Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability

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S Hashemolhosseini1, Y Nagamine, S J Morley

  • 1Institute for Experimental Cancer Research, Tumor Biology Center, P. O. Box 1120, 79011 Freiburg, Germany.

The Journal of Biological Chemistry
|June 11, 1998
PubMed

Insights

The immunosuppressant rapamycin inhibits cell cycle progression by reducing cyclin D1 protein levels through both transcriptional and post-transcriptional mechanisms. This ultimately impairs cell cycle transition, offering insights into rapamycin

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Rapamycin is a known immunosuppressant that inhibits the G1/S cell cycle transition.
  • This inhibition is partly mediated by the p70 S6 kinase (p70(S6k)) pathway and cyclin-dependent kinases (Cdks).

Purpose of the Study:

  • To investigate the precise molecular mechanisms by which rapamycin affects cyclin D1 during the G1/S transition.
  • To elucidate the role of transcriptional and post-transcriptional regulation of cyclin D1 by rapamycin.

Main Methods:

  • Treatment of serum-stimulated NIH 3T3 cells with rapamycin.
  • Analysis of cyclin D1 mRNA accumulation, stability, and protein degradation.
  • Assessment of cyclin D1/Cdk4 complex formation and p27(Kip1) inhibitor activity.
  • Use of proteasome inhibitor N-acetyl-Leu-Leu-norleucinal.

Main Results:

  • Rapamycin treatment delays cyclin D1 mRNA accumulation and affects its stability.
  • Rapamycin decreases overall cyclin D1 protein levels and accelerates its degradation via the proteasome.
  • Impaired formation of active cyclin D1/Cdk4 complexes and altered p27(Kip1) localization.

Conclusions:

  • Rapamycin exerts both transcriptional and post-transcriptional control over cyclin D1 levels.
  • These effects on cyclin D1 contribute to impaired Cdk4 complex formation and cell cycle arrest at G1/S.
  • Provides a detailed mechanism for rapamycin-induced G1/S cell cycle arrest.

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