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Cooperation between STAT5 and phosphatidylinositol 3-kinase in the IL-3-dependent survival of a bone marrow derived cell line

Oncogene volume 19, pages 1164–1172 (2000)Cite this article

Abstract

Cytokine-dependent activation of distinct signaling pathways is a common scheme thought to be required for the subsequent programmation into cell proliferation and survival. The PI 3-kinase/Akt, Ras/MAP kinase, Ras/NFIL3 and JAK/STAT pathways have been shown to participate in cytokine mediated suppression of apoptosis in various cell types. However the relative importance of these signaling pathways seems to depend on the cellular context. In several cases, individual inhibition of each pathway is not sufficient to completely abrogate cytokine mediated cell survival suggesting that cooperation between these pathways is required. Here we showed that individual inhibition of STAT5, PI 3-kinase or MEK activities did not or weakly affected the IL-3 dependent survival of the bone marrow derived Ba/F3 cell line. However, the simultaneous inhibition of STAT5 and PI 3-kinase activities but not that of STAT5 and MEK reduced the IL-3 dependent survival of Ba/F3. Analysis of the expression of the Bcl-2 members indicated that phosphorylation of Bad and Bcl-x expression which are respectively regulated by the PI 3-kinase/Akt pathway and STAT5 probably explain this cooperation. Furthermore, we showed by co-immunoprecipitation studies and pull down experiments with fusion proteins encoding the GST-SH2 domains of p85 that STAT5 in its phosphorylated form interacts with the p85 subunit of the PI 3-kinase. These results indicate that the activations of STAT5 and the PI 3-kinase by IL-3 in Ba/F3 cells are tightly connected and cooperate to mediate IL-3-dependent suppression of apoptosis by modulating Bad phosphorylation and Bcl-x expression.

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Acknowledgements

The authors would like to thank Isabelle Bouchaert for her help in the FACS analysis studies, Dr S Chretien for providing the anti-STAT5A antibody and Dr C Lacombe for critical reading of the manuscript. This work was supported by ARC (Association de Recherche contre le Cancer) and INSERM (Institut National de la Recherche Medicale). SCR Santos is supported by JNICT/Praxis XXI and S Dumon is supported by the Ministere de l'Education de la Recherche et de la Technologie (MERT).

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  1. The Institut Cochin de Génétique Moléculaire (ICGM), Institut National de la Santé et de la Recherche Médicale (INSERM U363), Hôpital Cochin, 27 rue du Fbg St Jacques, Paris, 75014, France

    Susana Constantino Rosa Santos, Stephanie Dumon, Patrick Mayeux, Sylvie Gisselbrecht & Fabrice Gouilleux

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  1. Susana Constantino Rosa Santos
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  2. Stephanie Dumon
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Santos, S., Dumon, S., Mayeux, P. et al. Cooperation between STAT5 and phosphatidylinositol 3-kinase in the IL-3-dependent survival of a bone marrow derived cell line. Oncogene 19, 1164–1172 (2000). https://doi.org/10.1038/sj.onc.1203418

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