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A role for c-Jun N-terminal kinase 1 (JNK1), but not JNK2, in the beta-amyloid-mediated stabilization of protein p53 and induction of the apoptotic cascade in cultured cortical neurons.

Authors: Fogarty, MP  Downer, EJ  Campbell, V 
Citation: Fogarty MP, etal., Biochem J. 2003 May 1;371(Pt 3):789-98.
Pubmed: (View Article at PubMed) PMID:12534344
DOI: Full-text: DOI:10.1042/BJ20021660

beta-Amyloid (A beta) peptide has been shown to induce neuronal apoptosis; however, the mechanisms underlying A beta-induced neuronal cell death remain to be fully elucidated. The stress-activated protein kinase, c-Jun N-terminal kinase (JNK), is activated in response to cellular stress and has been identified as a proximal mediator of cell death. In the present study, expression of active JNK was increased in the nucleus and cytoplasm of A beta-treated cells. Evaluation of the nature of the JNK isoforms activated by A beta revealed a transient increase in JNK1 activity that reached its peak at 1 h and a later activation (at 24 h) of JNK2. The tumour suppressor protein, p53, is a substrate for JNK and can serve as a signalling molecule in apoptosis. In cultured cortical neurons, we found that A beta increased p53 protein expression and phosphorylation of p53 at Ser(15). Thus it appears that A beta increases p53 expression via phosphorylation-mediated stabilization of the protein. Given the lack of availability of a JNK inhibitor that can distinguish between JNK1- and JNK2-mediated effects, we employed antisense technology to deplete cells of JNK1 or JNK2 selectively. Using this strategy, the respective roles of JNK1 and JNK2 on the A beta-mediated activation of the apoptotic cascade (i.e. p53 stabilization, caspase 3 activation and DNA fragmentation) were examined. The results obtained demonstrate a role for JNK1 in the A beta-induced stabilization of p53, activation of caspase 3 and DNA fragmentation. In contrast, depletion of JNK2 had no effect on the proclivity of A beta to activate capase 3 or induce DNA fragmentation. These results demonstrate a significant role for JNK1 in A beta-mediated induction of the apoptotic cascade in cultured cortical neurons.

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CRRD Object Information
CRRD ID: 10412678
Created: 2015-11-19
Species: All species
Last Modified: 2015-11-19
Status: ACTIVE



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