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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1568-1573. Prepublished online as a Blood First Edition Paper on October 5, 2006; DOI 10.1182/blood-2006-06-031856. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-06-031856v1 109/4/1568    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 Rodriguez, P. C. Articles by Ochoa, A. C. Search for Related Content PubMed PubMed Citation Articles by Rodriguez, P. C. Articles by Ochoa, A. C. Related Collections Immunobiology Cell Cycle Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY L-arginine availability regulates T-lymphocyte cell-cycle progression Paulo C. Rodriguez1,2, David G. Quiceno1, and Augusto C. Ochoa1,2 1 Tumor Immunology Program, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA; 2 Department of Pediatrics, Louisiana State University, Health Sciences Center, New Orleans, LA L-arginine (L-Arg) plays a central role in several biologic systems including the regulation of T-cell function. L-Arg depletion by myeloid-derived suppressor cells producing arginase I is seen in patients with cancer inducing T-cell anergy. We studied how L-Arg starvation could regulate T-cell–cycle progression. Stimulated T cells cultured in the absence of L-Arg are arrested in the G0-G1phase of the cell cycle. This was associated with an inability of T cells to up-regulate cyclin D3 and cyclin-dependent kinase 4 (cdk4), but not cdk6, resulting in an impaired downstream signaling with a decreased phosphorylation of Rb protein and a low expression and binding of E2F1. Silencing of cyclin D3 reproduced the cell cycle arrest caused by L-Arg starvation. The regulation of cyclin D3 and cdk4 by L-Arg starvation occurs at transcriptional and posttranscriptional levels. Signaling through GCN2 kinase is triggered during amino acid starvation. Experiments demonstrated that T cells from GCN2 knock-out mice did not show a decreased proliferation and were able to up-regulate cyclin D3 when cultured in the absence of L-Arg. These results contribute to the understanding of a central mechanism by which cancer and other diseases characterized by high arginase I production may cause T-cell dysfunction. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. C. McKenna, K. M. Beatty, R. A. Bilonick, L. Schoenfield, K. L. Lathrop, and A. D. Singh Activated CD11b+ CD15+ Granulocytes Increase in the Blood of Patients with Uveal Melanoma Invest. Ophthalmol. Vis. Sci., September 1, 2009; 50(9): 4295 - 4303. [Abstract] [Full Text] [PDF] J. Oberlies, C. Watzl, T. Giese, C. Luckner, P. Kropf, I. Muller, A. D. Ho, and M. Munder Regulation of NK Cell Function by Human Granulocyte Arginase J. Immunol., May 1, 2009; 182(9): 5259 - 5267. [Abstract] [Full Text] [PDF] L. A. Norian, P. C. Rodriguez, L. A. O'Mara, J. Zabaleta, A. C. Ochoa, M. Cella, and P. M. Allen Tumor-Infiltrating Regulatory Dendritic Cells Inhibit CD8+ T Cell Function via L-Arginine Metabolism Cancer Res., April 1, 2009; 69(7): 3086 - 3094. [Abstract] [Full Text] [PDF] P. C. Rodriguez, M. S. Ernstoff, C. Hernandez, M. Atkins, J. Zabaleta, R. Sierra, and A. C. 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