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Blood, 15 October 2009, Vol. 114, No. 16, pp. 3402-3412. Prepublished online as a Blood First Edition Paper on August 10, 2009; DOI 10.1182/blood-2008-08-175141. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2008-08-175141v1 114/16/3402    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 CrossRef Google Scholar Articles by Geest, C. R. Articles by Coffer, P. J. PubMed PubMed Citation Articles by Geest, C. R. Articles by Coffer, P. J. Related Collections Hematopoiesis and Stem Cells Phagocytes, Granulocytes, and Myelopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS Tight control of MEK-ERK activation is essential in regulating proliferation, survival, and cytokine production of CD34+-derived neutrophil progenitors Christian R. Geest1, Miranda Buitenhuis1, Marian J. A. Groot Koerkamp2, Frank C. P. Holstege2, Edo Vellenga3, and Paul J. Coffer1,4 1 Molecular Immunology Lab, Department of Immunology, and 2 Genomics Laboratory, Department of Physiological Chemistry, University Medical Center Utrecht, Utrecht; 3 Department of Hematology, University Medical Center, Groningen; and 4 Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands A plethora of extracellular stimuli regulate growth, survival, and differentiation responses through activation of the MEK-ERK MAPK signaling module. Using CD34+ hematopoietic progenitor cells, we describe a novel role for the MEK-ERK signaling module in the regulation of proliferation, survival, and cytokine production during neutrophil differentiation. Addition of the specific MEK1/2 inhibitor U0126 resulted in decreased proliferation of neutrophil progenitors. Conversely, transient activation of a conditionally active MEK1 mutant resulted in the expansion of progenitor cells, which thereafter differentiated normally into mature neutrophils. In contrast, chronic MEK1 activation was found to induce cell death of CD34+ neutrophil progenitors. Microarray analysis of CD34+ progenitor cells showed that activation of MEK1 resulted in changes in expression of a variety of cell-cycle modulating genes. Furthermore, conditional activation of MEK1 resulted in a dramatic increase in the expression of mRNA transcripts encoding a large number of hematopoietic cytokines, chemokines, and growth factors. These findings identify a novel role for MEK-ERK signaling in regulating the balance between proliferation and apoptosis during neutrophil differentiation, and they suggest the need for tight control of MEK-ERK activation to prevent the development of bone marrow failure. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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