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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1678-1686. Prepublished online as a Blood First Edition Paper on October 12, 2006; DOI 10.1182/blood-2006-01-029918. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-01-029918v1 109/4/1678    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 Harir, N. Articles by Gouilleux, F. Search for Related Content PubMed PubMed Citation Articles by Harir, N. Articles by Gouilleux, F. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 19, 2006 Accepted September 25, 2006 Constitutive activation of Stat5 promotes its cytoplasmic localization and association with PI 3-kinase in myeloid leukemias Noria Harir, Christian Pecquet, Marc Kerenyi, Karoline Sonneck, Boris Kovacic, Remy Nyga, Marie Brevet, Isabelle Dhennin, Valerie Gouilleux-Gruart, Hartmut Beug, Peter Valent, Kaiss Lassoued, Richard Moriggl, and Fabrice Gouilleux* Institut National de la Sante et de la Recherche Medicale (EMI 351), France Institute of Molecular Pathology, Austria Medical University of Vienna, Austria Centre Hospitalier Universitaire, France Ludwig Boltzmann Institute for Cancer Research, Austria * Corresponding author; email: fabrice.gouilleux{at}sa.u-picardie.fr. Persistent activation of Stat5 is frequently found in hematologic neoplasms. Studies conducted with constitutively active Stat5 mutants (Stat51*6 and cS5F) have shown that deregulated Stat5 activity promotes leukemogenesis. To investigate the oncogenic properties of these mutants, we used cS5F-expressing bone marrow cells which induce a multilineage leukemia when transplanted into recipient mice. Here, we show by immunocytochemistry that cS5F is localized mainly in the cytoplasmic compartment of leukemic cells suggesting that the transforming nature of cS5F may be associated with a cytoplasmic function. In support of this hypothesis, we found that cS5F forms a complex with the p85 subunit of the Phosphatidylinositol 3-kinase (PI3-K) and the scaffolding adapter Gab2 in leukemic bone marrow cells resulting in the activation of Akt/PKB, a crucial downstream target of PI3-K. By using transducible TAT-Gab2 or TAT-Akt recombinant proteins, we were able to demonstrate that activation of the PI 3-kinase/Akt pathway by cS5F molecules through Gab2 is essential for induction of cell growth. We also found that persistently phosphorylated Stat5 in primary cells from patients suffering from myeloid leukemias has a cytoplasmic localization. These data suggest that oncogenic Stat5 proteins exert dual transforming capabilities not only as transcriptional activators but also as cytoplasmic signalling effectors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Benekli, H. Baumann, and M. Wetzler Targeting Signal Transducer and Activator of Transcription Signaling Pathway in Leukemias J. Clin. Oncol., September 10, 2009; 27(26): 4422 - 4432. [Abstract] [Full Text] [PDF] A. T. J. Wierenga, E. Vellenga, and J. J. Schuringa Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels Mol. Cell. Biol., November 1, 2008; 28(21): 6668 - 6680. [Abstract] [Full Text] [PDF] N. Harir, C. Boudot, K. Friedbichler, K. Sonneck, R. Kondo, S. Martin-Lanneree, L. Kenner, M. Kerenyi, S. Yahiaoui, V. Gouilleux-Gruart, et al. Oncogenic Kit controls neoplastic mast cell growth through a Stat5/PI3-kinase signaling cascade Blood, September 15, 2008; 112(6): 2463 - 2473. [Abstract] [Full Text] [PDF] C. Sebastian, M. Serra, A. Yeramian, N. Serrat, J. Lloberas, and A. Celada Deacetylase Activity Is Required for STAT5-Dependent GM-CSF Functional Activity in Macrophages and Differentiation to Dendritic Cells J. Immunol., May 1, 2008; 180(9): 5898 - 5906. [Abstract] [Full Text] [PDF] F. Grebien, M. A. Kerenyi, B. Kovacic, T. Kolbe, V. Becker, H. Dolznig, K. Pfeffer, U. Klingmuller, M. Muller, H. Beug, et al. Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2 Blood, May 1, 2008; 111(9): 4511 - 4522. [Abstract] [Full Text] [PDF] G. Wernig, J. R. Gonneville, B. J. Crowley, M. S. Rodrigues, M. M. Reddy, H. E. Hudon, C. Walz, A. Reiter, K. Podar, Y. Royer, et al. The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes Blood, April 1, 2008; 111(7): 3751 - 3759. [Abstract] [Full Text] [PDF] J. A. Wofford, H. L. Wieman, S. R. Jacobs, Y. Zhao, and J. C. Rathmell IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival Blood, February 15, 2008; 111(4): 2101 - 2111. [Abstract] [Full Text] [PDF] H. M. Lockyer, E. Tran, and B. H. Nelson STAT5 Is Essential for Akt/p70S6 Kinase Activity during IL-2-Induced Lymphocyte Proliferation J. Immunol., October 15, 2007; 179(8): 5301 - 5308. [Abstract] [Full Text] [PDF] K. D. Bunting, X. Y. Xie, I. Warshawsky, and E. D. Hsi Cytoplasmic localization of phosphorylated STAT5 in human acute myeloid leukemia is inversely correlated with Flt3-ITD Blood, October 1, 2007; 110(7): 2775 - 2776. [Full Text] [PDF] H. Zhou, R. Miki, M. Eeva, F. M. Fike, D. Seligson, L. Yang, A. Yoshimura, M. A. Teitell, C. A.M. Jamieson, and N. A. Cacalano Reciprocal Regulation of SOCS 1 and SOCS3 Enhances Resistance to Ionizing Radiation in Glioblastoma Multiforme Clin. Cancer Res., April 15, 2007; 13(8): 2344 - 2353. [Abstract] [Full Text] [PDF]

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