Document Detail


Negative regulation of cell proliferation by mevalonate or one of the mevalonate phosphates.
MedLine Citation:
PMID:  1917936     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The role of mevalonate and its products in the regulation of cellular proliferation was examined using 6-fluoromevalonate (Fmev), a compound that blocks the conversion of mevalonate pyrophosphate to isopentenyl pyrophosphate. Fmev suppressed DNA synthesis by a variety of transformed and malignant T cell, B cell, and myeloid cell lines. In contrast to results previously reported with mitogen-stimulated human peripheral blood T cell DNA synthesis, low concentrations of low density lipoprotein (LDL) alone could not restore proliferation to these cell lines. The same concentrations of LDL were able to provide sufficient cholesterol and support the growth of all cell lines when mevalonate synthesis was blocked with a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, lovastatin. Fmev-mediated inhibition was totally prevented in some but not all cell lines when the concentration of exogenous LDL was increased 5-10-fold above that required to permit proliferation of lovastatin-blocked cells. Residual HMG-CoA reductase activity of cells cultured with LDL inversely correlated with the restoration of growth to Fmev-blocked cultures. Confirmation of the critical role of HMG-CoA reductase activity and mevalonate synthesis in the inhibition of cellular proliferation by Fmev was obtained by demonstrating that the specific inhibitor of this enzyme, lovastatin, restored proliferation of Fmev-blocked cells. Furthermore, supplementation of cultures with mevalonate, the product of HMG-CoA reductase activity, markedly inhibited proliferation of Fmev-blocked cells. These findings indicate that mevalonate or one of the mevalonate phosphates, which accumulates in Fmev-blocked cells, is a critical negative regulator of cellular proliferation.
Authors:
J A Cuthbert; P E Lipsky
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  266     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1991 Sep 
Date Detail:
Created Date:  1991-10-29     Completed Date:  1991-10-29     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  17966-71     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8887.
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MeSH Terms
Descriptor/Qualifier:
Cell Division / drug effects*
Cell Line
DNA / biosynthesis
Humans
Hydroxymethylglutaryl CoA Reductases / metabolism
Lipoproteins, LDL / metabolism
Lovastatin / pharmacology
Lymphocytes / drug effects
Mevalonic Acid / analogs & derivatives*,  pharmacology*
Sterols / metabolism
Grant Support
ID/Acronym/Agency:
AI17653/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Lipoproteins, LDL; 0/Sterols; 150-97-0/Mevalonic Acid; 2822-77-7/6-fluoromevalonolactone; 4872-34-8/5-diphosphomevalonic acid; 75330-75-5/Lovastatin; 9007-49-2/DNA; EC 1.1.1.-/Hydroxymethylglutaryl CoA Reductases

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