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Neuronal apoptotic death generally requires de novo transcription, and activation of the transcription factor c-Jun has been shown to be necessary in multiple neuronal death paradigms. Caspase-2 has been implicated in death of neuronal and non-neuronal cells, but its relationship to transcriptional activation has not been clearly elucidated. In the present study, using two different neuronal apoptotic paradigms, β-amyloid treatment and NGF (nerve growth factor) withdrawal, we examined the hierarchical role of caspase-2 activation in the transcriptional control of neuron death. Both paradigms induce rapid activation of caspase-2 as well as activation of the transcription factor c-Jun and subsequent induction of the pro-apoptotic BH3 (Bcl-homology domain 3)-only protein Bim (Bcl-2-interacting mediator of cell death). Caspase-2 activation is dependent on the adaptor protein RAIDD {RIP (receptor-interacting protein)-associated ICH-1 [ICE (interleukin-1β-converting enzyme)/CED-3 (cell-death determining 3) homologue 1] protein with a death domain}, and both caspase-2 and RAIDD are required for c-Jun activation and Bim induction. The present study thus shows that rapid caspase-2 activation is essential for c-Jun activation and Bim induction in neurons subjected to apoptotic stimuli. This places caspase-2 at an apical position in the apoptotic cascade and demonstrates for the first time that caspase-2 can regulate transcription.

Original publication

DOI

10.1042/BJ20130556

Type

Journal article

Journal

Biochem J

Publication Date

01/10/2013

Volume

455

Pages

15 - 25

Keywords

Amyloid beta-Peptides, Animals, Apoptosis, Apoptosis Regulatory Proteins, Bcl-2-Like Protein 11, CRADD Signaling Adaptor Protein, Caspase 2, Fetus, Membrane Proteins, Nerve Growth Factor, Neurons, Primary Cell Culture, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-jun, Rats, Rats, Sprague-Dawley, Signal Transduction, Transcription, Genetic, Transcriptional Activation