Cisplatinum and taxol induce different patterns of p53 phosphorylation

Posttranslational modifications of p53 induced by two widely used anticance r agents, cisplatinum (DDP) and taxol were investigated in two human cancer cell lines. Although both drugs were able to induce phosphorylation at ser ine 20 (Ser20), only DDP treatment induced p53 phosphorylation at serine 15 (Ser15). Moreover, both drug treatments were able to increase p53 levels a nd consequently the transcription of waf1 and mdm-2 genes, although DDP tre atment resulted in a stronger inducer of both genes. Using two ataxia telan giectasia mutated (ATM) cell lines, the role of ATM in drug-induced p53 pho sphorylations was investigated. No differences in drug-induced p53 phosphor ylation could be observed, indicating that ATM is not the kinase involved i n these phosphorylation events. In addition, inhibition of DNA-dependent pr otein kinase activity by wortmannin did not abolish p53 phosphorylation at Ser15 and Ser20, again indicating that DNA-PK is unlikely to be the kinase involved. After both taxol and DDP treatments, an activation of hCHK2 was f ound and this is likely to be responsible for phosphorylation at Ser20. In contrast, only DDP was able to activate ATR, which is the candidate kinase for phosphorylation of Ser15 by this drug. This data clearly suggests that differential mechanisms are involved in phosphorylation and activation of p 53 depending on the drug type.