title: Statin-induced depletion of geranylgeranyl pyrophosphate inhibits cell proliferation by a novel pathway of Skp2 degradation.
abstract: 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.
authors.affiliation: Division of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Vosper
authors.affiliation: Division of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Alessia
authors.initials: A
authors.lastname: Masuccio
authors.affiliation: Division of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Kullmann
authors.affiliation: Division of Molecular Pathophysiology, Biocenter/Clinic of Plastic and Reconstructive Surgery, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Ploner
authors.affiliation: Division of Molecular Pathophysiology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Geley
authors.affiliation: Division of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Ludger
authors.initials: L
authors.lastname: Hengst
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D064200:Cdh1 Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation; D017491:Genes, APC; D006367:HeLa Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D020298:U937 Cells
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C513384:CDH1 protein, human; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D015820:Cadherins; D064200:Cdh1 Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C577585:Fzr1 protein, mouse; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008148:Lovastatin; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D046988:Proteasome Endopeptidase Complex; C002963:geranylgeranyl pyrophosphate