SEARCH:   Advanced

Blood, 15 April 2007, Vol. 109, No. 8, pp. 3509-3512. Prepublished online as a Blood First Edition Paper on December 19, 2006; DOI 10.1182/blood-2006-06-030833. This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: blood-2006-06-030833v1 109/8/3509    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Zeng, Z. Articles by Konopleva, M. Search for Related Content PubMed PubMed Citation Articles by Zeng, Z. Articles by Konopleva, M. Related Collections Signal Transduction Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Brief Report Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML Zhihong Zeng1, Dos D. Sarbassov2,3, Ismael J. Samudio1, Karen W. L. Yee4, Mark F. Munsell5, C. Ellen Jackson1, Francis J. Giles4, David M. Sabatini2,3, Michael Andreeff1,4, and Marina Konopleva1 1 Section of Molecular Hematology and Therapy, Departments of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX; 2 Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, MA; 3 Department of Biochemistry, The Broad Institute, Cambridge, MA; 4 Section of Molecular Hematology and Therapy, Departments of Leukemia and 5 Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX The mTOR complex 2 (mTORC2) containing mTOR and rictor is thought to be rapamycin insensitive and was recently shown to regulate the prosurvival kinase AKT by phosphorylation on Ser473. We investigated the molecular effects of mTOR inhibition by the rapamycin derivatives (RDs) temsirolimus (CCI-779) and everolimus (RAD001) in acute myeloid leukemia (AML) cells. Unexpectedly, RDs not only inhibited the mTOR complex 1 (mTORC1) containing mTOR and raptor with decreased p70S6K, 4EPB1 phosphorylation, and GLUT1 mRNA, but also blocked AKT activation via inhibition of mTORC2 formation. This resulted in suppression of phosphorylation of the direct AKT substrate FKHR and decreased transcription of D-cyclins in AML cells. Similar observations were made in samples from patients with hematologic malignancies who received RDs in clinical studies. Our study provides the first evidence that rapamycin derivatives inhibit AKT signaling in primary AML cells both in vitro and in vivo, and supports the therapeutic potential of mTOR inhibition strategies in leukemias. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. R. Geest, F. J. Zwartkruis, E. Vellenga, P. J. Coffer, and M. Buitenhuis Mammalian target of rapamycin activity is required for expansion of CD34+ hematopoietic progenitor cells Haematologica, July 1, 2009; 94(7): 901 - 910. [Abstract] [Full Text] [PDF] W. W. Ma, H. Jacene, D. Song, F. Vilardell, W. A. Messersmith, D. Laheru, R. Wahl, C. Endres, A. Jimeno, M. G. Pomper, et al. [18F]Fluorodeoxyglucose Positron Emission Tomography Correlates With Akt Pathway Activity but Is Not Predictive of Clinical Outcome During mTOR Inhibitor Therapy J. Clin. Oncol., June 1, 2009; 27(16): 2697 - 2704. [Abstract] [Full Text] [PDF] F. Meric-Bernstam and A. M. Gonzalez-Angulo Targeting the mTOR Signaling Network for Cancer Therapy J. Clin. Oncol., May 1, 2009; 27(13): 2278 - 2287. [Abstract] [Full Text] [PDF] R. Crazzolara, A. Cisterne, M. Thien, J. Hewson, R. Baraz, K. F. Bradstock, and L. J. Bendall Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia Blood, April 2, 2009; 113(14): 3297 - 3306. [Abstract] [Full Text] [PDF] N. Balcazar, A. Sathyamurthy, L. Elghazi, A. Gould, A. Weiss, I. Shiojima, K. Walsh, and E. Bernal-Mizrachi mTORC1 Activation Regulates {beta}-Cell Mass and Proliferation by Modulation of Cyclin D2 Synthesis and Stability J. Biol. Chem., March 20, 2009; 284(12): 7832 - 7842. [Abstract] [Full Text] [PDF] C.-Y. Wang, H.-H. Kim, Y. Hiroi, N. Sawada, S. Salomone, L. E. Benjamin, K. Walsh, M. A. Moskowitz, and J. K. Liao Obesity Increases Vascular Senescence and Susceptibility to Ischemic Injury Through Chronic Activation of Akt and mTOR Sci. Signal., March 17, 2009; 2(62): ra11 - ra11. [Abstract] [Full Text] [PDF] A. Toschi, E. Lee, L. Xu, A. Garcia, N. Gadir, and D. A. Foster Regulation of mTORC1 and mTORC2 Complex Assembly by Phosphatidic Acid: Competition with Rapamycin Mol. Cell. Biol., March 15, 2009; 29(6): 1411 - 1420. [Abstract] [Full Text] [PDF] C. Billottet, L. Banerjee, B. Vanhaesebroeck, and A. Khwaja Inhibition of Class I Phosphoinositide 3-Kinase Activity Impairs Proliferation and Triggers Apoptosis in Acute Promyelocytic Leukemia without Affecting Atra-Induced Differentiation Cancer Res., February 1, 2009; 69(3): 1027 - 1036. [Abstract] [Full Text] [PDF] B. Vollenbroker, B. George, M. Wolfgart, M. A. Saleem, H. Pavenstadt, and T. Weide mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes Am J Physiol Renal Physiol, February 1, 2009; 296(2): F418 - F426. [Abstract] [Full Text] [PDF] A. Toschi, E. Lee, N. Gadir, M. Ohh, and D. A. Foster Differential Dependence of Hypoxia-inducible Factors 1{alpha} and 2{alpha} on mTORC1 and mTORC2 J. Biol. Chem., December 12, 2008; 283(50): 34495 - 34499. [Abstract] [Full Text] [PDF] N. Ferri, A. Granata, C. Pirola, F. Torti, P. J. Pfister, R. Dorent, and A. Corsini Fluvastatin Synergistically Improves the Antiproliferative Effect of Everolimus on Rat Smooth Muscle Cells by Altering p27Kip1/Cyclin E Expression Mol. Pharmacol., July 1, 2008; 74(1): 144 - 153. [Abstract] [Full Text] [PDF] D. Kong, S. Banerjee, W. Huang, Y. Li, Z. Wang, H.-R. C. Kim, and F. H. Sarkar Mammalian Target of Rapamycin Repression by 3,3'-Diindolylmethane Inhibits Invasion and Angiogenesis in Platelet-Derived Growth Factor-D-Overexpressing PC3 Cells Cancer Res., March 15, 2008; 68(6): 1927 - 1934. [Abstract] [Full Text] [PDF] E. A. Pickett, G. S. Olsen, and M. D. Tallquist Disruption of PDGFR{alpha}-initiated PI3K activation and migration of somite derivatives leads to spina bifida Development, February 1, 2008; 135(3): 589 - 598. [Abstract] [Full Text] [PDF] R. T. Woodland, C. J. Fox, M. R. Schmidt, P. S. Hammerman, J. T. Opferman, S. J. Korsmeyer, D. M. Hilbert, and C. B. Thompson Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival Blood, January 15, 2008; 111(2): 750 - 760. [Abstract] [Full Text] [PDF] J. Tamburini, N. Chapuis, V. Bardet, S. Park, P. Sujobert, L. Willems, N. Ifrah, F. Dreyfus, P. Mayeux, C. Lacombe, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways Blood, January 1, 2008; 111(1): 379 - 382. [Abstract] [Full Text] [PDF] M. Fouladi, F. Laningham, J. Wu, M. A. O'Shaughnessy, K. Molina, A. Broniscer, S. L. Spunt, I. Luckett, C. F. Stewart, P. J. Houghton, et al. Phase I Study of Everolimus in Pediatric Patients With Refractory Solid Tumors J. Clin. Oncol., October 20, 2007; 25(30): 4806 - 4812. [Abstract] [Full Text] [PDF]

	Copyright © 2007 by American Society of Hematology         Online ISSN: 1528-0020