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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2303-2310. Prepublished online as a Blood First Edition Paper on November 10, 2005; DOI 10.1182/blood-2005-07-3005. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-07-3005v1 107/6/2303    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 Raslova, H. Articles by Vainchenker, W. Search for Related Content PubMed PubMed Citation Articles by Raslova, H. Articles by Vainchenker, W. Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Cell Cycle Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Mammalian target of rapamycin (mTOR) regulates both proliferation of megakaryocyte progenitors and late stages of megakaryocyte differentiation Hana Raslova, Véronique Baccini, Lamya Loussaief, Béatrice Comba, Jérôme Larghero, Najet Debili, and William Vainchenker From the Institut Nationale de la Santé et de la Recherche Médicale (INSERM) U790, Institut Gustave Roussy PR1, Villejuif; and Laboratoire de Biologie Cellulaire Hématopoiétique, Hôpital Saint Louis, Paris, France. A major determinant in platelet production is the megakaryocyte (MK) size that is regulated both by ploidization and the increase in cytoplasmic volume at the end of maturation. Here we investigated the involvement of the mammalian target of rapamycin (mTOR) pathway in the regulation of megakaryopoiesis. We show that phosphorylation of mTOR, p70S6K1, and 4E-BP1 was diminished in thrombopoietin-cultured human MKs after rapamycin treatment. Rapamycin induced an inhibition in the G1/S transition and a decrease in the mean MK ploidy via a diminution of p21 and cyclin D3 occurring at a transcriptional level. Both cycling (2N/4N) and polyploid (8N/16N) MKs were reduced in size, with a size reduction slightly more pronounced in mature polyploid MKs than in immature ones. Rapamycin also induced a delay in the expression of MK markers and prevented the generation of proplatelet MKs. Additional experiments performed in vitro with MKs from mutant mice showed that the decrease in mean ploidy level and the delay in MK differentiation in the presence of rapamycin were less pronounced in CdknIa (p21)–/– MKs than in CdknIa (p21)+/+ MKs. These findings indicate that the mTOR pathway plays an important role during megakaryopoiesis by regulating ploidy, cell size, and maturation, in part by regulating p21 and cyclin D3. 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] A. Selvapandiyan, P. Kumar, J. C. Morris, J. L. Salisbury, C. C. Wang, and H. L. Nakhasi Centrin1 Is Required for Organelle Segregation and Cytokinesis in Trypanosoma brucei Mol. Biol. Cell, September 1, 2007; 18(9): 3290 - 3301. [Abstract] [Full Text] [PDF] A. G. Muntean, L. Pang, M. Poncz, S. F. Dowdy, G. A. Blobel, and J. D. Crispino Cyclin D-Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization Blood, June 15, 2007; 109(12): 5199 - 5207. [Abstract] [Full Text] [PDF] M. K. Larson and S. P. Watson Regulation of proplatelet formation and platelet release by integrin {alpha}IIbbeta3 Blood, September 1, 2006; 108(5): 1509 - 1514. [Abstract] [Full Text] [PDF]

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