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Geranylgeranylpyrophosphate, a metabolite of mevalonate, regulates the cell cycle progression and DNA synthesis in
1Second Department of Internal Medicine, Chiba University School of Medicine, Japan.
Abstract:
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.
Insights
The mevalonate cascade is crucial for DNA synthesis and cell cycle progression in human immune cells. Geranylgeranyl-pyrophosphate (GGPP) is essential for this process, enabling cells to enter the S phase.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- The mevalonate pathway is vital for producing isoprenoids.
- Its role in immune cell proliferation requires further elucidation.
Purpose of the Study:
- To investigate the mevalonate cascade's function in DNA synthesis and cell cycle progression.
- To identify key mevalonate metabolites involved in phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cell (PBMC) activation.
Main Methods:
- PBMCs were stimulated with PHA.
- 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase mRNA expression was measured.
- Pravastatin (HMG-CoA reductase inhibitor) effects on DNA synthesis were assessed.
- Mevalonate, geranylgeranyl-pyrophosphate (GGPP), and farnesyl-pyrophosphate (FPP) were used to restore inhibited functions.
Main Results:
- PHA stimulation increased HMG-CoA reductase mRNA expression before DNA synthesis (S phase).
- Pravastatin inhibited DNA synthesis and S phase entry.
- Mevalonate rescued these inhibitory effects.
- GGPP, but not FPP, restored pravastatin-induced inhibition, indicating its critical role.
Conclusions:
- The intrinsic mevalonate cascade is essential for DNA synthesis and entry into S phase in PHA-stimulated PBMCs.
- Geranylgeranyl-pyrophosphate (GGPP) is a key metabolite required for cell cycle progression in this context.