Mutually exclusive subsets of BH3-only proteins are activated by the p53 and c-Jun N-terminal kinase/c-Jun signaling pathways during cortical neuron apoptosis induced by arsenite
Wong, Hon Kit, Fricker, Michael, Wyttenbach, Andreas, Villunger, Andreas, Michalak, Ewa M., Strasser, Andreas and Tolkovsky, Aviva M. (2005) Mutually exclusive subsets of BH3-only proteins are activated by the p53 and c-Jun N-terminal kinase/c-Jun signaling pathways during cortical neuron apoptosis induced by arsenite. Molecular and Cellular Biology, 25, (19), 8732-8747. (doi:10.1128/MCB.25.19.8732-8747.2005).
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The c-Jun N-terminal protein kinase (JNK)/c-Jun and p53 pathways form distinct death-signaling modules in neurons that culminate in Bax-dependent apoptosis. To investigate whether this signaling autonomy is due to recruitment of particular BH3-only proteins, we searched for a toxic signal that would activate both pathways in the same set of neurons. We show that arsenite activates both the JNK/c-Jun and p53 pathways in cortical neurons, which together account for >95% of apoptosis, as determined by using the mixed-lineage kinase (JNK/c-Jun) pathway inhibitor CEP11004 and p53-null mice. Despite the coexistence of both pathways in at least 30% of the population, Bim mRNA and protein expression was increased only by the JNK/c-Jun signaling pathway, whereas Noxa and Puma mRNA and Puma protein expression was entirely JNK/c-Jun independent. About 50% of Puma/Noxa expression was p53 dependent, with the remaining signal being independent of both pathways and possibly facilitated by arsenite-induced reduction in P-Akt. However, functionally, Puma was predominant in mediating Bax-dependent apoptosis, as evidenced by the fact that more than 90% of apoptosis was prevented in Puma-null neurons, although Bim was still upregulated, while Bim- and Noxa-null neurons died similarly to wild-type neurons. Thus, the p53 and JNK/c-Jun pathways can activate mutually exclusive subclasses of BH3-only proteins in the same set of neurons. However, other factors besides expression may determine which BH3-only proteins mediate apoptosis.
|Subjects:||Q Science > QH Natural history > QH301 Biology|
|Divisions:||University Structure - Pre August 2011 > School of Biological Sciences
|Date Deposited:||07 Aug 2008|
|Last Modified:||01 Jun 2011 00:29|
|Contributors:||Wong, Hon Kit (Author)
Fricker, Michael (Author)
Wyttenbach, Andreas (Author)
Villunger, Andreas (Author)
Michalak, Ewa M. (Author)
Strasser, Andreas (Author)
Tolkovsky, Aviva M. (Author)
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