Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF) can induce proliferation as well as apoptosis in acute myeloid leukemia (AML)-derived cells. We have shown recently that these seemingly contradictory effects are based on the divergent capacities of the cells to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) upon stimulation with TNF. Only those cells that produce GM-CSF survive the TNF attack and start growing. Here, we set out to elucidate the mechanisms of the antiapoptotic effect of GM-CSF. Protection from apoptosis was achieved by preincubating TF-1 cells with exogeneous GM-CSF. Cycloheximide prevented protection, indicating that GM-CSF might induce synthesis of antiapoptotic proteins. Regulation of protective genes was analyzed using cDNA expression arrays and the results were verified by Northern and Western blot analysis. This screen revealed the elevated expression of BCL-2, BCL-2A1, BAG-1 and TACE upon stimulation with GM-CSF. The major novelty of our study is that GM-CSF carries protective effects against TNF-induced apoptosis, not only against apoptosis induced by irradiation or cytokine-starvation. This protection requires de novo protein synthesis and is not-or at least not exclusively-the consequence of a direct crosstalk between the GM-CSF and TNF signaling pathways.
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PMID:Granulocyte-macrophage colony-stimulating factor: inhibitor of tumor necrosis factor-induced apoptosis. 1264 14

Monocytes give rise to macrophages, osteoclasts (OCs), and dendritic cells (DCs). Macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB (RANK) ligand induce OC differentiation from monocytes, whereas granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) trigger monocytic differentiation into DCs. However, regulatory mechanisms for the polarization of monocytic differentiation are still unclear. The present study was undertaken to clarify the mechanism of triggering the deflection of OC and DC differentiation from monocytes. GM-CSF and IL-4 abolished monocytic differentiation into OCs while inducing DC differentiation even in the presence of M-CSF and RANK ligand. GM-CSF and IL-4 in combination potently up-regulate tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE) and activity in monocytes, causing ectodomain shedding of M-CSF receptor, resulting in the disruption of its phosphorylation by M-CSF as well as the induction of osteoclastogenesis from monocytes by M-CSF and RANK ligand. Interestingly, TACE inhibition robustly causes the resumption of the surface expression of M-CSF receptor on monocytes, facilitating M-CSF-mediated phosphorylation of M-CSF receptor and macrophage/OC differentiation while impairing GM-CSF- and IL-4-mediated DC differentiation from monocytes. These results reveal a novel proteolytic regulation of M-CSF receptor expression in monocytes to control M-CSF signaling and monocytic differentiation into macrophage/OC-lineage cells or DCs.
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PMID:GM-CSF and IL-4 induce dendritic cell differentiation and disrupt osteoclastogenesis through M-CSF receptor shedding by up-regulation of TNF-alpha converting enzyme (TACE). 1976 88