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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3550-3557. Prepublished online as a Blood First Edition Paper on July 29, 2004; DOI 10.1182/blood-2004-03-1066. This Article Full Text (PDF) All Versions of this Article: 2004-03-1066v1 104/12/3550    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 Tonozuka, Y. Articles by Kitamura, T. Search for Related Content PubMed PubMed Citation Articles by Tonozuka, Y. Articles by Kitamura, T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 26, 2004 Accepted July 6, 2004 A GTPase activating protein binds STAT3 and is required for IL-6-induced STAT3 activation and for differentiation of a leukemic cell line Yukio Tonozuka, Yukinori Minoshima, Ying C Bao, Yuseok Moon, Yohei Tsubono, Tomonori Hatori, Hideaki Nakajima, Tetsuya Nosaka, Toshiyuki Kawashima, and Toshio Kitamura* Division of Cellular Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan Division of Hematopoietic Factors, Institute of Medical Science, University of Tokyo, Tokyo, Japan * Corresponding author; email: kitamura{at}ims.u-tokyo.ac.jp. We previously identified a GTPase-activating-protein MgcRacGAP that enhanced IL-6-induced macrophage differentiation of murine M1 leukemia cells. Later, MgcRacGAP was found to play crucial roles in cell division. However, how MgcRacGAP enhanced IL-6-induced differentiation remained elusive. Here we show that MgcRacGAP enhances IL-6-induced differentiation through enhancement of STAT3 activation. MgcRacGAP, Rac and STAT3 formed a complex in IL-6-stimulated M1 cells, where MgcRacGAP interacted with Rac1 and STAT3 through its cysteine-rich domain and GAP domain. In reporter assays, the wild type MgcRacGAP enhanced transcriptional activation of STAT3 while a GAP domain deletion mutant (GAP) did not significantly enhance it, suggesting that the GAP domain was required for enhancement of STAT3-dependent transcription. Intriguingly, expression of GAP had no effect on the differentiation signal of IL-6 in M1 cells, while forced expression of MgcRacGAP rendered M1 cells hyper-responsive to the IL-6-induced differentiation. Moreover, knockdown of MgcRacGAP by RNA interference profoundly suppressed STAT3 activation, implicating MgcRacGAP in the STAT3-dependent transcription. Altogether, our data not only reveal an important role for MgcRacGAP in STAT3 activation, but also demonstrate that MgcRacGAP regulates IL-6-induced cellular differentiation in which STAT3 plays a pivotal role. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Barros, P. Jordan, and P. Matos Rac1 Signaling Modulates BCL-6-Mediated Repression of Gene Transcription Mol. Cell. Biol., August 1, 2009; 29(15): 4156 - 4166. [Abstract] [Full Text] [PDF] T. Kawashima, Y. C. Bao, Y. Minoshima, Y. Nomura, T. Hatori, T. Hori, T. Fukagawa, T. Fukada, N. Takahashi, T. Nosaka, et al. A Rac GTPase-Activating Protein, MgcRacGAP, Is a Nuclear Localizing Signal-Containing Nuclear Chaperone in the Activation of STAT Transcription Factors Mol. Cell. Biol., April 1, 2009; 29(7): 1796 - 1813. [Abstract] [Full Text] [PDF] S. Grewal, J. G. Carver, A. J. Ridley, and H. J. Mardon Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration PNAS, October 21, 2008; 105(42): 16189 - 16194. [Abstract] [Full Text] [PDF] M. C. Simeone-Penney, M. Severgnini, L. Rozo, S. Takahashi, B. H. Cochran, and A. R. Simon PDGF-induced human airway smooth muscle cell proliferation requires STAT3 and the small GTPase Rac1 Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L698 - L704. [Abstract] [Full Text] [PDF] T. Kawashima, Y. C. Bao, Y. Nomura, Y. Moon, Y. Tonozuka, Y. Minoshima, T. Hatori, A. Tsuchiya, M. Kiyono, T. Nosaka, et al. Rac1 and a GTPase-activating protein, MgcRacGAP, are required for nuclear translocation of STAT transcription factors J. Cell Biol., December 18, 2006; 175(6): 937 - 946. [Abstract] [Full Text] [PDF] R. Ono, M. Ihara, H. Nakajima, K. Ozaki, Y. Kataoka-Fujiwara, T. Taki, K.-i. Nagata, M. Inagaki, N. Yoshida, T. Kitamura, et al. Disruption of Sept6, a Fusion Partner Gene of MLL, Does Not Affect Ontogeny, Leukemogenesis Induced by MLL-SEPT6, or Phenotype Induced by the Loss of Sept4 Mol. Cell. Biol., December 15, 2005; 25(24): 10965 - 10978. [Abstract] [Full Text] [PDF] E. E. Spangenburg SOCS-3 Induces Myoblast Differentiation J. Biol. Chem., March 18, 2005; 280(11): 10749 - 10758. [Abstract] [Full Text] [PDF]

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