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Expression of a mutated form of the p85α regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO)

Leukemia volume 16, pages 894–901 (2002)Cite this article

Abstract

Phosphatidylinositol (PI) 3-kinase plays an important role in a variety of biological processes, including proliferation and apoptosis. PI3-kinase is a heterodimer consisting of an 85 kDa adapter protein (p85) containing one SH3 domain and two SH2 domains and a 110 kDa catalytic subunit (p110). Recently an oncogenic form of p85 named p65-PI3K lacking the C-terminal SH2 domain has been cloned from an irradiation-induced murine thymic lymphoma and transgenic mice expressing p65-PI3K in T lymphocytes develop a lymphoproliferative disorder. Here we describe the cloning of a C-terminal truncated form of p85 expressed in a human lymphoma cell line (CO) with a T cell phenotype derived from a patient with Hodgkin's disease. As a result of a frame-shift mutation at amino acid 636, p76 is lacking most of the C-terminal SH2 domain, but contains the inter-SH2 domain and is associated with an active form of PI3-kinase. A PI3-kinase-dependent constitutive activation of Akt was detected in CO cells which was only partially reduced after serum starvation. Treatment of CO cells with the PI3-kinase inhibitor wortmannin resulted in a concentration-dependent inhibition of cell proliferation associated with an increased number of apoptotic cells. This is the first detection of a mutated form of the p85 subunit of PI3-kinase in human hematopoietic cells further underlining a potential role of PI3-kinase/Akt signaling in human leukemogenesis.

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Acknowledgements

This work was supported by grants from the National Cancer Institute (CA55293) and the National Leukemia Association to RAF and by a grant from the Deutsche Forschungsgemeinschaft (JU255/2–1) to MJ. We are grateful to Margaret A Tate and Sigrid Poll for excellent technical assistance. We also thank Drs H Tesch, V Diehl, DB Jones, S Poppema, H Kamesaki, HG Drexler and A Guse for generously providing cell lines.

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  1. Abteilung für Zelluläre Signaltransduktion, Institut für Medizinische Biochemie und Molekularbiologie, Universitätsklinikum Hamburg-Eppendorf, Universität Hamburg, Hamburg, Germany

    M Jücker, K Südel, S Horn & W Wegner

  2. Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD, USA

    M Jücker, M Sickel & RA Feldman

  3. Abteilung für Hämatologie/Onkologie, Universitätsklinikum Hamburg-Eppendorf, Universität Hamburg, Hamburg, Germany

    W Fiedler

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Jücker, M., Südel, K., Horn, S. et al. Expression of a mutated form of the p85α regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO). Leukemia 16, 894–901 (2002). https://doi.org/10.1038/sj.leu.2402484

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