The oncogenic RAS2(val19) mutation locks respiration, independently of PKA, in a mode prone to generate ROS

EMBO J. 2003 Jul 1;22(13):3337-45. doi: 10.1093/emboj/cdg314.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Mutation*
  • Oncogene Protein p21(ras) / genetics
  • Oncogene Protein p21(ras) / physiology*
  • Oxidative Stress
  • Phosphorylation
  • Reactive Oxygen Species / metabolism*
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae / metabolism
  • Valine / genetics*


  • Reactive Oxygen Species
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Oncogene Protein p21(ras)
  • Valine