The oncogenic RAS2(val19) mutation locks respiration, independently of PKA, in a mode prone to generate ROS.
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.
Hlavatá
Lydie
L
Institute of Microbiology, Czech Academy of Sciences, CZ-142 20 Prague, Czech Republic.
Aguilaniu
Hugo
H
Pichová
Alena
A
Nyström
Thomas
T
D000483:Alleles; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D009154:Mutation; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000254:growth & development / Q000378:metabolism; D014633:Valine / Q000235:genetics*
D017382:Reactive Oxygen Species; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015689:Oncogene Protein p21(ras); D014633:Valine