Macrophage inflammatory protein-1α and interferon-inducible protein 10 inhibit synergistically induced growth factor stimulation of MAP kinase activity and suppress phosphorylation of eukaryotic initiation factor 4E and 4E binding protein 1

Susan M. Aronica, Anne Claude Gingras, Nahum Sonenberg, Scott Cooper, Nancy Hague, Hal E. Broxmeyer

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and Steel factor (SLF) synergistically stimulate Raf-1 kinase activity, protein synthesis, and proliferation in hematopoietic MO7e cells; synergistic action of these factors is blocked by the suppressive chemokines macrophage inflammatory protein-1α (MIP-1α) and interferon-inducible protein 10 (IP- 10; Aronica et el, J Biol Chem 270:21998, 1995). We assessed the potential for both stimulatory and inhibitory factors to act through the MAP kinase signaling pathway by studying the effects of growth factors and chemokines on MAP kinase activation. Also, because activation of kinase signaling pathways and stimulation of protein synthesis by peptide growth factors are associated with increased phosphorylation of eukaryotic initiation factor 4E (elF-4E) and the translational repressor 4E-binding protein 1 (4E-BP1) in some target cells, we investigated whether growth factor treatment could alter elF-4E or 4E-BP1 phosphorylation state in MO7e cells. We report that treatment of MO7e cells with GM-CSF and SLF stimulated significant, greater-than-additive increases in MAP kinase activity and the phosphorylation of both elF-4E and 4E-BP1. Increased 4E-BP1 phosphorylation correlated with a decrease in the association of 4E-BP1 with elF-4E. Growth factor-induced phosphorylation of 4E-BP1 end dissociation of 4E-BP1 from elF-4E was blocked in cells treated with rapamycin, wortmannin, or PD098059. Treatment of cells with IP-10 or MIP-1α blocked the stimulatory effects of GM-CSF end SLF, resulting in suppression of MAP kinase activity, elF-4E and 4E-BP1 phosphorylation, and elF-4E/4E-BP1 dissociation. Our results suggest that GM-CSF and SLF exert part of their combined growth-promoting effects on MO7e cells through activation of MAP kinase and enhancement of elF-4E and 4E-BP1 phosphorylation and dissociation and that suppression of growth factor-induced protein synthesis by MIP-1α and IP-10 involves translational repression at the level of elF-4E.

Original languageEnglish (US)
Pages (from-to)3582-3595
Number of pages14
JournalBlood
Volume89
Issue number10
DOIs
StatePublished - May 15 1997

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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