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

Biochem J. 2003 May 1;371(Pt 3):789-98. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Animals
  • Apoptosis*
  • Base Sequence
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / enzymology
  • Cerebral Cortex / metabolism*
  • DNA Primers
  • Enzyme Activation
  • Kinetics
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinases / metabolism*
  • Oligonucleotides, Antisense / pharmacology
  • Phosphorylation
  • RNA, Messenger / genetics
  • Rats
  • Rats, Wistar
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Amyloid beta-Peptides
  • DNA Primers
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases