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

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Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transition metal cadmium (Cd) has been shown to induce apoptosis in a variety of cell lines and tissues. Caspase activation of the tumor suppressor gene p53 and mitogen-activated protein kinase (MAPK) signaling cascades have been reported to be involved in Cd-induced apoptosis. However, the underlying pathways of Cd-induced apoptosis have not been clearly elucidated in the in vivo systems, primarily for the lack of appropriate animal models. The nematode Caenorhabditis elegans has been shown to be a good model to study basic biological processes, including apoptosis. In this study, we used the mutated alleles of C. elegans homologs of known mammalian genes that are involved in regulation of apoptosis. Sublethal doses of Cd exposure increased C. elegans germline apoptosis in a dose- and time-dependent manner. The loss-of-function mutations of DNA damage response (DDR) genes HUS1 and p53 exhibited significant increase in germline apoptosis under Cd exposure, and the depletion of p53 antagonist ABL1 significantly enhanced apoptosis. Cd-induced apoptosis was blocked in the loss-of-function alleles of both c-Jun N-terminal kinase (JNK) and p38 MAPK cascades, which behaved normally under gamma-irradiation. Our findings implicate that both JNK and p38 MAPK cascades participate in Cd-induced apoptosis. Together, the results of this study suggest the nonessential roles of the DDR genes hus1 and p53 in Cd-induced germline apoptosis and that the apoptosis occurs through the ASK1/2-MKK7-JNK and ASK1/2-MKK3/6-p38 signaling pathways in a caspase-dependent manner. Finally, our study demonstrates that C. elegans is a mammalian in vivo substitute model to study the mechanisms of Cd-induced apoptosis.
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PMID:Cadmium-induced germline apoptosis in Caenorhabditis elegans: the roles of HUS1, p53, and MAPK signaling pathways. 1772 84

Co-activation of GABA A and GABA B receptors results in neuroprotection during in vitro ischemia. However, it is unclear whether this mode of action is responsible for its neuroprotective effects in animal models of ischemia in vivo, and the precise mechanisms are also unknown. This study compared the neuroprotective efficacies of muscimol, a GABA A receptor agonist, and a GABA B receptor agonist baclofen in rat brain ischemia. The additive neuroprotection could be obtained in the hippocampal CA1 pyramidal cells prominently when muscimol and baclofen were co-applied. In particular, our study showed that co-activation of GABA A and GABA B receptors could strongly increase Akt activation and inhibit ASK1 activation by phosphorylation of serine 83 of ASK1. PI-3K inhibitor LY294002 reversed the increasing Akt activation and ASK1 (S83) phosphorylation. Moreover, MKK4/MKK7-JNK signaling activation was inhibited during ischemia/reperfusion (I/R) by co-treatment of muscimol with baclofen. JNK substrate, Bcl-2 and c-jun phosphorylation were also attenuated. Our results indicated that co-activation of GABA A receptor and GABA B receptor exerted neuroprotective effect via PI-3K/Akt pathway, which could inhibit the ASK1-c-Jun N-terminal protein kinase (JNK) cascade.
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PMID:Additive neuroprotection of GABA A and GABA B receptor agonists in cerebral ischemic injury via PI-3K/Akt pathway inhibiting the ASK1-JNK cascade. 1841 Sep 48

TNFalpha exerts apoptosis throughout an intracellular transduction pathway that involves the kinase proteins TRAF-2 (integration point of apoptotic and survival signals), ASK1 (pro-apoptotic protein), MEK-4 (p38 activator and metastasis suppressor gene), JNK (stress mitogen activated protein kinase) and the transcription factor AP-1. TNFalpha also exerts proliferation by p38 activation, or when TRAF-2 simultaneously induces the transcription factor NF-kappaB by NIK. NIK and p38 may also be activated by IL-1. P38 activated several transcription factors such as Elk-1, ATF-2 and NF-kappaB. NIK also may activate NF-kappaB. The aim of the present article was to evaluate the different components of this TNFalpha/IL-1 transduction pathway in human prostate carcinoma (PC) in comparison with normal human prostate. In prostate cancer, pro-apoptotic TNFalpha/AP-1 pathway is probably inactivated by different factors such as p21 (at ASK-1 level) and bcl-2 (at JNK level), or diverted towards p38 or NIK activation. IL-1alpha enhances proliferation through IL-1RI that activates either NIK or p38 transduction pathway. P38 and NIK activate different transcription factors related with cell proliferation and survival such as ATF-2, Elk-1 or NF-kappaB. In order to search a possible target to cancer prostate treatment we proposed that inhibition of several proinflamatory cytokines such as IL-1 and TNFalpha might be a possible target for PC treatment, because decrease the activity of all transduction pathway members that activate transcription factors as NF-kappaB, Elk-1 or ATF-2.
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PMID:TNF-alpha/IL-1/NF-kappaB transduction pathway in human cancer prostate. 1871 80

Arrestins bind active phosphorylated G protein-coupled receptors, precluding G protein activation and channeling signaling to alternative pathways. Arrestins also function as mitogen-activated protein kinase (MAPK) scaffolds, bringing together three components of MAPK signaling modules. Here we have demonstrated that all four vertebrate arrestins interact with JNK3, MKK4, and ASK1, but only arrestin3 facilitates JNK3 activation. Thus, the functional specificity of arrestins is not determined by differential binding of the kinases. Using receptor binding-impaired mutant, we have shown that free arrestin3 readily promotes JNK3 phosphorylation. We identified key arrestin-binding elements in JNK3 and ASK1 and investigated the molecular interactions of arrestin2 and arrestin3 and their individual domains with the components of the two MAPK cascades, ASK1-MKK4-JNK3 and c-Raf-1-MEK1-ERK2. We found that both arrestin domains interact with all six kinases. These findings shed new light on the mechanism of arrestin-mediated MAPK activation and the spatial arrangement of the three kinases on arrestin molecule.
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PMID:How does arrestin assemble MAPKs into a signaling complex? 1900 75

Heat shock protein 27 (Hsp27), a recently discovered member of the heat shock protein family, is markedly induced in the brain after cerebral ischemia and other injury states. In non-neuronal systems, Hsp27 has potent cell death-suppressing functions. However, the mechanism of Hsp27-mediated neuroprotection has not yet been elucidated. Using transgenic and viral overexpression of Hsp27, we investigated the molecular mechanism by which Hsp27 exerts its neuroprotective effect. Overexpression of Hsp27 conferred long-lasting tissue preservation and neurobehavioral recovery, as measured by infarct volume, sensorimotor function, and cognitive tasks up to 3 weeks following focal cerebral ischemia. Examination of signaling pathways critical to neuronal death demonstrated that Hsp27 overexpression led to the suppression of the MKK4/JNK kinase cascade. While Hsp27 overexpression did not suppress activation of an upstream regulatory kinase of the MKK/JNK cascade, ASK1, Hsp27 effectively inhibited ASK1 activity via a physical association through its N-terminal domain and the kinase domain of ASK1. The N-terminal region of Hsp27 was required for neuroprotective function against in vitro ischemia. Moreover, knockdown of ASK1 or inhibition of the ASK1/MKK4 cascade effectively inhibited cell death following neuronal ischemia. This underscores the importance of this kinase cascade in the progression of ischemic neuronal death. Inhibition of PI3K had no effect on Hsp27-mediated neuroprotection, suggesting that Hsp27 does not promote cell survival via activation of PI3K/Akt. Based on these findings, we conclude that overexpression of Hsp27 confers long-lasting neuroprotection against ischemic brain injury via a previously unexplored association and inhibition of ASK1 kinase signaling.
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PMID:Hsp27 protects against ischemic brain injury via attenuation of a novel stress-response cascade upstream of mitochondrial cell death signaling. 1905 95

Excess copper is toxic to life. Copper has been shown to induce apoptosis in various cell lines and tissues. However, due to the lack of appropriate gene knockout animal models, data concerning the underlying pathways of copper-induced apoptosis are insufficient, especially with regards to in vivo systems. The nematode Caenorhabditis elegans is a good model to study basic biological processes, including stress responses and apoptosis. In the present study, we investigated copper-induced germline apoptosis in the C. elegans strains carrying mutated alleles of homologs to known mammalian genes that are involved in apoptosis regulation. We show here that exposing C. elegans to copper causes dose- and time-dependent germline apoptosis. The knockout of checkpoint genes hus-1, clk-2, the Bcl-2 homolog ced-9, and the BH3-only domain egl-1 did not prevent cells of the germline from copper-induced apoptosis. The loss-of-function of the tumor suppressor gene, p53/cep-1, caused a significant increase in germline apoptosis with exposure to copper, and the depletion of p53 antagonist ABL1 significantly enhanced apoptosis. The knockout of the caspase gene ced-3 and the Apaf-1 homolog ced-4 abrogated both copper-induced and physiological germline apoptosis. Germline apoptosis stopped increase in the strains lin-45(ku51), mek-2(n1989), mpk-1(ku1) under copper stresses, respectively. Copper-induced apoptosis was blocked in the loss-of-function alleles of both JNK and p38 MAPK cascades excepting pmk-3, one of the three p38 MAPK components. Together, the results of this study suggest that caspase and Apaf-1 are required for copper-induced germline apoptosis while DNA damage response genes are not essential, and that the Raf-MEK-ERK, ASK1/2-MKK7-JNK, ASK1/2-MKK3/6-p38 signaling pathways are indispensable in mediating this apoptotic response.
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PMID:Copper-induced germline apoptosis in Caenorhabditis elegans: the independent roles of DNA damage response signaling and the dependent roles of MAPK cascades. 1949 12

Microbes represent both an essential source of nutrition and a potential source of lethal infection to the nematode Caenorhabditis elegans. Immunity in C. elegans requires a signaling module comprised of orthologs of the mammalian Toll-interleukin-1 receptor (TIR) domain protein SARM, the mitogen-activated protein kinase kinase kinase (MAPKKK) ASK1, and MAPKK MKK3, which activates p38 MAPK. We determined that the SARM-ASK1-MKK3 module has dual tissue-specific roles in the C. elegans response to pathogens--in the cell-autonomous regulation of innate immunity and the neuroendocrine regulation of serotonin-dependent aversive behavior. SARM-ASK1-MKK3 signaling in the sensory nervous system also regulates egg-laying behavior that is dependent on bacteria provided as a nutrient source. Our data demonstrate that these physiological responses to bacteria share a common mechanism of signaling through the SARM-ASK1-MKK3 module and suggest the co-option of ancestral immune signaling pathways in the evolution of physiological responses to microbial pathogens and nutrients.
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PMID:Tissue-specific activities of an immune signaling module regulate physiological responses to pathogenic and nutritional bacteria in C. elegans. 1983 72

Human immunodeficiency virus-1 (HIV-1) impairs tumor necrosis factor-alpha (TNF-alpha)-mediated macrophage apoptosis induced by Mycobacterium tuberculosis (Mtb). HIV Nef protein plays an important role in the pathogenesis of AIDS. We have tested the hypothesis that exogenous Nef is a factor that inhibits TNF-alpha production/apoptosis in macrophages infected with Mtb. We demonstrate that Mtb and Nef individually trigger TNF-alpha production in macrophages. However, TNF-alpha production is dampened when the two are present simultaneously, probably through cross-regulation of the individual signaling pathways leading to activation of the TNF-alpha promoter. Mtb-induced TNF-alpha production is abrogated upon mutation of the Ets, Egr, Sp1, CRE, or AP1 binding sites on the TNF-alpha promoter, whereas Nef-mediated promoter activation depends only on the CRE and AP1 binding sites, pointing to differences in the mechanisms of activation of the promoter. Mtb-dependent promoter activation depends on the mitogen-activated kinase (MAPK) kinase kinase ASK1 and on MEK/ERK signaling. Nef inhibits ASK1/p38 MAPK-dependent Mtb-induced TNF-alpha production probably by inhibiting binding of ATF2 to the TNF-alpha promoter. It also inhibits MEK/ERK-dependent Mtb-induced binding of FosB to the promoter. Nef-driven TNF-alpha production occurs in an ASK1-independent, Rac1/PAK1/p38 MAPK-dependent, and MEK/ERK-independent manner. The signaling pathways used by Mtb and Nef to trigger TNF-alpha production are therefore distinctly different. In addition to attenuating Mtb-dependent TNF-alpha promoter activation, Nef also reduces Mtb-dependent TNF-alpha mRNA stability probably through its ability to inhibit ASK1/p38 MAPK signaling. These results provide new insight into how HIV Nef probably exacerbates tuberculosis infection by virtue of its ability to dampen Mtb-induced TNF-alpha production.
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PMID:Exogenous Nef is an inhibitor of Mycobacterium tuberculosis-induced tumor necrosis factor-alpha production and macrophage apoptosis. 2674 89

Cytochrome P4502E1 (CYP2E1) potentiates TNFalpha toxicity by a mechanism involving increased oxidative stress and activation of JNK and p38 MAPKs. This study evaluated the upstream mediators of this MAPK activation with a special focus on studying whether apoptosis signal regulating kinase-1 (ASK-1) is activated in the CYP2E1-TNFalpha hepatotoxic model. Wild-type and CYP2E1(-/-) mice were treated with pyrazole (PY) for 3days to induce CYP2E1 and challenged with TNFalpha on day 3. Liver injury occurred between 8 and 12h after TNFalpha administration only to the wild-type PY-treated mice. Oxidative stress was elevated in the PY mice at 4h, a time before the liver injury. ASK-1 was dissociated from the thioredoxin-ASK-1 complex and was activated at 4h after administration of TNFalpha to PY mice. This was followed by activation of MKK3/MKK6 and MKK4/MKK7 at 4-8 or 12h and then JNK/p38 MAPK at 8 to 12h. MAPK phosphatase-1 was decreased 12 to 24h after TNFalpha administration. This may promote a sustained activation of JNK. Bax was elevated, whereas Bcl-2 and cFLIP(S/L) were lowered at 4h after administration of TNFalpha. These changes were followed by increases in caspase 8 and 3 activities and apoptosis. None of the above changes were observed when TNFalpha was administered to PY-treated CYP2E1(-/-) mice. These studies show that TNFalpha increases oxidative stress in mice with elevated CYP2E1, with subsequent activation of ASK-1 via a mechanism involving thioredoxin-ASK-1 dissociation, followed by activation of downstream MKK and MAPK. We speculate that similar interactions between CYP2E1 and TNFalpha may be important for alcohol-induced liver injury.
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PMID:Activation of ASK-1 and downstream MAP kinases in cytochrome P4502E1 potentiated tumor necrosis factor alpha liver injury. 2043 34

Neurodegenerative disorders, such as Alzheimer's disease (AD), is associated with the loss of neuronal cells, and it has been suggested that apoptosis is a crucial pathway in neuronal loss in AD patients. Recent evidence suggests that amyloid beta peptide (Abeta) induces neuronal apoptosis in the brain and in primary neuronal cultures. In this study, we investigated the impact of beta-asarone against the apoptosis induced by Abeta in rat hippocampus. The results showed that intrahippocampal injections of Abeta (1-42) caused apoptosis in rat hippocampus. Oral administration of beta-asarone (12.5, 25, or 50 mg/kg) for 28 d reverse the increase in the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells in the hippocampus tissue. Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neuronal toxicity in AD. Therefore, we investigated nuclear translocation of apoptosis induction factors. Our results showed that beta-asarone afforded a beneficial inhibition on both mRNA and protein expression of Bad, Bax, and cleavage of caspases 9 in rat hippocampus following intrahippocampal injections of Abeta (1-42). Our further investigation revealed that ASK1, p-MKK7, and p-c-Jun were significantly decreased after beta-asarone treatment, implicating that the modulation of ASK1/c-JNK-mediated intracellular signaling cascades might be involved in therapeutic effect of beta-asarone against Abeta toxicity. Taken together, these results suggest that beta-asarone may be a potential candidate for development as a therapeutic agent for AD.
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PMID:Beta-asarone attenuates neuronal apoptosis induced by Beta amyloid in rat hippocampus. 2046 Aug 73


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