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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-02-0539. This Article Full Text (PDF) All Versions of this Article: 2002-02-0539v1 100/10/3741    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 Ringshausen, I. Articles by Decker, T. Search for Related Content PubMed PubMed Citation Articles by Ringshausen, I. Articles by Decker, T. Social Bookmarking                   What's this? Submitted February 20, 2002 Accepted June 25, 2002 Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with Proteinkinase C Ingo Ringshausen*, Folker Schneller, Christian Bogner, Susanne Hipp, Justus Duyster, Christian Peschel, and Thomas Decker IIIrd Department of Medicine, Technical University of Munich, Munich, Germany, Munich, Germany * Corresponding author; email: i.ringshausen{at}lrz.tum.de. In the present study we analyzed the role of phophatidylinositol-3 kinase (PI-3K) in B-CLL cells. PI-3 kinase is activated by many stimuli and is linked to several different signaling pathways. We demonstrated that inhibition of PI-3 kinase by a specific inhibitor LY294002 induced apoptosis in B-CLL cells in vitro. This effect was specific for the inhibition of PI-3 kinase as inhibition of other signaling pathways like extracellular signaling-regulated kinase (ERK), p38 or p70S6 kinase did not affect spontaneous apoptosis. Furthermore PI-3 kinase was constitutively activated in freshly isolated B-CLL cells. Corresponding to enhanced apoptosis, LY294002 downregulated expression of the antiapoptotic proteins XIAP and Mcl-1. Next we investigated which factors downstream of PI-3 kinase were activated in B-CLL cells. We demonstrated that Proteinkinase B/Akt is expressed in all tested CLL samples but no activation of Akt was detected. In contrast, we observed a constitutive activation of PKC in freshly isolated B-CLL cells. PKC is linked to PI-3 kinase and phosphorylated at threonine 505 in response to PI-3 kinase activation. We further demonstrated that tyrosinephosphorylation and activity of PKC were depending on PI-3 kinase activity in B-CLL cells. Inhibition of PKC by the specific inhibitor Rottlerin strikingly enhanced apoptosis. In contrast, peripheral blood B-cells of healthy donors were resistant to inhibition of PI-3K or PKC. We conclude that activated PI-3 kinase might be important in the pathogenesis of B-CLL and survival signals might be mediated via PKC. Therefore inhibition of PI-3 kinase or PKC may be an innovative approach to treat B-CLL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Herling, K. A. Patel, N. Weit, N. Lilienthal, M. Hallek, M. J. Keating, and D. Jones High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia Blood, November 19, 2009; 114(21): 4675 - 4686. [Abstract] [Full Text] [PDF] J. L. Costantini, S. M. S. Cheung, S. Hou, H. Li, S. K. Kung, J. B. Johnston, J. A. Wilkins, S. B. Gibson, and A. J. 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