Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin

The p53 tumor suppressor protein is a transcription factor that plays a maj or role in the DNA damage response. After DNA damage, p53 levels increase d ue primarily to stabilization of the protein. The molecular mechanisms lead ing to stabilization of p53 after DNA damage have not been completely eluci dated. Recently we reported that cisplatin treatment activated extracellula r signal-regulated kinase 1 and 2 (ERK1/2) and that inhibition of ERK1/2 re sulted in enhanced sensitivity to cisplatin. In the present study, we exami ned the potential role of ERK1/2 activation in regulation of the p53 respon se to cisplatin. In the ovarian carcinoma cell line A2780, inhibition of ER K1/2 activation with the mitogen-activated protein kinase/ERK kinase 1 (MEK 1) inhibitor PD98059 resulted in decreased p53 protein half-life and dimini shed accumulation of p53 protein during exposure to cisplatin. We also demo nstrated that p53 protein co-immunoprecipitated with ERK1/2 protein and was phosphorylated by activated recombinant murine ERK2 in vitro. Furthermore, PD98059 decreased the phosphorylation of p53 at serine 15 during cisplatin exposure, suggesting that ERK1/2 mediates in part phosphorylation of p53 d uring the cisplatin DNA response. These results strongly suggest that cispl atin-induced ERK activation is an up-stream regulator of the p53 response t o DNA damage caused by cisplatin.