Abstract
Mevalonic acid-derived intermediates in the cholesterol biosynthetic pathway have been recognized as being critical to the isoprenylation of a variety of growth-regulating proteins, including those of the RAS superfamily. Treatment of cells with lovastatin, a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, depletes cells of mevalonic acid and thus blocks the isoprenylation of proteins in the RAS superfamily. In NIH3T3 cells pretreated with lovastatin, subsequent addition of farnesol (FOH), but not geranylgeraniol (GGOH), reverses lovastatin's block of RAS isoprenylation. Neither FOH nor GGOH prevents lovastatin-induced inhibition of RAS isoprenylation when added to cells concurrently with lovastatin. In intact cells, 167 μM FOH and 125 μM GGOH decrease incorporation of [14C]acetate into cholesterol by approximately 50 and 75%, respectively. Results suggest that the radio-label from either [3H]FOH or [3H]GGOH is incorporated into cholesterol. Co-treatment of cells with lovastatin or mevalonic acid did not significantly alter [3H]FOH or [3H]GGOH incorporation into cholesterol. Lovastatin induces cell rounding; GGOH, but not FOH, both prevents and reverses lovastatin-induced cell rounding. These results provide additional evidence for the existence of a novel "isoprenoid shunt" that differentially utilizes FOH and GGOH as metabolic precursors for isoprenoids that have been depleted by lovastatin treatment.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 185-192 |
| Number of pages | 8 |
| Journal | Lipids |
| Volume | 37 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 1 2002 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Organic Chemistry
- Cell Biology
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Farnesol and geranylgeraniol : Prevention and reversion of lovastatin-induced effects in NIH3T3 cells. / Ownby, Susan E.; Hohl, Raymond.
In: Lipids, Vol. 37, No. 2, 01.01.2002, p. 185-192.Research output: Contribution to journal › Article
TY - JOUR
T1 - Farnesol and geranylgeraniol
T2 - Prevention and reversion of lovastatin-induced effects in NIH3T3 cells
AU - Ownby, Susan E.
AU - Hohl, Raymond
PY - 2002/1/1
Y1 - 2002/1/1
N2 - Mevalonic acid-derived intermediates in the cholesterol biosynthetic pathway have been recognized as being critical to the isoprenylation of a variety of growth-regulating proteins, including those of the RAS superfamily. Treatment of cells with lovastatin, a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, depletes cells of mevalonic acid and thus blocks the isoprenylation of proteins in the RAS superfamily. In NIH3T3 cells pretreated with lovastatin, subsequent addition of farnesol (FOH), but not geranylgeraniol (GGOH), reverses lovastatin's block of RAS isoprenylation. Neither FOH nor GGOH prevents lovastatin-induced inhibition of RAS isoprenylation when added to cells concurrently with lovastatin. In intact cells, 167 μM FOH and 125 μM GGOH decrease incorporation of [14C]acetate into cholesterol by approximately 50 and 75%, respectively. Results suggest that the radio-label from either [3H]FOH or [3H]GGOH is incorporated into cholesterol. Co-treatment of cells with lovastatin or mevalonic acid did not significantly alter [3H]FOH or [3H]GGOH incorporation into cholesterol. Lovastatin induces cell rounding; GGOH, but not FOH, both prevents and reverses lovastatin-induced cell rounding. These results provide additional evidence for the existence of a novel "isoprenoid shunt" that differentially utilizes FOH and GGOH as metabolic precursors for isoprenoids that have been depleted by lovastatin treatment.
AB - Mevalonic acid-derived intermediates in the cholesterol biosynthetic pathway have been recognized as being critical to the isoprenylation of a variety of growth-regulating proteins, including those of the RAS superfamily. Treatment of cells with lovastatin, a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, depletes cells of mevalonic acid and thus blocks the isoprenylation of proteins in the RAS superfamily. In NIH3T3 cells pretreated with lovastatin, subsequent addition of farnesol (FOH), but not geranylgeraniol (GGOH), reverses lovastatin's block of RAS isoprenylation. Neither FOH nor GGOH prevents lovastatin-induced inhibition of RAS isoprenylation when added to cells concurrently with lovastatin. In intact cells, 167 μM FOH and 125 μM GGOH decrease incorporation of [14C]acetate into cholesterol by approximately 50 and 75%, respectively. Results suggest that the radio-label from either [3H]FOH or [3H]GGOH is incorporated into cholesterol. Co-treatment of cells with lovastatin or mevalonic acid did not significantly alter [3H]FOH or [3H]GGOH incorporation into cholesterol. Lovastatin induces cell rounding; GGOH, but not FOH, both prevents and reverses lovastatin-induced cell rounding. These results provide additional evidence for the existence of a novel "isoprenoid shunt" that differentially utilizes FOH and GGOH as metabolic precursors for isoprenoids that have been depleted by lovastatin treatment.
UR - http://www.scopus.com/inward/record.url?scp=0036198699&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036198699&partnerID=8YFLogxK
U2 - 10.1007/s11745-002-0879-1
DO - 10.1007/s11745-002-0879-1
M3 - Article
C2 - 11908910
AN - SCOPUS:0036198699
VL - 37
SP - 185
EP - 192
JO - Lipids
JF - Lipids
SN - 0024-4201
IS - 2
ER -