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Rapamycin-mediated G1 arrest involves regulation of the Cdk inhibitor Sic1 in Saccharomyces cerevisiae

Vittoria Zinzalla1, Michele Graziola, Andrea Mastriani

  • 1Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126, Milano, Italy.

Molecular Microbiology
|February 17, 2007
PubMed

Insights

Rapamycin treatment halts yeast cell growth by downregulating G1-cyclins and increasing the Sic1 protein, a dual mechanism essential for nutrient starvation survival.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The nutrient-sensing target of rapamycin (TOR) pathway regulates yeast growth and proliferation.
  • Rapamycin inhibits TOR signaling, leading to G1 cell cycle arrest, but the precise mechanism remains unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which TOR inhibition by rapamycin induces G1 cell cycle arrest in Saccharomyces cerevisiae.
  • To investigate the roles of G1-cyclins and the Cdk inhibitor Sic1 in this process.

Main Methods:

  • Rapamycin treatment of Saccharomyces cerevisiae.
  • Analysis of G1-cyclin (Cln1-3) levels.
  • Assessment of Cdk inhibitor protein Sic1 levels and phosphorylation.
  • Investigation of Sic1 nuclear localization and ubiquitination.
  • Gene deletion and overexpression studies (SIC1, CLN2, CLN3).

Main Results:

  • Rapamycin induces G1 arrest via a dual mechanism: downregulation of G1-cyclins (Cln1-3) and upregulation of Sic1.
  • Sic1 upregulation is largely independent of G1-cyclin downregulation but requires Sic1 phosphorylation at Thr173.
  • Rapamycin promotes Sic1 nuclear accumulation, stabilizing the protein by preventing ubiquitination.
  • SIC1 deletion or CLN3 overexpression leads to non-cell-cycle-specific arrest and increased sensitivity to rapamycin and nutrient starvation.

Conclusions:

  • Sic1 plays a crucial role in rapamycin-induced G1 arrest.
  • Dysregulated entry into S phase compromises cellular ability to withstand nutrient starvation conditions mimicked by rapamycin.

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