Statin-induced depletion of geranylgeranyl pyrophosphate inhibits cell proliferation by a novel pathway of Skp2 degradation
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Jonathan Vosper1, Alessia Masuccio1, Michael Kullmann1, Christian Ploner2, Stephan Geley3 and Ludger Hengst1
1 Division of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
2 Division of Molecular Pathophysiology, Biocenter/Clinic of Plastic and Reconstructive Surgery, Medical University of Innsbruck, Innsbruck, Austria
3 Division of Molecular Pathophysiology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
Ludger Hengst, email:
Keywords: cell cycle, geranylgeranylation, lovastatin, p27, Skp2
Received: September 16, 2014 Accepted: December 21, 2014 Published: December 26, 2014
Statins, such as lovastatin, can induce a cell cycle arrest in the G1 phase. This robust antiproliferative activity remains intact in many cancer cells that are deficient in cell cycle checkpoints and leads to an increased expression of CDK inhibitor proteins p27Kip1 and p21Cip1. The molecular details of this statin-induced growth arrest remains unclear. Here we present evidence that lovastatin can induce the degradation of Skp2, a subunit of the SCFSkp2 ubiquitin ligase that targets p27Kip1 and p21Cip1 for proteasomal destruction.
The statin-induced degradation of Skp2 is cell cycle phase independent and does not require its well characterised degradation pathway mediated by APC/CCdh1- or Skp2 autoubiquitination. An N-terminal domain preceding the F-box of Skp2 is both necessary and sufficient for its statin mediated degradation. The degradation of Skp2 results from statin induced depletion of geranylgeranyl isoprenoid intermediates of cholesterol biosynthesis. Inhibition of geranylgeranyl-transferase-I also promotes APC/CCdh1- independent degradation of Skp2, indicating that de-modification of a geranylgeranylated protein triggers this novel pathway of Skp2 degradation.
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