The oncogenic RAS2val19 mutation locks respiration, independently of PKA, in a mode prone to generate ROS

被引:91
作者
Hlavatá, L
Aguilaniu, H
Pichová, A
Nyström, T
机构
[1] Univ Gothenburg, Dept Cell & Mol Biol Microbiol, S-40530 Gothenburg, Sweden
[2] Acad Sci Czech Republ, Inst Microbiol, CZ-14220 Prague, Czech Republic
关键词
PKA; RAS2; reactive oxygen species; replicative aging; respiratory state; UCP1;
D O I
10.1093/emboj/cdg314
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The RAS2(val19) allele, which renders the cAMP-PKA pathway constitutively active and decreases the replicative life-span of yeast cells, is demonstrated to increase production of reactive oxygen species (ROS) and to elevate oxidative protein damage. Mito chondrial respiration in the mutant is locked in a non-phosphorylating mode prone to generate ROS but this phenotype is not linked to a constitutively active PKA pathway. In contrast, providing RAS2(val19) cells with the mammalian uncoupling protein UCP1 restores phosphorylating respiration and reduces ROS levels, but does not correct for PKA-dependent defects. Thus, the RAS2(val19) allele acts like a double-edged sword with respect to oxidation management: (i) it diminishes expression of STRE element genes required for oxidative stress defenses in a PKA-dependent fashion, and (ii) it affects endogenous ROS production and the respiratory state in a PKA-independent way. The effect of the oncogenic RAS allele on the replicative life-span is primarily asserted via the PKA-dependent pathway since Pde2p, but not UCP1, overproduction suppressed premature aging of the RAS2(val19) mutant.
引用
收藏
页码:3337 / 3345
页数:9
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