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)

High levels of cytokines are associated with a poor prognosis in acute myeloid leukemia (AML). However, cytokines may induce, on one hand, survival factor expression and cell proliferation and, on the other hand, expression of inhibitory signals such as up-regulation of suppressors of cytokine signaling (SOCS) and induce apoptotic cell death. Because blasts from patients with AML express high procaspase protein levels, we asked whether granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances procaspase protein production in AML cells. In the GM-CSF-responsive OCIM2 AML cell line, GM-CSF induced signal transducer and activator of transcription 5 (Stat 5) phosphorylation, up-regulated cyclin D2, and stimulated cell cycle progression. Concurrently, GM-CSF stimulated expression of SOCS-2 and -3 and of procaspases 2 and 3 and induced caspase 3 activation, poly(ADP[adenosine 5'-diphosphate]-ribose) polymerase (PARP) cleavage, and apoptotic cell death. The Janus kinase (Jak)-Stat inhibitor AG490 abrogated GM-CSF-induced expression of procaspase 3 and activation of caspase 3. Under the same conditions GM-CSF up-regulated production of BAX as well as Bcl-2, Bcl-XL, survivin, and XIAP. GM-CSF also increased procaspase 3 protein levels in OCI/AML3 and Mo7e cells, suggesting that this phenomenon is not restricted to a single leukemia cell line. Our data suggest that GM-CSF exerts a dual effect: it stimulates cell division but contemporaneously up-regulates Jak-Stat-dependent proapoptotic proteins. Up-regulation of procaspase levels in AML is thus a beacon for an ongoing growth-stimulatory signal.
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PMID:Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces antiapoptotic and proapoptotic signals in acute myeloid leukemia. 1266 43

Normal spontaneous apoptosis in neutrophils is enhanced by "stress" stimuli such as tumor necrosis factor-alpha, Fas ligand, and oxidants, and this effect is inhibited by anti-apoptotic stimuli including granulocyte-macrophage colony-stimulating factor, lipopolysaccharide, and formylmethionine-leucine-phenylalanine. In this report we demonstrate that anti-apoptotic stimuli protect neutrophils from stress-induced apoptosis via activation of the ERK/MAPK pathway. The protection occurs downstream of mitochondrial alterations assessed as a decrease in membrane potential concomitant with enhanced cytochrome c release. ERK activation was shown to inhibit apoptosis by maintaining levels of XIAP, which is normally decreased in the presence of the pro-apoptotic/stress stimuli. This report also demonstrates that potent intra- and extracellular oxidants inhibit the protective effect of ERK. Oxidant-dependent inhibition of ERK was because of activation of p38 MAPK and activation of the protein phosphatases PP1 and PP2A. Our data suggest that ERK suppresses stress-induced apoptosis downstream of mitochondrial alterations by maintaining XIAP levels and that oxidants block this effect through activation of p38 and protein phosphatases.
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PMID:Oxidants inhibit ERK/MAPK and prevent its ability to delay neutrophil apoptosis downstream of mitochondrial changes and at the level of XIAP. 1529 76

Nbs1, a member of the Mre11-RAD50-Nbs1 complex, is phosphorylated by ATM, the product of the ataxia-telangiectasia mutated gene and a member of the phosphatidylinositol 3-kinase-related family of serine-threonine kinases, in response to DNA double-strand breaks (DSBs) to regulate DNA damage checkpoints. Here we show that BCR/ABL stimulated Nbs1 expression by induction of c-Myc-dependent transactivation and protection from caspase-dependent degradation. BCR/ABL-related fusion tyrosine kinases (FTKs) such as TEL/JAK2, TEL/PDGFbetaR, TEL/ABL, TEL/TRKC, BCR/FGFR1, and NPM/ALK as well as interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF) also stimulated Nbs1 expression. Enhanced ATM kinase-dependent phosphorylation of Nbs1 on serine 343 (S343) in response to genotoxic treatment was detected in leukemia cells expressing BCR/ABL and other FTKs in comparison to normal counterparts stimulated with IL-3, GM-CSF, and SCF. Expression of Nbs1-S343A mutant disrupted the intra-S-phase checkpoint, decreased homologous recombinational repair (HRR) activity, down-regulated XIAP expression, and sensitized BCR/ABL-positive cells to cytotoxic drugs. Interestingly, inhibition of Nbs1 phosphorylation by S343A mutant enhanced the antileukemia effect of the combination of imatinib and genotoxic agent.
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PMID:Enhanced phosphorylation of Nbs1, a member of DNA repair/checkpoint complex Mre11-RAD50-Nbs1, can be targeted to increase the efficacy of imatinib mesylate against BCR/ABL-positive leukemia cells. 1743 Nov 32

We studied the role of c-Jun N-terminal kinase (JNK) in human neutrophils stimulated by tumor necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Stimulation of neutrophils with TNF-alpha and GM-CSF caused phosphorylation of p54 or p46 JNK or both. The phosphorylated p46 JNK band in TNF-alpha-stimulated neutrophils mobilized faster than that in GM-CSF-stimulated cells. The JNK isoform transcripts expressed in neutrophils were JNK1beta1, JNK1beta2, JNK2alpha1, and JNK2alpha2. The JNK isoforms phosphorylated by TNF-alpha and GM-CSF stimulation were found to be JNK1 and JNK2, respectively, on the basis of the molecular mass and the capture assay. TNF-alpha-induced JNK phosphorylation was sustained in the presence of cycloheximide, which was accompanied by accelerated neutrophil apoptosis. The JNK inhibitors (SP600125 and TAT-TI-JIP(153163)) suppressed neutrophil apoptosis induced by TNF-alpha plus cycloheximide, whereas they attenuated the GM-CSF-mediated antiapoptotic effect on neutrophils. The JNK inhibitor did not affect the levels of Mcl-1 and XIAP (antiapoptotic molecules), which were regulated by TNF-alpha plus cycloheximide and GM-CSF. The JNK inhibitor markedly suppressed TNF-alpha-induced and GM-CSF-induced superoxide release. These findings suggest that JNK1 and JNK2 are involved in TNF-alpha-induced neutrophil apoptosis and GM-CSF-mediated antiapoptotic effect on neutrophils, respectively, and both JNK isoforms are involved in TNF-alpha-induced and GM-CSF-induced superoxide release.
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PMID:Distinct role of c-Jun N-terminal kinase isoforms in human neutrophil apoptosis regulated by tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor. 1843 1