Xenobiotics-induced phosphorylations of MDM2

The aim of the present study was to characterize the Mdm2 and p53 responses induced by DNA damaging xenobiotics and how these responses can be modified by non-genotoxic xenobiotics. During control conditions cellular levels of p53 are low. The level is regulated by Mdm2 and Mdm2 and p53 forms an autoregulatory loop. When DNA is damaged, the p53-Mdm2 feedback loop is perturbed, and the cellular levels of p53 are increased so that p53 can regulate the transcriptional activity of proteins mediating responses such as apoptosis or cell cycle arrest. DNA damage may induce posttranslational modifications on p53 and Mdm2, such as phosphorylation or dephosphorylation induced by different kinases. These posttranslational modifications may modify the functions of Mdm2 and p53. This study focuses on Mdm2 phosphorylation within the epitopes of antibody 2A 10, and phosphorylation of Mdm2 on Ser 166. Both TCDD and the cholesterol lowering drugs statins were shown to attenuate the p53 stabilization in response to DNA damaging agents in HepG2 cells and in rodents. TCDD is a persistent, bioaccumulating pollutant. It is a carcinogen without being genotoxic. The detailed mechanisms for cancer induction are unknown, however. Statins are drugs used to treat hypercholesterolemia, and have also anticarcinogenic properties. The attenuation of p53 DNA damage response was associated with Mdm2 phosphorylation on Ser166. Thus, statins and TCDD induces Mdm2 Ser166. phosphorylation and attenuates p53 stabilization in response to DNA damage in HepG2 cells. TCDD also attenuated p53 stabilization in response to DNA damage in rats. As statin-induced Mdm2 Ser166. phosphorylation was attenuated by rapamycin (an inhibitor of MTOR) and Mdm2 Ser166. phosphorylation occurred in parallel to MTOR) phosphorylation, it is likely that MTOR) induced Ser166. phosphorylation. Our findings thus suggests that mTOR is one of the kinases inducing Mdm2 Ser166. phosphorylation. TCDDand statin-induced attenuation of p53 response might interfere with the cells ability to handle genotoxic agents. TCDD has been associated with cancer, especially liver cancer in rodents. Statins, on the other hand, rather seems to have anti care i nogenic properties. However, if statins are used together with genotoxic substances, attenuation of p53 response could affect its capacity to kill cells. Mdm2 phosphorylation within the epitopes of antibody 2A10 occurred at much lower concentrations of genotoxic substances benzo[a]pyrene,