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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 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 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 Harir, N. Articles by Gouilleux, F. Search for Related Content PubMed PubMed Citation Articles by Harir, N. Articles by Gouilleux, F. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Constitutive activation of Stat5 promotes its cytoplasmic localization and association with PI3-kinase in myeloid leukemias Noria Harir1, Christian Pecquet1, Marc Kerenyi2, Karoline Sonneck3, Boris Kovacic2, Remy Nyga1, Marie Brevet4, Isabelle Dhennin1, Valerie Gouilleux-Gruart1, Hartmut Beug2, Peter Valent3, Kaiss Lassoued1, Richard Moriggl5, and Fabrice Gouilleux1 1 Institut National de la Santé et de la Recherche Médicale (EMI 351), Faculté de Médecine, Université de Picardie J. Verne, Amiens, France; 2 Institute of Molecular Pathology, Vienna, Austria; 3 Department of Internal Medicine I, Division of Hematology, Medical University of Vienna, Austria; 4 Laboratory of Anatomo-Pathology, Centre Hospitalier Universitaire, Amiens, France; 5 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria 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 PI3-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 with 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 signaling effectors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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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