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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2436-2443. Prepublished online as a Blood First Edition Paper on March 24, 2005; DOI 10.1182/blood-2004-10-4003. This Article Full Text (PDF) All Versions of this Article: 2004-10-4003v1 106/7/2436    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 Parmar, S. Articles by Platanias, L. C Search for Related Content PubMed PubMed Citation Articles by Parmar, S. Articles by Platanias, L. C Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 19, 2004 Accepted March 16, 2005 Differential regulation of the p70 S6 kinase pathway by interferon and imatinib mesylate (STI571) in chronic myelogenous leukemia cells Simrit Parmar, Jessica Smith, Antonella Sassano, Shahab Uddin, Efstratios Katsoulidis, Beata Majchrzak, Suman Kambhampati, Elizabeth A Eklund, Martin S Tallman, Eleanor N Fish, and Leonidas C Platanias* Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School, and Lakeside Veterans Administration Medical Center, Chicago, IL, USA Section of Hematology-Oncology, University of Chicago, Chicago, IL, USA Division of Cell & Molecular Biology, Toronto Research Institute, University Network and Department of Immunology, University of Toronto, Toronto, ON, Canada * Corresponding author; email: l-platanias{at}northwestern.edu. The precise mechanisms by which imatinib mesylate and IFN exhibit antileukemic effects are not known. We examined the effects of IFNs or imatinib mesylate on signaling pathways regulating initiation of mRNA translation in BCR-ABL expressing cells. Treatment of IFN sensitive KT-1 cells with IFN resulted in phosphorylation/activation of mTOR and downstream activation of p70S6K. The IFN activated p70S6K was found to regulate phosphorylation of S6 ribosomal protein, which regulates translation of mRNAs with oligopyrimidine tracts in the 5'-untranslated region. In addition, IFN -treatment resulted in an mTOR- and/or PI3'kinase-dependent phosphorylation of 4E-BP1 repressor of mRNA translation on sites that are required for its de-activation and dissociation from the eIF4E-complex. In contrast to the effects of IFNs, STI571 suppressed p70 S6K activity, consistent with inhibition of BCR-ABL mediated activation of the mTOR/p70S6K pathway. Moreover, the mTOR inhibitor rapamycin enhanced the suppressive effects of STI571 on primary leukemic CFU-GM progenitors from CML-patients. Taken altogether, our data demonstrate that IFNs and STI571 differentially regulate PI3'-kinase/mTOR-dependent signaling cascades in BCR-ABL-transformed cells, consistent with distinct effects of these agents on pathways regulating mRNA translation. They also support the concept that combined use of STI571 with mTOR inhibitors may be an appropriate future therapeutic strategy for the treatment of CML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Kroczynska, S. Kaur, E. Katsoulidis, B. Majchrzak-Kita, A. Sassano, S. C. Kozma, E. N. Fish, and L. C. Platanias Interferon-Dependent Engagement of Eukaryotic Initiation Factor 4B via S6 Kinase (S6K)- and Ribosomal Protein S6K-Mediated Signals Mol. Cell. Biol., May 15, 2009; 29(10): 2865 - 2875. [Abstract] [Full Text] [PDF] A. J. Redig, A. Sassano, B. Majchrzak-Kita, E. Katsoulidis, H. Liu, J. K. Altman, E. N. Fish, A. Wickrema, and L. C. Platanias Activation of Protein Kinase C{eta} by Type I Interferons J. Biol. Chem., April 17, 2009; 284(16): 10301 - 10314. [Abstract] [Full Text] [PDF] E. Katsoulidis, A. Sassano, B. Majchrzak-Kita, N. Carayol, P. Yoon, A. Jordan, B. J. Druker, E. N. Fish, and L. C. Platanias Suppression of Interferon (IFN)-inducible Genes and IFN-mediated Functional Responses in BCR-ABL-expressing Cells J. Biol. Chem., April 18, 2008; 283(16): 10793 - 10803. [Abstract] [Full Text] [PDF] N. Carayol, E. Katsoulidis, A. Sassano, J. K. Altman, B. J. Druker, and L. C. Platanias Suppression of Programmed Cell Death 4 (PDCD4) Protein Expression by BCR-ABL-regulated Engagement of the mTOR/p70 S6 Kinase Pathway J. Biol. Chem., March 28, 2008; 283(13): 8601 - 8610. [Abstract] [Full Text] [PDF] J. K. Altman, P. Yoon, E. Katsoulidis, B. Kroczynska, A. Sassano, A. J. Redig, H. Glaser, A. Jordan, M. S. Tallman, N. Hay, et al. Regulatory Effects of Mammalian Target of Rapamycin-mediated Signals in the Generation of Arsenic Trioxide Responses J. Biol. Chem., January 25, 2008; 283(4): 1992 - 2001. [Abstract] [Full Text] [PDF] C. Yoshida, F. Yoshida, D. E. Sears, S. M. Hart, D. Ikebe, A. Muto, S. Basu, K. Igarashi, and J. V. Melo Bcr-Abl signaling through the PI-3/S6 kinase pathway inhibits nuclear translocation of the transcription factor Bach2, which represses the antiapoptotic factor heme oxygenase-1 Blood, February 1, 2007; 109(3): 1211 - 1219. [Abstract] [Full Text] [PDF] S. Kaur, L. Lal, A. Sassano, B. Majchrzak-Kita, M. Srikanth, D. P. Baker, E. Petroulakis, N. Hay, N. Sonenberg, E. N. Fish, et al. Regulatory Effects of Mammalian Target of Rapamycin-activated Pathways in Type I and II Interferon Signaling J. Biol. Chem., January 19, 2007; 282(3): 1757 - 1768. [Abstract] [Full Text] [PDF] P. Yoon, N. Giafis, J. Smith, H. Mears, E. Katsoulidis, A. Sassano, J. Altman, A. J. Redig, M. S. Tallman, and L. C. Platanias Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL-expressing cells. Mol. Cancer Ther., November 1, 2006; 5(11): 2815 - 2823. [Abstract] [Full Text] [PDF]

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