6533b85efe1ef96bd12bfe16
RESEARCH PRODUCT
Ultraviolet light-induced apoptotic death is impaired by the HMG-CoA reductase inhibitor lovastatin.
Bernd KainaGerhard FritzRenate V. Bardelebensubject
DNA ReplicationUltraviolet Raysp38 mitogen-activated protein kinasesBiophysicsApoptosisCHO CellsBiochemistryp38 Mitogen-Activated Protein KinasesCricetinaemedicineUltraviolet lightAnimalsMitogen-Activated Protein Kinase 8LovastatinMolecular BiologyCaspasebiologyKinaseCell BiologyCell biologyrac GTP-Binding ProteinsEnzyme ActivationCell killingApoptosisCaspasesHMG-CoA reductasebiology.proteinLovastatinHydroxymethylglutaryl-CoA Reductase InhibitorsMitogen-Activated Protein Kinasesmedicine.drugdescription
HMG-CoA reductase inhibitors (i.e., statins) attenuate C-terminal isoprenylation of Rho GTPases, thereby inhibiting UV-C-induced activation of c-Jun-N-terminal kinases/stress-activated protein kinases (JNKs/SAPKs). Inhibition of UV-C-triggered JNK/SAPK activation by lovastatin is due to inhibition of Rac-SEK1/MKK4-mediated phosphorylation of JNKs/SAPKs at Thr183/Tyr185. UV-C-stimulated phosphorylation of p38 kinase (Thr180/Tyr182) is also impaired by lovastatin. Cell killing provoked by UV-C irradiation was significantly inhibited by lovastatin. This was paralleled by a reduced frequency of chromosomal aberrations, accelerated recovery from UV-C-induced transient replication blockage, inhibition of Chk1 kinase activation and impaired cyclinB1 expression. Furthermore, UV-C-induced activation of caspases and apoptotic death was largely reduced by lovastatin. Inhibition of JNK/SAPK by transient overexpression of dominant-negative JNK1/SAPK1 also conferred resistance to UV-C light and attenuated activation of caspase 3. Based on the data, we suggest that lovastatin-provoked resistance to UV-C light is due to the inhibition of UV-C-inducible Rac-SEK1/MKK4-JNK/SAPK-dependent signal mechanisms regulating cell cycle progression and activation of caspases and apoptotic death.
year | journal | country | edition | language |
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2003-07-01 | Biochemical and biophysical research communications |