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Effect of cyclin E overexpression on lovastatin-induced G1 arrest and RhoA inactivation in NIH3T3 cells

P M Ghosh1, M L Moyer, G E Mott

  • 1Department of Pathology, University of Texas Health Science Center, San Antonio, Texas 78284, USA.

Journal of Cellular Biochemistry
|August 10, 1999
PubMed

Insights

Lovastatin inhibits cell growth by blocking protein prenylation, affecting RhoA activity. Overexpressing cyclin E prevents lovastatin

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Lovastatin, an HMG-CoA reductase inhibitor, disrupts protein prenylation, essential for small GTPase function.
  • Rho and Ras GTPases regulate cell growth, cytoskeleton organization, and cell cycle progression.
  • Cyclin E is a key regulator of the G1/S phase transition in the cell cycle.

Purpose of the Study:

  • To investigate the role of cyclin E in mediating cellular responses to lovastatin.
  • To determine how cyclin E overexpression affects lovastatin-induced growth arrest and cell morphology.
  • To elucidate the relationship between cyclin E activity and RhoA signaling in response to lovastatin.

Main Methods:

  • NIH3T3 cells, both control and overexpressing human cyclin E, were treated with lovastatin.
  • Cell cycle progression, protein levels (p27kip1, pRb), and kinase activities (cyclin E/A-CDK) were analyzed.
  • Active RhoA levels in the membrane fraction were assessed using western blotting and treatment with botulinum C3 transferase and cycloheximide.

Main Results:

  • Lovastatin induced G1 growth arrest, cell rounding, and loss of active RhoA in control cells.
  • Cyclin E overexpression conferred resistance to lovastatin-induced growth arrest and RhoA loss within 24 hours.
  • Lovastatin failed to inhibit cyclin E/A-dependent kinase activity or alter pRb phosphorylation in cyclin E overexpressors, despite increased p27kip1.

Conclusions:

  • RhoA activation is downstream of cyclin E-dependent kinase activation.
  • Overexpression of cyclin E reduces the turnover rate of active RhoA, contributing to resistance against lovastatin.
  • Cyclin E plays a critical role in regulating cellular sensitivity to lovastatin by modulating RhoA signaling.

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