Related Experiment Video

Updated: Jul 6, 2025

A Suppressor Screen for the Characterization of Genetic Links Regulating Chronological Lifespan in Saccharomyces cerevisiae
10:39

A Suppressor Screen for the Characterization of Genetic Links Regulating Chronological Lifespan in Saccharomyces cerevisiae

Published on: September 17, 2020

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Inactivation of Ymr1, Sjl2/3 phosphatases promotes stress resistance and longevity in wild type and Ras2G19V yeast

M G Mirisola1, V D Longo2

  • 1SteBiCeF Department, University of Palermo, Palermo, Italy.

Biomedical Journal
|December 28, 2023
PubMed

Insights

Researchers identified yeast phosphatases YMR1, SJL2, and SJL3 as key suppressors of oncogenic Ras signaling. These mutations reversed Ras-induced stress sensitivity and extended lifespan, offering potential cancer therapy targets.

Area of Science:

  • Cellular signaling
  • Oncogenesis
  • Aging research

Background:

  • Ras activity in Saccharomyces cerevisiae regulates stress resistance and longevity, influenced by glucose.
  • Constitutive Ras activation mutations are linked to cell growth and oncogenesis.
  • The Ras2G19V mutation in yeast is an orthologue of the mammalian KRASG12C oncogene.

Purpose of the Study:

  • Identify suppressors of constitutively active Ras2G19V in yeast.
  • Investigate the role of phosphatases in regulating Ras activity and its effects.
  • Explore the link between Ras signaling, stress resistance, longevity, and the PI3K pathway.

Main Methods:

  • Transposon mutagenesis in yeast to screen for Ras2G19V suppressors.
  • Analysis of mutations in YMR1, SJL2, and SJL3 phosphatases.
  • Assessing Ras-GTP localization and stress sensitization in mutant strains.
  • Investigating the effects of Sjl2 phosphatase and VPS34 kinase expression.

Main Results:

  • YMR1, SJL2, and SJL3 phosphatases were identified as potent suppressors of constitutive Ras activity.
  • Mutations in these phosphatases reversed Ras-induced stress sensitization and extended yeast longevity.
  • In sjl2 mutants, Ras-GTP localization shifted from the membrane to the cytoplasm, inhibiting Ras activity.
  • Sjl2 mediated stress sensitization in both Ras2G19V and wild-type yeast, while VPS34 overexpression sensitized only Ras2G19V cells.

Conclusions:

  • Yeast phosphatases YMR1, SJL2, and SJL3 are critical regulators of Ras signaling, stress resistance, and longevity.
  • Inhibition of Ras activity by phosphatases offers potential therapeutic targets for cancers with constitutive Ras.
  • This study links the glucose-dependent yeast Ras pathway to the conserved PI3K-AKT pathway, suggesting a shared mechanism in aging.
Keywords:
AgingPhosphoinositidesRas PathwayRas activity modulatorsRas suppressorsTransposon mutagenesis

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