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Blood, 15 January 2005, Vol. 105, No. 2, pp. 775-783. Prepublished online as a Blood First Edition Paper on September 7, 2004; DOI 10.1182/blood-2004-04-1242. This Article Full Text (PDF) All Versions of this Article: 2004-04-1242v1 105/2/775    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 Tomoda, K. Articles by Yoneda-Kato, N. Search for Related Content PubMed PubMed Citation Articles by Tomoda, K. Articles by Yoneda-Kato, N. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 6, 2004 Accepted August 29, 2004 The Jab1/ COP9 signalosome subcomplex is a downstream mediator of Bcr-Abl kinase activity and facilitates cell cycle progression Kiichiro Tomoda, Jun-ya Kato, Eiji Tatsumi, Takayuki Takahashi, Yoshinobu Matsuo, and Noriko Yoneda-Kato* Department of Animal Molecular Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara, Japan International Center for Medical Research, Kobe University School of Medicine, Kobe, Japan Department of Hematology and Clinical Immunology, Kobe City General Hospital, Kobe, Japan Fujisaki Cell Center, Hayashibara Biochemical Labs Inc., Fujisaki, Okayama, Japan * Corresponding author; email: noriko-k{at}bs.naist.jp. Jab1 is a multifunctional protein associated with the signaling pathway, cell cycle regulation and development, and acts as a key subunit of COP9 signalosome (CSN). Jab1 promotes degradation of the cyclin-dependent kinase inhibitor p27Kip1 by transportation from the nucleus to the cytoplasm. However, there has been no clear evidence for whether and how Jab1 contributes to malignant transformation in human cancers. Here we show that Bcr-Abl tyrosine kinase facilitates the downregulation of p27 by modulating complex formation of Jab1/CSN through the MAP kinase and PI3 kinase signaling pathways. Nearly half of the chronic myelogenous leukemia cell lines and the murine hematopoietic precursor cells expressing Bcr-Abl exhibited a marked increase in the small Jab1complex located in the cytoplasm. Inhibition of Bcr-Abl kinase by STI571 induced G1 arrest and caused a recovery of the p27 level with reduction of the small Jab1complex from the cytoplasm. Either blockade of the MAP kinase and PI3 kinase pathways by specific inhibitors or Jab1-knockdown by siRNA prevented p27 downregulation as well as formation of the small complex. Thus, regulation of p27 via modulation of the Jab1 subcomplex is a novel mechanism whereby Bcr-Abl oncogenic signals accelerate abnormal cell proliferation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M.-C. Hsu, C.-C. Huang, H.-C. Chang, T.-H. Hu, and W.-C. Hung Overexpression of Jab1 in Hepatocellular Carcinoma and Its Inhibition by Peroxisome Proliferator-Activated Receptor{gamma} Ligands In vitro and In vivo Clin. Cancer Res., July 1, 2008; 14(13): 4045 - 4052. [Abstract] [Full Text] [PDF] Y. Miyauchi, M. Kato, F. Tokunaga, and K. Iwai The COP9/Signalosome Increases the Efficiency of von Hippel-Lindau Protein Ubiquitin Ligase-mediated Hypoxia-inducible Factor-{alpha} Ubiquitination J. Biol. Chem., June 13, 2008; 283(24): 16622 - 16631. [Abstract] [Full Text] [PDF]

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