Therapeutic levels of the hydroxmethylglutaryl-coenzyme A reductase inhibitor lovastatin activate Ras signaling via phospholipase D2

Cho, Kwang-jin, Hill, Michelle M., Chigurupati, Sravanthi, Du, Guangwei, Parton, Robert G. and Hancock, John F. (2011) Therapeutic levels of the hydroxmethylglutaryl-coenzyme A reductase inhibitor lovastatin activate Ras signaling via phospholipase D2. Molecular and Cellular Biology, 31 6: 1110-1120. doi:10.1128/MCB.00989-10

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Author Cho, Kwang-jin
Hill, Michelle M.
Chigurupati, Sravanthi
Du, Guangwei
Parton, Robert G.
Hancock, John F.
Title Therapeutic levels of the hydroxmethylglutaryl-coenzyme A reductase inhibitor lovastatin activate Ras signaling via phospholipase D2
Journal name Molecular and Cellular Biology   Check publisher's open access policy
ISSN 0270-7306
1098-5549
Publication date 2011-03
Sub-type Article (original research)
DOI 10.1128/MCB.00989-10
Open Access Status File (Publisher version)
Volume 31
Issue 6
Start page 1110
End page 1120
Total pages 11
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2012
Language eng
Formatted abstract
Hydroxmethylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) lower serum cholesterol but exhibit pleiotropic biological effects that are difficult to ascribe solely to cholesterol depletion. Here, we investigated the effect of lovastatin on protein prenylation and cell signaling. We show that high concentrations (50 µM) of lovastatin inhibit Ras, Rho, and Rap prenylation but that therapeutic levels of lovastatin (50 nM to 500 nM) do not. In contrast, depletion of cellular cholesterol by therapeutic levels of lovastatin increased Ras GTP loading and mitogen-activated protein kinase (MAPK) activation in human umbilical vein endothelial cells and rodent fibroblasts. Elevated Ras signaling was not seen in statin-treated cells if cholesterol levels were maintained by supplementation. Activation of Ras-MAPK signaling was a consequence of, and dependent on, activation of phospholipase D2 (PLD2). Expression of dominant interfering PLD2 or biochemical inhibition of PLD2 abrogated Ras and MAPK activation induced by lovastatin. In contrast, ectopic expression of wild-type PLD2 enhanced Ras and MAPK activation in response to therapeutic levels of lovastatin. Statin-induced cholesterol depletion also modestly activated the epidermal growth factor receptor (EGFR), resulting in downregulation of EGFR expression. These results suggest that statins modulate key cell signaling pathways as a direct consequence of cholesterol depletion and identify the EGFR-PLD2-Ras-MAPK axis as an important statin target.
Keyword Endothelial nitric-oxide
Bone morphogenetic protein-2
Growth-factor receptor
Plasma-membrane
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Sun, 13 Mar 2011, 00:08:16 EST