Regulation of p53 target gene expression by cisplatin-induced extracellular signal-regulated kinase

Abstract.

The extracellular signal-regulated kinase (ERK) pathway is among several signal transduction pathways that are activated in response to exposure to the DNA damage-inducing chemotherapeutic agent cisplatin. We have previously reported that inhibition of cisplatin-induced ERK activity enhances sensitivity to cisplatin. Furthermore, we have demonstrated that cisplatin-induced ERK activation is required for optimal p53 protein accumulation following cisplatin-induced DNA damage. In the present study, we expanded our investigations to examine the effect of cisplatin-induced ERK activation on the expression of p53-targeted genes that have been shown to be important in the cellular response to DNA damage including Bax, Bcl-2, Bcl-_xl, Cyclin G, Gadd45, p21^WAF1, and Mdm2. In the ovarian carcinoma cell line A2780, cisplatin was shown to induce expression of p21^WAF1, Gadd45 and Mdm2, but cisplatin had no effect on expression of Bax, Bcl-2, Bcl-_xl, or Cyclin G. Inhibition of cisplatin-induced ERK activity by PD98059 resulted in decreased levels of p21^WAF1, Gadd45 and Mdm2. These results provide evidence that ERK activity during the cisplatin DNA damage response, regulates in part, these cell cycle control (p21^WAF1, Gadd45), DNA repair (Gadd45) and p53-regulatory (Mdm2) proteins.