Dexamethasone-induced decrease in HMG-CoA reductase and protein-farnesyl transferase activities does not impair ras processing in AR 4-2J cells.
Rat pancreatic acinar cells AR 4-2J respond to dexamethasone by differentiation and a decreased proliferation rate. Protein labelling by [3H]-mevalonolactone, used as a precursor of farnesyl and geranylgeranyl isoprenoid groups, was increased in the presence of dexamethasone. In these same conditions, dexamethasone decreased HMG-CoA reductase activity, leading to a diminished isotopic dilution of the mevalonate precursor. As ras proteins, known to be involved in the regulation of proliferation and differentiation, need to be farnesylated for full biological function, we also measured the level of farnesyl transferase activity and found a dose-dependent decrease in dexamethasone treated cells. Despite these negative effects of dexamethasone on mevalonate pathway, there was no appearance of non-isoprenylated forms of ras, indicating that the level of isoprenoid precursors and farnesyl transferase activity were not limiting in this model.
Lambert
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Department of Biochemistry and Nutrition, Medical School, Université Libre de Bruxelles, Brussels, Belgium.
Bui
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D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D011905:Genes, ras / Q000187:drug effects*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D010190:Pancreatic Neoplasms; D051381:Rats; D014316:Tritium; D014407:Tumor Cells, Cultured
D014316:Tritium; C015367:mevalonolactone; D003907:Dexamethasone; D006903:Hydroxymethylglutaryl CoA Reductases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D008798:Mevalonic Acid