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, HK; Fricker, M; Wyttenbach, A; Villunger, A; Michalak, EM; Strasser, A; Tolkovsky, AM;
- Publication Year 2005-10,Volume 25,Issue #19,Page 8732-8747
- Journal Title
- MOLECULAR AND CELLULAR BIOLOGY
- Publication Type
- Journal Article
- 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.
- AMER SOC MICROBIOLOGY
- PROGRAMMED CELL-DEATH; BCL-2 FAMILY-MEMBERS; TROPHIC FACTOR DEPRIVATION; CEREBELLAR GRANULE CELLS; COLORECTAL-CANCER CELLS; RETINAL GANGLION-CELLS; BAX-DEFICIENT MICE; SYMPATHETIC NEURONS; DNA-DAMAGE; SODIUM ARSENITE
- Publisher's Version
- Refer to copyright notice on published article.
Creation Date: 2005-10-01 12:00:00