The yeast forkhead transcription factors fkh1 and fkh2 regulate lifespan and stress response together with the anaphase-promoting complex

PLoS Genet. 2012;8(3):e1002583. doi: 10.1371/journal.pgen.1002583. Epub 2012 Mar 15.

Abstract

Forkhead box O (FOXO) transcription factors have a conserved function in regulating metazoan lifespan. A key function in this process involves the regulation of the cell cycle and stress responses including free radical scavenging. We employed yeast chronological and replicative lifespan assays, as well as oxidative stress assays, to explore the potential evolutionary conservation of function between the FOXOs and the yeast forkhead box transcription factors FKH1 and FKH2. We report that the deletion of both FKH genes impedes normal lifespan and stress resistance, particularly in stationary phase cells, which are non-responsive to caloric restriction. Conversely, increased expression of the FKHs leads to extended lifespan and improved stress response. Here we show the Anaphase-Promoting Complex (APC) genetically interacts with the Fkh pathway, likely working in a linear pathway under normal conditions, as fkh1Δ fkh2Δ post-mitotic survival is epistatic to that observed in apc5(CA) mutants. However, under stress conditions, post-mitotic survival is dramatically impaired in apc5(CA) fkh1Δ fkh2Δ, while increased expression of either FKH rescues APC mutant growth defects. This study establishes the FKHs role as evolutionarily conserved regulators of lifespan in yeast and identifies the APC as a novel component of this mechanism under certain conditions, likely through combined regulation of stress response, genomic stability, and cell cycle regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome
  • Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome
  • Cell Cycle
  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Cell Survival
  • Forkhead Transcription Factors* / genetics
  • Forkhead Transcription Factors* / metabolism
  • Gene Expression Regulation, Fungal
  • Genomic Instability
  • Longevity / genetics
  • Mitosis
  • Saccharomyces cerevisiae Proteins* / genetics
  • Saccharomyces cerevisiae Proteins* / metabolism
  • Saccharomyces cerevisiae* / genetics
  • Saccharomyces cerevisiae* / growth & development
  • Saccharomyces cerevisiae* / metabolism
  • Stress, Physiological / genetics
  • Ubiquitin-Protein Ligase Complexes* / genetics
  • Ubiquitin-Protein Ligase Complexes* / metabolism

Substances

  • APC5 protein, S cerevisiae
  • Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome
  • Cell Cycle Proteins
  • Fkh1 protein, S cerevisiae
  • Fkh2 protein, S cerevisiae
  • Forkhead Transcription Factors
  • Saccharomyces cerevisiae Proteins
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome