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Modulation of MEK activity during G-CSF signaling alters proliferative versus differentiative balancing†
Article first published online: 6 SEP 2001
DOI: 10.1002/ajh.1160
Copyright © 2001 Wiley-Liss, Inc.
Additional Information
How to Cite
Baumann, M. A., Paul, C. C., Lemley-Gillespie, S., Oyster, M. and Gomez-Cambronero, J. (2001), Modulation of MEK activity during G-CSF signaling alters proliferative versus differentiative balancing. Am. J. Hematol., 68: 99–105. doi: 10.1002/ajh.1160
- †
Publication History
- Issue published online: 6 SEP 2001
- Article first published online: 6 SEP 2001
- Manuscript Accepted: 15 MAY 2001
- Manuscript Received: 14 DEC 2000
Funded by
- Wright State University School of Medicine. Grant Number: Medical Innovations Program
- Ohio State Board of Regents. Grant Number: Research Challenge Program
- National Institutes of Health. Grant Number: HL056653
- Abstract
- References
- Cited By
Keywords:
- MAP kinase;
- neutrophils;
- stem cells;
- signal transduction;
- G-CSF receptor
Abstract
Previous studies of the granulocyte colony stimulating factor (G-CSF) receptor have demonstrated that discrete signals direct proliferative and maturation signaling. Receptor deletion/mutant studies have shown that although activation of the ras-mitogen activated protein (MAP) kinase pathway is necessary for G-CSF directed proliferation, it is not necessary for maturation induced by this cytokine. We have assessed the effects of selective inhibition or overexpression of MAP kinase kinase (MEK) in a cell line model of G-CSF-induced neutrophil progenitor growth. Using the human G-CSF responsive MPD cell line, we specifically inhibited MEK using PD 98059 and also transfected MPD cells with a constitutively active MEK construct. We then exposed the cells to G-CSF and assessed the effects of MEK inhibition and forced expression on proliferation and differentiation. Inhibition of MEK followed by G-CSF stimulation consistently resulted in an early 2.5-fold increase in morphologically differentiated neutrophils expressing CD11b and CD16 and containing lactoferrin over that produced by G-CSF alone. MEK inhibition alone had little effect on the differentiation stage of these cells, although proliferation was impaired. Forced expression of activated MEK resulted in a three- to five-fold decrease in differentiated, lactoferrin containing neutrophilic cells resultant from G-CSF induction, and a commensurate increase in cell proliferation. These observations suggest that modulation of MAPK activation may be a control point for altering the balance between proliferation and differentiation in response to G-CSF. Physiologically, this control is likely exerted by costimulatory cytokines. Am. J. Hematol. 68:99–105, 2001. Published 2001 Wiley-Liss, Inc.