CSF-1 and cell cycle control in macrophages.
Control of cell proliferation involves a finely interwoven network of positive and negative cell cycle regulators. Signal transduction pathways linking c-fms (CSF-1R) to cellular proliferation and differentiation are being explored. Part of the strategy is to use a series of G1 inhibitors to help pinpoint relevant targets. Several inhibitors-8Br-cAMP, interferon gamma (IFN gamma), INF alpha/beta, lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF alpha), and dimethylamiloride-suppress CSF-1-stimulated proliferation in murine bone marrow-derived macrophages (BMM) even when added in the mid- to late-G1 phase of the cell cycle. The down-modulating effects of the inhibitors on the expression of the following cell cycle regulators have been examined: c-myc, cyclin D1 and D2, cdk4, Rb phosphorylation, E2F binding activity, ribonucleotide reductase subunits, and PCNA. Some differences in the negative control of such regulators were found, for example, in the manner in which IFN gamma and cAMP down-regulate c-myc expression. Using blocking antibodies and BMM from type I IFN receptor knockout mice, it appears that one of these inhibitors, IFN alpha/beta, acts as an endogenous inhibitor in CSF-1-treated BMM and is also responsible, at least in part, for the inhibition of cell cycle progression by LPS and TNF alpha. Another strategy has been to attempt to relate early biochemical changes induced by CSF-1 to later changes in the G1 phase, partly by studying cycling versus noncycling macrophages and partly by using cells expressing c-fms with tyrosine mutations in the intracytoplasmic region. CSF-1-mediated effects on the following signal transduction molecules in these systems will be described: PI3-kinase, myelin basic protein kinases, Erks, and STAT transcription factors.
Hamilton
J A
JA
University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.
D000818:Animals; D001854:Bone Marrow Cells; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D016898:Interferon-alpha / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology / Q000502:physiology*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016898:Interferon-alpha; D008070:Lipopolysaccharides; D019384:Nucleic Acid Synthesis Inhibitors; D017471:Receptors, Interferon; D016160:Retinoblastoma Protein; D014409:Tumor Necrosis Factor-alpha; D053633:Receptor, Interferon alpha-beta; D016173:Macrophage Colony-Stimulating Factor; D011494:Protein Kinases