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Blood, 1 March 2007, Vol. 109, No. 5, pp. 1975-1983. Prepublished online as a Blood First Edition Paper on November 16, 2006; DOI 10.1182/blood-2006-08-042192. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2006-08-042192v1 109/5/1975    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 Weyrich, A. S Articles by Zimmerman, G. A. Search for Related Content PubMed PubMed Citation Articles by Weyrich, A. S Articles by Zimmerman, G. A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 21, 2006 Accepted October 11, 2006 mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets Andrew S Weyrich, Melvin M Denis, Hansjorg Schwertz, Neal D Tolley, Jason Foulks, Eliott Spencer, Larry W Kraiss, Kurt H Albertine, Thomas M. McIntyre, and Guy A. Zimmerman* University of Utah Eccles Institute of Human Genetics, University of Utah * Corresponding author; email: guy.zimmerman{at}hmbg.utah.edu. New activities of human platelets continue to emerge. One unexpected response is new synthesis of proteins from previously-transcribed RNAs in response to activating signals. We previously reported that activated human platelets synthesize B-cell lymphoma-3 (Bcl-3) under translational control by mammalian target of rapamycin (mTOR). Characterization of the ontogeny and distribution of the mTOR signaling pathway in CD34+ stem cell-derived magakaryocytes now demonstrates that they transfer this regulatory system to developing proplatelets. We also found that Bcl-3 is required for condensation of fibrin by activated platelets, demonstrating functional significance for mTOR-regulated synthesis of the protein. Inhibition of mTOR by rapamycin blocks clot retraction by human platelets. Platelets from wild type mice synthesize Bcl-3 in response to activation, as do human platelets, and platelets from mice with targeted deletion of Bcl-3 have defective retraction of fibrin in platelet-fibrin clots mimicking treatment of human platelets with rapamycin. In contrast, overexpression of Bcl-3 in a surrogate cell line enhanced clot retraction. These studies identify new features of post-transcriptional gene regulation and signal-dependant protein synthesis in activated platelets that may contribute to thrombus and wound remodeling, and suggest that post-transcriptional pathways are targets for molecular intervention in thrombotic disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Full clot retraction: running on mTOR Michael C. Berndt and Robert K. Andrews Blood 2007 109: 1791-1792. [Full Text] [PDF] This article has been cited by other articles: J. M. Foulks, G. K. Marathe, N. Michetti, D. M. Stafforini, G. A. Zimmerman, T. M. McIntyre, and A. S. Weyrich PAF-acetylhydrolase expressed during megakaryocyte differentiation inactivates PAF-like lipids Blood, June 25, 2009; 113(26): 6699 - 6706. [Abstract] [Full Text] [PDF] R. J. Freishtat, J. Natale, A. S. Benton, J. Cohen, M. Sharron, A. A. Wiles, W.-M. Ngor, B. Mojgani, M. Bradbury, A. Degnan, et al. Sepsis Alters the Megakaryocyte-Platelet Transcriptional Axis Resulting in Granzyme B-mediated Lymphotoxicity Am. J. Respir. Crit. Care Med., March 15, 2009; 179(6): 467 - 473. [Abstract] [Full Text] [PDF] F. A. Bozza, A. M. Shah, A. S. Weyrich, and G. A. Zimmerman Amicus or Adversary: Platelets in Lung Biology, Acute Injury, and Inflammation Am. J. Respir. Cell Mol. Biol., February 1, 2009; 40(2): 123 - 134. [Abstract] [Full Text] [PDF] G. Cagney and J. McRedmond A Central Resource for Platelet Proteomics Arterioscler Thromb Vasc Biol, July 1, 2008; 28(7): 1214 - 1215. [Full Text] [PDF] G. A. Zimmerman and A. S. Weyrich Signal-Dependent Protein Synthesis by Activated Platelets: New Pathways to Altered Phenotype and Function Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): s17 - s24. [Abstract] [Full Text] [PDF] C. M. Maya-Monteiro, P. E. Almeida, H. D'Avila, A. S. Martins, A. P. Rezende, H. Castro-Faria-Neto, and P. T. Bozza Leptin Induces Macrophage Lipid Body Formation by a Phosphatidylinositol 3-Kinase- and Mammalian Target of Rapamycin-dependent Mechanism J. Biol. Chem., January 25, 2008; 283(4): 2203 - 2210. [Abstract] [Full Text] [PDF] G. Davi and C. Patrono Platelet Activation and Atherothrombosis N. Engl. J. Med., December 13, 2007; 357(24): 2482 - 2494. [Full Text] [PDF]

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