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Molecular and Cellular Biology, October 2005, p. 8732-8747, Vol. 25, No. 19
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.19.8732-8747.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Hon Kit Wong ,1,{dagger},{ddagger} Michael Fricker,1,{dagger} Andreas Wyttenbach,1,§ Andreas Villunger,2 Ewa M. Michalak,3 Andreas Strasser,3 and Aviva M. Tolkovsky1*

Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, United Kingdom,1 Institute of Pathophysiology, University of Innsbruck Medical School, Fritz-Pregl-Str. 3, A-6020 Innsbruck, Austria,2 Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3050 Victoria, Australia3

Received 3 March 2005/ Returned for modification 6 April 2005/ Accepted 12 July 2005

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.

* Corresponding author. Mailing address: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, United Kingdom. Phone: 441223 339319. Fax: 441223 333345. E-mail: amt{at}mole.bio.cam.ac.uk.

{dagger} H.K.W. and M.F. contributed equally to this study.

{ddagger} Present address: RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.

§ Present address: School of Biological Sciences, Bassett Crescent East, Southampton SO16 7PX, United Kingdom.

Molecular and Cellular Biology, October 2005, p. 8732-8747, Vol. 25, No. 19
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.19.8732-8747.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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