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Blood, 15 May 2008, Vol. 111, No. 10, pp. 5142-5151. Prepublished online as a Blood First Edition Paper on March 13, 2008; DOI 10.1182/blood-2007-07-103481. This Article Full Text (PDF) All Versions of this Article: blood-2007-07-103481v1 111/10/5142    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dal Col, J. Articles by Dolcetti, R. Search for Related Content PubMed PubMed Citation Articles by Dal Col, J. Articles by Dolcetti, R. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 27, 2007 Accepted March 7, 2008 Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma Jessica Dal Col, Paola Zancai, Liliana Terrin, Massimo Guidoboni, Maurilio Ponzoni, Alessandro Pavan, Michele Spina, Stefano Bergamin, Silvana Rizzo, Umberto Tirelli, Anita De Rossi, Claudio Doglioni, and Riccardo Dolcetti* Cancer Bio-Immunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, IRCCS- National Cancer Institute, Aviano, Italy Department of Oncology and Surgical Sciences, University of Padova and Istituto Oncologico Veneto, Padova, Italy Pathology Unit, Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy Medical Oncology A, Department. of Medical Oncology, Centro di Riferimento Oncologico, IRCCS- National Cancer Institute, Aviano, Italy * Corresponding author; email: rdolcetti{at}cro.it. Functional characterization of signaling pathways that critically control mantle cell lymphoma (MCL) cell growth and survival is relevant to design new therapies for this lymphoma. We herein demonstrate that the constitutive activation of Akt correlates with the expression of the phosphorylated, inactive form of PTEN. PI3-K/Akt or mTOR inhibition decreased the growth of both primary MCL cultures and established cell lines and antagonizes the growth-promoting activity of CD40 triggering and IL-4. These effects are mediated by nuclear accumulation of the p27Kip1 inhibitor induced by down-regulation of the p45Skp2 and Cks1 proteins, which target p27Kip1 for degradation. Moreover, Akt inhibition down-regulated cyclin D1 by promoting its proteasome-dependent degradation driven by GSK-3. Intriguingly, mTOR inhibition affected cyclin D1 proteolysis only in MCL cells in which GSK-3 is under the direct control of mTOR, suggesting that different MCL subsets could be differently responsive to mTOR inhibition. Finally, PI3-K/Akt inhibitors, but not rapamycin, induced variable levels of caspase-dependent apoptosis and reduced telomerase activity. These results indicate that Akt and mTOR activation have distinct functional relevance in MCL and suggest that targeting Akt may result in more effective therapeutic effects compared to mTOR inhibition. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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