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Modulation of MEK activity during G‐CSF signaling alters proliferative versus differentiative balancing
Author(s) -
Baumann Michael A.,
Paul Cassandra C.,
LemleyGillespie Susan,
Oyster Marlo,
GomezCambronero Julian
Publication year - 2001
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.1160
Subject(s) - mapk/erk pathway , mek inhibitor , signal transduction , microbiology and biotechnology , biology , cellular differentiation , cell growth , granulocyte colony stimulating factor receptor , mitogen activated protein kinase , cytokine , cancer research , lactoferrin , endocrinology , immunology , stem cell , haematopoiesis , biochemistry , gene
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.