] B. Wang, J. Tsukada, T. Higashi, T. Mizobe, A. Matsuura, F. Mouri, N. Sawamukai, C. Ra, and Y. Tanaka Growth suppression of human mast cells expressing constitutively active c-kit receptors by JNK inhibitor SP600125. Genes Cells, September 1, 2006; 11(9): 983 - 992. [Abstract] [Full Text] [PDF] N. P. Shah, F. Y. Lee, R. Luo, Y. Jiang, M. Donker, and C. Akin Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis Blood, July 1, 2006; 108(1): 286 - 291. [Abstract] [Full Text] [PDF] M. Inayama, Y. Nishioka, M. Azuma, S. Muto, Y. Aono, H. Makino, K. Tani, H. Uehara, K. Izumi, A. Itai, et al. A Novel I{kappa}B Kinase-beta Inhibitor Ameliorates Bleomycin-induced Pulmonary Fibrosis in Mice Am. J. Respir. Crit. Care Med., May 1, 2006; 173(9): 1016 - 1022. [Abstract] [Full Text] [PDF] A. Tanaka, S. Muto, M. Konno, A. Itai, and H. Matsuda A New I{kappa}B Kinase {beta} Inhibitor Prevents Human Breast Cancer Progression through Negative Regulation of Cell Cycle Transition Cancer Res., January 1, 2006; 66(1): 419 - 426. [Abstract] [Full Text] [PDF]

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