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Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
Published on: January 16, 2020
Dexamethasone-induced decrease in HMG-CoA reductase and protein-farnesyl transferase activities does not impair ras
1Department of Biochemistry and Nutrition, Medical School, Université Libre de Bruxelles, Brussels, Belgium.
Abstract:
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.
Insights
Dexamethasone induces differentiation in rat pancreatic cells by altering isoprenoid synthesis. Despite decreased farnesyl transferase activity, ras proteins remained functional, suggesting precursor availability was not limiting.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Rat pancreatic acinar cells (AR 4-2J) differentiate and reduce proliferation when treated with dexamethasone.
- Isoprenoid synthesis, involving farnesyl and geranylgeranyl groups, is crucial for protein function, including ras proteins involved in cell regulation.
Purpose of the Study:
- To investigate the effects of dexamethasone on the mevalonate pathway and farnesyl transferase activity in AR 4-2J cells.
- To determine if changes in isoprenoid precursor levels or enzyme activity limit ras protein farnesylation and function.
Main Methods:
- AR 4-2J cells were treated with dexamethasone.
- Protein labeling with [3H]-mevalonolactone was used to assess isoprenoid synthesis.
- HMG-CoA reductase activity and farnesyl transferase activity were measured.
- Levels of isoprenylated ras proteins were analyzed.
Main Results:
- Dexamethasone treatment increased protein labeling with [3H]-mevalonolactone.
- HMG-CoA reductase activity decreased, reducing isotopic dilution of the mevalonate precursor.
- Farnesyl transferase activity showed a dose-dependent decrease in dexamethasone-treated cells.
- No non-isoprenylated ras proteins were observed, even with reduced enzyme activity.
Conclusions:
- Dexamethasone impacts the mevalonate pathway and farnesyl transferase activity in rat pancreatic acinar cells.
- Despite observed decreases, isoprenoid precursor levels and farnesyl transferase activity were sufficient to maintain ras protein farnesylation in this model.
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