The oncogenic RAS2val19 mutation locks respiration, independently of PKA, in a mode prone to generate ROS
Open Access
- 1 July 2003
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 22 (13), 3337-3345
- https://doi.org/10.1093/emboj/cdg314
Abstract
The RAS2val19 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 RAS2val19 cells with the mammalian uncoupling protein UCP1 restores phosphorylating respiration and reduces ROS levels, but does not correct for PKA‐dependent defects. Thus, the RAS2val19 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 RAS2val19 mutant.This publication has 58 references indexed in Scilit:
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