PMU-Autor/inn/en
Paulmichl MarkusAbstract
In previous studies we have shown that the expression of the transforming Ha-ras oncogene in NIH 3T3 fibroblasts stimulates cellular calcium entry, which triggers oscillatory calcium induced calcium release from internal stores. The intracellular calcium oscillations lead to cytoskeletal remodeling by actin stress fiber depolymerization and activation of the Na(+)/H(+) exchanger thus mediating cell swelling and intracellular alkalosis, both important mitogenic signals. This is evidenced by abrogation of Ha-ras induced growth factor independent cell proliferation by interference with any of these events, i.e. by inhibition of cellular calcium entry or inhibition of the Na(+)/H(+) exchanger. As shown in this study, simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme for cholesterol biosynthesis, is able to prevent these events following the expression of the transforming Ha-ras oncogene. We show, that simvastatin inhibits farnesylation dependent membrane translocation of a CAAX motive bearing yellow fluorescent protein and suppresses Ha-ras stimulated cellular calcium influx, which can be identified as capacitative calcium entry. In addition simvastatin is able to block regulatory volume decrease channels and to suppress the cytoskeletal remodeling, intracellular alkalinization, increase in cell volume and growth factor independent cell proliferation induced by the oncogene. Thus simvastatin is able to prevent crucial cellular events following expression of the transforming Ha-ras oncogene.
Useful keywords (using NLM MeSH Indexing)
3T3 Cells
Actins/metabolism
Animals
Bacterial Proteins/genetics
Calcium/metabolism
Cell Division/drug effects
Cell Membrane/metabolism
Cell Size/drug effects
Cell Size/physiology
Cell Transformation, Neoplastic/drug effects*
Cytoskeleton/drug effects
Fibroblasts/cytology
Fibroblasts/drug effects*
Fibroblasts/metabolism
Gene Expression
Genes, ras/physiology*
Hydrogen-Ion Concentration
Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology*
Intracellular Fluid/metabolism
Ion Channels/drug effects
Luminescent Proteins/genetics
Mice
Patch-Clamp Techniques
Protein Prenylation/physiology
Protein Transport/physiology
Recombinant Fusion Proteins/genetics
Recombinant Fusion Proteins/metabolism
Simvastatin/pharmacology*
Transfection
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