Geranylgeranylpyrophosphate, a metabolite of mevalonate, regulates the cell cycle progression and DNA synthesis in human lymphocytes.
We investigated the role of the intrinsic mevalonate cascade in DNA synthesis and cell cycle progression in human peripheral blood mononuclear cells (PBMC) stimulated by phytohemagglutinin (PHA). PHA stimulated the expression of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase mRNA prior to the DNA synthesis (S phase). Pravastatin, an HMG-CoA reductase inhibitor, inhibited DNA synthesis and blocked the entry to S phase in PHA-stimulated PBMC. Mevalonate restored these inhibitory effects. Thus, we examined two major metabolites of mevalonate, geranylgeranyl-pyrophosphate (GGPP) and farnesyl-pyrophosphate (FPP), using a novel liposome system for uptake into the cells. GGPP, not FPP, restored the pravastatin-induced inhibitions. These data indicated that 1) the intrinsic mevalonate cascade plays critical roles for the entry to S phase and DNA synthesis, and that 2) GGPP is an essential metabolite of mevalonate cascade for cell cycle progression in PBMC stimulated by PHA.
Tatsuno
I
I
Second Department of Internal Medicine, Chiba University School of Medicine, Japan.
Tanaka
T
T
Oeda
T
T
Yasuda
T
T
Kitagawa
M
M
Saito
Y
Y
Hirai
A
A
D000214:Acyl Coenzyme A / Q000096:biosynthesis / Q000235:genetics; D001692:Biological Transport; D002453:Cell Cycle / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008081:Liposomes; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects; D008798:Mevalonic Acid / Q000494:pharmacology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism / Q000494:pharmacology*; D017035:Pravastatin / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012717:Sesquiterpenes
D000214:Acyl Coenzyme A; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008081:Liposomes; D010835:Phytohemagglutinins; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D012717:Sesquiterpenes; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; C004808:farnesyl pyrophosphate; D004247:DNA; D017035:Pravastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid