Macrophage inflammatory protein-1alpha 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.
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-1alpha (MIP-1alpha) and interferon-inducible protein 10 (IP-10; Aronica et al, 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 eIF-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 eIF-4E and 4E-BP1. Increased 4E-BP1 phosphorylation correlated with a decrease in the association of 4E-BP1 with eIF-4E. Growth factor-induced phosphorylation of 4E-BP1 and dissociation of 4E-BP1 from eIF-4E was blocked in cells treated with rapamycin, wortmannin, or PD098059. Treatment of cells with IP-10 or MIP-1alpha blocked the stimulatory effects of GM-CSF and SLF, resulting in suppression of MAP kinase activity, eIF-4E and 4E-BP1 phosphorylation, and eIF-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 eIF-4E and 4E-BP1 phosphorylation and dissociation and that suppression of growth factor-induced protein synthesis by MIP-1alpha and IP-10 involves translational repression at the level of eIF-4E.
Aronica
S M
SM
Department of Microbiology/Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis 46202-5121, USA.
Gingras
A C
AC
Sonenberg
N
N
Cooper
S
S
Hague
N
N
Broxmeyer
H E
HE
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; C087000:EIF4EBP1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D006131:Growth Inhibitors; D019402:Macrophage Inflammatory Proteins; D009363:Neoplasm Proteins; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000242:Cyclic AMP; D017871:Calcium-Calmodulin-Dependent Protein Kinases