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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

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
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
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.
0270-7306
8732-8747
Wong, Hon Kit
53dfb501-ceb0-4b6d-9891-8a32a077307c
Fricker, Michael
44d38ce4-a65e-42c0-8384-573c4cce7602
Wyttenbach, Andreas
05019897-52b1-4bb6-b259-5d51abae7540
Villunger, Andreas
38b7ab19-bb1c-444e-8107-da520d3d5638
Michalak, Ewa M.
efd1edfc-9d7f-4f0b-9545-f72582f96b56
Strasser, Andreas
c9774edf-fa89-481c-8cc4-21f403859700
Tolkovsky, Aviva M.
c7bfa481-5040-4558-8100-d83b8aff45b2
Wong, Hon Kit
53dfb501-ceb0-4b6d-9891-8a32a077307c
Fricker, Michael
44d38ce4-a65e-42c0-8384-573c4cce7602
Wyttenbach, Andreas
05019897-52b1-4bb6-b259-5d51abae7540
Villunger, Andreas
38b7ab19-bb1c-444e-8107-da520d3d5638
Michalak, Ewa M.
efd1edfc-9d7f-4f0b-9545-f72582f96b56
Strasser, Andreas
c9774edf-fa89-481c-8cc4-21f403859700
Tolkovsky, Aviva M.
c7bfa481-5040-4558-8100-d83b8aff45b2

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).

Record type: Article

Abstract

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.

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Submitted date: 3 March 2005
Published date: October 2005

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Local EPrints ID: 37525
URI: https://eprints.soton.ac.uk/id/eprint/37525
ISSN: 0270-7306
PURE UUID: 277b3f0d-991d-4260-87f1-4c80299e6487

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Date deposited: 22 May 2006
Last modified: 12 Apr 2018 16:31

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