Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The consequences of activation of tumour necrosis factor receptor 1 (TNFR1) during neuronal injury remain controversial. The apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase, can mediate cell death downstream of TNFR1. Presently, we examined the formation of the TNFR1 signalling cascade and response of ASK1 during seizure-induced neuronal death. Brief (40 min) seizures were induced in rats by intra-amygdala microinjection of kainic acid, which elicited unilateral hippocampal CA3 neuronal death. Seizures caused a rapid decline in the expression of the silencer of death domains protein within injured CA3. Co-immunoprecipitation analysis revealed a commensurate assembly of a TNFR1 scaffold complex containing TNFR-associated death domain protein, receptor interacting protein and TNFR-activating factor 2. In addition, recruitment of TNFR-activating factor 2 was likely promoted by Bcl10-mediated sequestering of cellular inhibitor of apoptosis protein 2. Apoptosis signal-regulating kinase 1 was sequestered in a complex that contained the molecular chaperone 14-3-3beta and protein phosphatase 5. Seizures triggered its dissociation, and the phosphorylation of the ASK1 substrates, mitogen-activated protein kinase kinase 3/6 and 4. Subsequently, protein phosphatase 5 translocated into the nuclei of degenerating CA3 neurons, while ASK1 colocalized with the adaptor proteins Daxx and TNFR-activating factor 2 at the outer membrane of injured CA3 neurons. Neutralizing antibodies to TNFalpha reduced the numbers of DNA damaged cells within the injured hippocampus. These data suggest ASK1 may be involved in the mechanism of seizure-induced neuronal death downstream of a TNFR1 death-signalling complex.
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PMID:Formation of a tumour necrosis factor receptor 1 molecular scaffolding complex and activation of apoptosis signal-regulating kinase 1 during seizure-induced neuronal death. 1278 73

We examined if the relative expression of JNK-interacting protein 1 (JIP1) and phosphorylated c-Jun N-terminal kinase (JNK) regulates cell signaling and contributes to selective neuronal vulnerability in response to environmental stress. In clonal neuroblastoma cultures, stresses such as hypoxia, ischemia, Abeta peptides, and UV irradiation rapidly reduced JIP1 expression. JIP1 mRNA expression was also down-regulated by UV stress and was accompanied by increased JNK and c-Jun activation and cell death. JIP1 protein reduction was partially reversed both by inhibitors predominantly of caspase 3 and of the JNK pathway and resulted in significantly increased cell survival. Conversely, overexpression of JIP1 decreased both nuclear translocation of activated-JNK, and c-Jun phosphorylation induced by either UV irradiation, or the JNK upstream activators, MKK7 or MEKK1. Cell death was reduced about 50% compared to GFP-transfected controls. JIP1 overexpression did not facilitate either JNK expression or activation. In the normal, non-stressed human hippocampus and rat hippocampal organotypic cultures, JIP1 and JNK3 were inversely expressed with more JIP1 in CA2 and CA3 and less in CA1 neurons. In the human hippocampus, transient hypoxia/ischemia selectively spares neurons in CA2 and CA3 and induces death of neurons in the hippocampal CA1 subregion. In the cultures, ischemia reduced JIP1 expression and activated JNK, c-Jun, and caspase 3. Inhibitors of the JNK pathway, JNK activation directly and of caspase 3 activation each partially reversed these effects. Thus, under certain stress conditions, down-regulation of JIP1 expression makes neurons more susceptible to apoptosis, suggesting JIP may serve as an anti-apoptosis factor.
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PMID:JIP1 regulates neuronal apoptosis in response to stress. 1583 24