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      • HARVEST
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      The forkhead box transcription factors, FKH1 and FKH2, along with the Anaphase-Promoting Complex regulate Saccharomyces cerevisiae lifespan

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      POSTNIKOFF-DISSERTATION.pdf (3.666Mb)
      Date
      2014-07-22
      Author
      Postnikoff, Spike
      Type
      Thesis
      Degree Level
      Doctoral
      Metadata
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      Abstract
      Forkhead box (Fox) transcription factors have a conserved function in regulating lifespan and onset of age related disease in organisms from worms to mammals. Key functions in this process are the regulation of the cell cycle, oxidative stress response, and apoptosis. A complex post-translational code from nutrient, growth factor, and stress induced signals regulates Fox activity, target specificity, stability, and subcellular localization; however, many of the Fox mechanisms and targets responsible for regulating lifespan remain elusive. The budding yeast, Saccharomyces cerevisiae, is a powerful model for unravelling the genetic mechanism and pathways. Yeast encodes four Fox transcription factors, Fkh1, Fkh2, Fhl1 and Hcm1, and their roles in aging are only recently being examined. In this study, we utilized the chronological lifespan and oxidative stress assays, to explore evolutionary conservation of lifespan regulation in two of the yeast Fox orthologs, FKH1 and FKH2. We observed that deletion of both FKH genes in S. cerevisiae, impedes normal lifespan and stress resistance. Furthermore, fkh1Δ fkh2Δ cells were found to be non-responsive to caloric restriction, an intervention that extends lifespan from yeast to mammals. Conversely, increased expression of the FKHs leads to extended lifespan and improved stress resistance. Additionally, we show the Anaphase-Promoting Complex (APC) genetically interacts with the FKHs, likely functioning in a linear pathway under normal conditions, as fkh1Δ fkh2Δ post-mitotic survival defect is epistatic to that observed in apc5CA mutants. However, under stress conditions, post-mitotic survival is dramatically impaired in apc5CA fkh1Δ fkh2Δ beyond either apc5CA or fkh1Δ fkh2Δ. Finally, we observed that both the FKHs and APC genetically interact with nutrient-responsive lifespan-regulating kinase encoding genes SCH9 and TOR1. This study establishes that the yeast FKHs play a role as regulators of lifespan in yeast and identifies the APC as a novel component of this mechanism. We speculate this involves combined regulation of stress response, genomic stability, and cell cycle.
      Degree
      Doctor of Philosophy (Ph.D.)
      Department
      Anatomy and Cell Biology
      Program
      Anatomy and Cell Biology
      Supervisor
      Harkness, Troy A.
      Committee
      Krone, Patrick; Kulyk, William; Arnason, Terra; Carvalho, Carlos
      Copyright Date
      June 2014
      URI
      http://hdl.handle.net/10388/ETD-2014-06-1592
      Subject
      FKH1
      FKH2
      yeast
      Saccharomyces cerevisiae
      aging
      lifespan
      APC
      Anaphase-Promoting Complex
      nutrient signaling
      oxidative stress resistance
      forkhead box transcription factors
      SCH9
      TOR
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      • Graduate Theses and Dissertations
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