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. Mitochondrial 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.

Institute of Microbiology Czech Academy of Sciences CZ 142 20 Prague Czech Republic

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EMBO J. 2003 Sep 1;22(17):4577 PubMed

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