Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein tyrosine kinases activate the STAT (signal transducer and activator of transcription) signaling pathway, which can play essential roles in cell differentiation, cell cycle control, and development. However, the potential role of the STAT signaling pathway in the induction of apoptosis remains unexplored. Here we show that gamma interferon (IFN-gamma) activated STAT1 and induced apoptosis in both A431 and HeLa cells, whereas epidermal growth factor (EGF) activated STAT proteins and induced apoptosis in A431 but not in HeLa cells. EGF receptor autophosphorylation and mitogen-activated protein kinase activation in response to EGF were similar in both cell lines. The breast cancer cell line MDA-MB-468 exhibited a similar response to A431 cells, i.e., STAT activation and apoptosis correlatively resulted from EGF or IFN-gamma treatment. In addition, in a mutant A431 cell line in which STAT activation was abolished, no apoptosis was induced by either EGF or IFN-gamma. We further demonstrated that both EGF and IFN-gamma induced caspase 1 (interleukin-1beta converting enzyme [ICE]) gene expression in a STAT-dependent manner. IFN-gamma was unable to induce ICE gene expression and apoptosis in either JAK1-deficient HeLa cells (E2A4) or STAT1-deficient cells (U3A). However, ICE gene expression and apoptosis were induced by IFN-gamma in U3A cells into which STAT1 had been reintroduced. Moreover, both EGF-induced apoptosis and IFN-gamma-induced apoptosis were effectively blocked by Z-Val-Ala-Asp-fluoromethylketone (ZVAD) in all the cells tested, and studies from ICE-deficient cells indicated that ICE gene expression was necessary for IFN-gamma-induced apoptosis. We conclude that activation of the STAT signaling pathway can induce apoptosis through the induction of ICE gene expression.
...
PMID:Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. 927 10

Stimulation of epidermal growth factor receptor (EGFR) leads to cell proliferation and plays an important role in cancerogenesis. It seems that these effects are a consequence of triggering of various signal transduction pathways involving PI-3K and MAP kinase activation. Surprisingly, under certain circumstances stimulation of EGFR may also result in cell growth arrest and apoptosis induction. It is possible that anti-proliferative effect of EGF depends on STAT protein activation. It has been reported, that STAT upregulates expression of cyclin-dependent kinase inhibitor, which blocks the cell cycle. Additionally, STAT may increase caspase 1 (ICE) expression, which seems to be necessary for apoptosis induced by EGF. Intracellular mechanisms involved in EGFR proapoptotic activity still remains poorly understood and, because of their potential clinical significance, require further investigation.
...
PMID:[Signal transduction mechanisms induced by epidermal growth factor receptor (EGFR) and their role in apoptosis regulation]. 1035 96

Burn injury induces many metabolic disorders, including altered protein kinetics with muscle weakness. The skeletal muscle weakness that occurs as a result of the loss of muscle mass causes hypoventilation and dependence on respirators, a condition that increases morbidity and mortality. The presence or absence of apoptosis in muscle, which can be a cause of the loss of muscle mass, was studied in rats after they had received scald burns to 40% of their body surface areas. The potential pro-apoptotic pathways that were activated were also examined. The burn injury produced did not directly destroy the muscle beneath; muscles just beneath the burned surface showed dramatic apoptotic changes according to assessments with the cell death enzyme-linked immunosorbent assay and in situ TdT-mediated dUTP-X nick-end labeling staining. The extent of apoptosis reached a peak on postburn days 3 and 7. Of note is that apoptosis was also confirmed in muscles at sites distant from the burn injury (eg, tibialis anterior) on both postburn days 3 and 7, a condition that is suggestive of the systemic effects of pro-apoptotic factors. To show that heat itself causes the initiation of the pro-apoptotic signaling, muscle-derived C2C12 cells were subjected to heat treatment at 55 degrees C. Ceramide, a key apoptotic second messenger, was observed to increase in the caveolae fraction but not in non-caveolae fraction of these muscle cells. In muscle tissue from burned rats, stress-activated protein kinase (a downstream-signaling kinase of ceramide) was activated soon after burn injury; this finding is consistent with the hypothesis that ceramide plays a role in burn-induced apoptosis. Caspase-1, -3, and -9, important final apoptotic enzymes involved with the downstream signaling of stress-activated protein kinase, were also activated after burn injury in muscle tissue from burned rats. These findings confirm the hypothesis that apoptosis occurs in skeletal muscle and that major apoptotic pathways are activated after a burn injury. Further characterization of these apoptotic signaling cascades may provide new therapeutic targets for the prevention of burn-induced muscle wasting.
...
PMID:The 1999 Moyer award. Burn injury induces skeletal muscle apoptosis and the activation of caspase pathways in rats. 1061 83

Human GM-CSF (hGM-CSF) induces proliferation and sustains the viability of a mouse IL-3-dependent lymphoid cell line BA/F3 that expresses the functional hGM-CSF receptor (hGMR). To reveal an antiapoptotic mechanism of hGM-CSF, we analyzed various apoptotic markers of BA/F3 cells in various conditions. Within 24 hours of factor depletion, caspase 3-like, but not caspase 1-like, enzyme activity and DNA fragmentation were augmented. Analysis with the tyrosine kinase inhibitor (genistein) and an MEK1 inhibitor (PD98059) on antiapoptosis activity indicates that the activation of either the genistein-sensitive signaling pathway or the PD98059-sensitive signaling pathway of the betac subunit may be sufficient to suppress apoptosis through hGMR. Because hGMR mutants (which activate JAK2 but neither STAT5 nor the MAPK cascade) have antiapoptotic activity in BA/F3 cells, the involvement of JAK2, excluding the molecules mentioned earlier, for antiapoptosis activity seems likely. Because the JAK2 inhibitor AG-490 suppressed the antiapoptotic activity of hGM-CSF, the essential role for JAK2 activation to maintain the viability is considered. Interestingly, hGMR mutants, which lack MAPK cascade activation, require a higher dose of hGM-CSF than that for wild-type hGMR. Because the expression level and affinity to hGM-CSF among wild-type hGMR and mutant hGMR are the same, we speculated that biologic response is determined by a combination of strength of various signaling events.
...
PMID:Analysis of antiapoptosis activity of human GM-CSF receptor. 1088 29

Recent etiological study in twins (Tanner et al. 1999) strongly suggests that environmental factors play an important role in typical, non-familial Parkinson's disease (PD), beginning after age 50. Epidemiological risk factor analyses of typical PD cases have identified several neurotoxicants, including MPP(+) (the active metabolite of MPTP), paraquat, dieldrin, manganese and salsolinol. Here, we tested the hypothesis that these neurotoxic agents might induce cell death in our nigral dopaminergic cell line, SN4741 (Son et al. 1999) through a common molecular mechanism. Our initial experiments revealed that treatment with both MPP(+) and the other PD-related neurotoxicants induced apoptotic cell death in SN4741 cells, following initial increases of H(2)O(2)-related ROS activity and subsequent activation of JNK1/2 MAP kinases. Moreover, we have demonstrated that during dopaminergic cell death cascades, MPP(+), the neurotoxicants and an oxidant, H(2)O(2) equally induce the ROS-dependent events. Remarkably, the oxidant treatment alone induced similar sequential molecular events: ROS increase, activation of JNK MAP kinases, activation of the PITSLRE kinase, p110, by both Caspase-1 and Caspase-3-like activities and apoptotic cell death. Pharmacological intervention using the combination of the antioxidant Trolox and a pan-caspase inhibitor Boc-(Asp)-fmk (BAF) exerted significant neuroprotection against ROS-induced dopaminergic cell death. Finally, the high throughput cDNA microarray screening using the current model identified downstream response genes, such as heme oxygenase-1, a constituent of Lewy bodies, that can be the useful biomarkers to monitor the pathological conditions of dopaminergic neurons under neurotoxic insult.
...
PMID:Dopaminergic cell death induced by MPP(+), oxidant and specific neurotoxicants shares the common molecular mechanism. 1118 20

Parkinson's disease is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. We now report that minocycline, a semisynthetic tetracycline, recently shown to have neuroprotective effects in animal models of stroke/ischemic injury and Huntington's disease, prevents nigrostriatal dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Minocycline treatment also blocked dopamine depletion in the striatum as well as in the nucleus accumbens after MPTP administration. The neuroprotective effect of minocycline is associated with marked reductions in inducible NO synthase (iNOS) and caspase 1 expression. In vitro studies using primary cultures of mesencephalic and cerebellar granule neurons (CGN) and/or glia demonstrate that minocycline inhibits both 1-methyl-4-phenylpyridinium (MPP(+))-mediated iNOS expression and NO-induced neurotoxicity, but MPP(+)-induced neurotoxicity is inhibited only in the presence of glia. Further, minocycline also inhibits NO-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in CGN and the p38 MAPK inhibitor, SB203580, blocks NO toxicity of CGN. Our results suggest that minocycline blocks MPTP neurotoxicity in vivo by indirectly inhibiting MPTP/MPP(+)-induced glial iNOS expression and/or directly inhibiting NO-induced neurotoxicity, most likely by inhibiting the phosphorylation of p38 MAPK. Thus, NO appears to play an important role in MPTP neurotoxicity. Neuroprotective tetracyclines may be effective in preventing or slowing the progression of Parkinson's and other neurodegenerative diseases.
...
PMID:Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. 1172 29

Microvascular endothelial cell (EC) apoptosis or programmed cell death (PCD) during free radical injury may be involved in the development of cerebral ischemic and degenerative diseases. Yet, the cellular mechanisms that mediate cerebral EC injury require further definition. We therefore used the agent nicotinamide as an investigative tool in EC cultures to examine the role of free radical nitric oxide (NO)-induced PCD. EC injury was evaluated by the trypan blue dye exclusion method, DNA fragmentation, membrane phosphatidylserine (PS) exposure, cysteine protease activity, mitochondrial membrane potential, and mitogen-activated protein kinase phosphorylation. We demonstrate that cerebrovascular PCD consists of two distinct pathways that involve the degradation of genomic DNA and the exposure of membrane PS residues. Each of these pathways is reversible in nature and is controlled independently by caspase 8, caspase 1, and caspase 3. As a cytoprotectant, nicotinamide is novel in the vascular system and functions at two levels. Nicotinamide not only maintains the mitochondrial membrane potential and the prevention of cytochrome c release, but also prevents the induction of caspase-8-, caspase-1- and caspase-3-like activities linked to the DNA repair enzyme poly(ADP-ribose) polymerase through mechanisms that are independent from the MAP kinase systems of p38 and JNK. The work begins to identify therapeutic strategies for the protection of the cerebral vasculature during both acute and chronic degenerative disorders.
...
PMID:Nicotinamide modulates mitochondrial membrane potential and cysteine protease activity during cerebral vascular endothelial cell injury. 1201 85

Erythropoietin (EPO) modulates primarily the proliferation of immature erythroid precursors, but little is known of the potential protective mechanisms of EPO in the central nervous system. We therefore examined the ability of EPO to modulate a series of death-related cellular pathways during anoxia and free radical induced neuronal degeneration. Neuronal injury was evaluated by trypan blue, DNA fragmentation, membrane phosphatidylserine exposure, protein kinase B phosphorylation, cysteine protease activity, mitochondrial membrane potential, and mitogen-activated protein (MAP) kinase phosphorylation. We demonstrate that constitutive neuronal EPO is insufficient to prevent cellular injury, but that signaling through the EPO receptor remains biologically responsive to exogenous EPO administration. Exogenous EPO is both necessary and sufficient to prevent acute genomic DNA destruction and subsequent phagocytosis through membrane PS exposure, because neuronal protection by EPO is completely abolished by co-treatment with an anti-EPO neutralizing antibody. Through pathways that involve the initial activation of protein kinase B, EPO maintains mitochondrial membrane potential. Subsequently, EPO inhibits caspase 8-, caspase 1-, and caspase 3-like activities linked to cytochrome c release through mechanisms that are independent from the MAP kinase systems of p38 and JNK. Elucidating some of the novel neuroprotective pathways employed by EPO may further the development of new therapeutic strategies for neurodegenerative disorders.
...
PMID:Erythropoietin prevents early and late neuronal demise through modulation of Akt1 and induction of caspase 1, 3, and 8. 1258 24

Brief activation of the ATP-sensitive P2X(7) receptor (P2X(7)R) stimulates the maturation and release of interleukin 1beta (IL-1beta)in macrophages, whereas prolonged agonist activation induces the formation of cytolytic pores in cell membranes. The present study investigated potential downstream mechanisms associated with native human P2X(7)R activation in lipopolysaccharide and interferon-gamma differentiated THP-1 cells. 2,3-O-(4-Benzoylbenzoyl)-ATP (BzATP)-induced pore formation (EC(50) = 35 microM) was blocked by a selective P2X(7)R antagonist, 1[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine (KN-62) (IC(50) = 44 nM) and by pyridoxal phosphate-6-azophenyl-2-4-disulfonic acid (PPADS) (IC(50) = 344 nM). KN-62 and PPADS also blocked BzATP-induced IL-1beta release (EC(50) = 617 microM) with IC(50) values of 75 and 3500 nM, respectively. The selective p38 mitogen-activated protein kinase (MAPK) inhibitor, 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB 202190), potently inhibited BzATP-induced pore formation (IC(50) = 75 nM) but did not alter P2X(7)-mediated calcium influx or IL-1beta release. SB 202190 and KN-62 also attenuated BzATP-mediated activation of phosphorylated p38 MAPK (pp38 MAPK). Two caspase inhibitors, YVAD (caspase 1) and DEVD (caspase 3), attenuated both BzATP-induced pore formation and IL-1beta release in a concentration-dependent fashion. Neither DEVD nor p38-MAPK inhibitors blocked cell membrane pore formation evoked by maitotoxin or by activation of human P2X(2a) receptors. These results indicate that P2X(7)R-mediated pore formation results from a coordinated cascade involving both the p38 MAPK and caspase pathways that is distinct from other cytolytic pore-forming mechanisms. In contrast, P2X(7)R-mediated IL-1beta release is dependent on caspase activity but not p38 MAPK. Taken together, these results support the hypothesis that downstream cellular signaling mechanisms, rather than channel dilation, mediate cytolytic pore formation after prolonged agonist activation, which underlies P2X(7) receptors.
...
PMID:Mitogen-activated protein kinase and caspase signaling pathways are required for P2X7 receptor (P2X7R)-induced pore formation in human THP-1 cells. 1463 45

Anthrax lethal toxin (LT), a critical virulence factor for Bacillus anthracis, has been demonstrated to cleave and to inactivate mitogen-activated protein kinase kinases (MAPKKs) that propagate prosurvival signals in macrophages (1-5). Whether this action of anthrax LT leads to the production of proinflammatory cytokines by macrophages has been more controversial (6, 7). We now report that anthrax LT treatment leads to the specific extracellular release of interleukin (IL)-1beta and IL-18 by the murine macrophage cell lines, RAW264.7 and J774A.1. Studies of the processing of IL-1beta reveal that the levels of activated/cleaved IL-1beta in RAW264.7 and J774.A1 cells are increased following treatment with anthrax LT. Enhanced processing of IL-1beta directly correlates with increased levels in the activation of its upstream regulator, IL-1beta-converting enzyme/Caspase-1 (ICE). The extracellular release of IL-1beta and IL-18 in response to anthrax LT is ICE-dependent, as an ICE-specific inhibitor blocks this process. These data indicate that ICE, IL-1beta, and IL-18 are downstream effectors of anthrax LT in macrophages, providing the basis for new bioassays for anthrax LT activity and representing potential therapeutic targets.
...
PMID:Anthrax lethal toxin rapidly activates caspase-1/ICE and induces extracellular release of interleukin (IL)-1beta and IL-18. 1501 Apr 63


1 2 3 4 5 Next >>

---