Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

We report here the cleavage of the c-Jun N-terminal Kinase (JNK) pathway scaffold protein, JNK Interacting Protein-1 (JIP1), by caspases during both Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) and staurosporine-induced apoptosis in HeLa cells. During the initiation of apoptosis, maximal JNK activation is observed when JIP1 is intact, whereas cleavage of JIP1 correlates with JNK inactivation and progression of apoptosis. JIP1 is cleaved by caspase-3 at two sites, leading to disassembly of the JIP1/JNK complex. Inhibition of JIP1 cleavage by the caspase-3 inhibitor DEVD.fmk inhibits this disassembly, and is accompanied by sustained JNK activation. These data suggest that TRAIL and staurosporine induce JNK activation in a caspase-3-independent manner and that caspase-3-mediated JIP1 cleavage plays a role in JNK inactivation via scaffold disassembly during the execution phase of apoptosis. Caspase-mediated cleavage of JIP scaffold proteins may therefore represent an important mechanism for modulation of JNK signalling during apoptotic cell death.
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PMID:Disassembly of the JIP1/JNK molecular scaffold by caspase-3-mediated cleavage of JIP1 during apoptosis. 2123 54