3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, statins, are 
widely used cholesterol-lowering drugs and have been shown to have anticancer 
effects in many models. We have investigated the effect of statins on Mdm2, a 
p53-specific ubiquitin ligase. It was found that pravastatin induced Mdm2 
phosphorylation at Ser166 and at 2A10 antibody-specific epitopes in HepG2 cells, 
while mRNA levels were unchanged. Furthermore, pravastatin was found to induce 
phosphorylation of mTOR at Ser2448. Ser166 phosphorylation of Mdm2 was abrogated 
by an inhibitor of mTOR, rapamycin, but not by the PI3-kinase inhibitors 
LY294002 and wortmannin. Ser166 phosphorylation of Mdm2 has been associated to 
active Mdm2 and has been shown to increase its ubiquitin ligase activity and 
lead to increased p53 degradation. Our data show that statins attenuated the p53 
response to DNA damage. Thus, in HepG2 cells pravastatin and simvastatin 
pretreatment attenuated the p53 response to DNA damage induced by 5-fluorouracil 
and benzo(a)pyrene. Similar attenuation was induced when p53 stabilization was 
induced by the inhibitor of nuclear export, leptomycin B. Furthermore, in the 
DNA-damaged cells, half-lives of Mdm2 and p53 were decreased by statins, 
indicating a more rapid formation of p53/Mdm2 complexes and facilitated p53 
degradation. The induction of p53 responsive genes and apoptosis was attenuated. 
Mdm2 and p53 were also studied in vivo in rat liver employing 
immunohistochemistry, and it was found that constitutive Mdm2 expression was 
changed in livers of pravastatin-treated rats. We also show that the p53 
response to a challenging dose of diethylnitrosamine was attenuated in 
hepatocytes in situ and in primary cultures of hepatocytes by pravastatin 
pretreatment. Taken together, these data indicate that statins induce an 
mTOR-dependent Ser166 phosphorylation of Mdm2, and this effect may attenuate the 
duration and intensity of the p53 response to DNA damage in hepatocytes.