SEARCH:   Advanced

Blood, 1 March 2006, Vol. 107, No. 5, pp. 1847-1856. Prepublished online as a Blood First Edition Paper on November 10, 2005; DOI 10.1182/blood-2005-04-1612. This Article Full Text (PDF) All Versions of this Article: 2005-04-1612v1 107/5/1847    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 Zhu, Q.-s. Articles by Corey, S. J Search for Related Content PubMed PubMed Citation Articles by Zhu, Q.-s. Articles by Corey, S. J Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 20, 2005 Accepted September 9, 2005 G-CSF induced reactive oxygen species involves Lyn-PI 3-kinase-Akt and contributes to myeloid cell growth Quan-sheng Zhu, Ling Xia, Gordon B Mills, Clifford A Lowell, Ivo P Touw, and Seth J Corey* Division of Pediatrics, University of Texas-MD Anderson Cancer Center, Houston, TX, USA Programs in Cancer Biology and Immunology, University of Texas-MD Anderson Cancer Center, Houston, TX, USA; Department of Molecular Therapeutics, University of Texas-MD Anderson Cancer Center, Houston, TX, USA University of California-San Francisco, San Francisco, CA, USA Department of Hematology, Eramus University, Rotterdam, The Netherlands Division of Pediatrics, University of Texas-MD Anderson Cancer Center, Houston, TX, USA; Programs in Cancer Biology and Immunology, University of Texas-MD Anderson Cancer Center, Houston, TX, USA * Corresponding author; email: sjcorey{at}mdanderson.org. Granulocyte colony-stimulating factor (G-CSF) is a pleiotropic cytokine that drives the production, survival, differentiation, and inflammatory functions of granulocytes. Reactive oxygen species (ROS) provide a major thrust of the inflammatory response, though excessive ROS production may be deleterious. G-CSF stimulation showed a time and dose-dependent increase in ROS production, correlating with activation of the Src kinase Lyn and Akt. Inhibition of Lyn, PI 3-kinase, and Akt, but not Erk1/2, abrogated G-CSF-induced ROS production. Following G-CSF stimulation, neutrophils from bone marrow of lyn-/- mice produced less ROS than wild-type littermates. G-CSF induced both serine phosphorylation and membrane translocation of p47phox, a subunit of NADPH oxidase. The NADPH oxidase inhibitor DPI blocked the G-CSF-induced ROS production in G-CSFR expressing Ba/F3 cells. Because patients with a truncated G-CSF Receptor have a high risk of developing acute myeloid leukemia (AML), we hypothesized that dysregulation of ROS production might contribute to leukemogenesis. Cells expressing the truncated G-CSF Receptor produced more ROS than those with the full-length receptor. G-CSF-induced ROS production was also enhanced in bone marrow-derived neutrophils expressing G-CSFR715, a truncated receptor. The antioxidant N-Acetyl-L-Cysteine diminished G-CSF-induced ROS production and cell proliferation by inhibiting Akt activation. These data suggest that the Lyn-PI3K-Akt pathway plays a critical role in the G-CSF-induced production of ROS. Hyperactivation of Lyn with subsequent augmented ROS production may constitute one mechanism by which AML arises. These studies suggest that one beneficial effect of therapeutic targeting of Lyn-PI 3K-kinase-Akt cascade is blocking ROS production. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Kannan, A. Audet, H. Huang, L.-j. Chen, and M. Wu Cholesterol-Rich Membrane Rafts and Lyn Are Involved in Phagocytosis during Pseudomonas aeruginosa Infection J. Immunol., February 15, 2008; 180(4): 2396 - 2408. [Abstract] [Full Text] [PDF] C. Dos Santos, C. Demur, V. Bardet, N. Prade-Houdellier, B. Payrastre, and C. Recher A critical role for Lyn in acute myeloid leukemia Blood, February 15, 2008; 111(4): 2269 - 2279. [Abstract] [Full Text] [PDF] M. B. Miranda, R. L. Redner, and D. E. Johnson Inhibition of Src family kinases enhances retinoic acid induced gene expression and myeloid differentiation Mol. Cancer Ther., December 1, 2007; 6(12): 3081 - 3090. [Abstract] [Full Text] [PDF] I. P. Touw and M. Bontenbal Granulocyte Colony-Stimulating Factor: Key (F)actor or Innocent Bystander in the Development of Secondary Myeloid Malignancy? J Natl Cancer Inst, February 7, 2007; 99(3): 183 - 186. [Full Text] [PDF] K. Bedard and K.-H. Krause The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology Physiol Rev, January 1, 2007; 87(1): 245 - 313. [Abstract] [Full Text] [PDF] Y. Wang, M. M. Zeigler, G. K. Lam, M. G. Hunter, T. D. Eubank, V. V. Khramtsov, S. Tridandapani, C. K. Sen, and C. B. Marsh The Role of the NADPH Oxidase Complex, p38 MAPK, and Akt in Regulating Human Monocyte/Macrophage Survival Am. J. Respir. Cell Mol. Biol., January 1, 2007; 36(1): 68 - 77. [Abstract] [Full Text] [PDF] R. Rexhepaj, F. Grahammer, H. Volkl, C. Remy, C. A. Wagner, D. Sandulache, F. Artunc, G. Henke, S. Nammi, G. Capasso, et al. Reduced intestinal and renal amino acid transport in PDK1 hypomorphic mice FASEB J, November 1, 2006; 20(13): 2214 - 2222. [Abstract] [Full Text] [PDF] C. H. Mermel, M. L. McLemore, F. Liu, S. Pereira, J. Woloszynek, C. A. Lowell, and D. C. Link Src family kinases are important negative regulators of G-CSF-dependent granulopoiesis Blood, October 15, 2006; 108(8): 2562 - 2568. [Abstract] [Full Text] [PDF]

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020