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

DeHaan RD, Yazlovitskaya EM, Persons DL
Cancer Chemother Pharmacol. 2001 48 (5): 383-8

PMID: 11761456 · DOI:10.1007/s002800100318

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-x1, Cyclin G, Gadd45, p21WAF1, and Mdm2. In the ovarian carcinoma cell line A2780, cisplatin was shown to induce expression of p21WAF1, Gadd45 and Mdm2, but cisplatin had no effect on expression of Bax, Bcl-2, Bcl-x1, or Cyclin G. Inhibition of cisplatin-induced ERK activity by PD98059 resulted in decreased levels of p21WAF1, Gadd45 and Mdm2. These results provide evidence that ERK activity during the cisplatin DNA damage response, regulates in part, these cell cycle control (p21WAF1, Gadd45), DNA repair (Gadd45) and p53-regulatory (Mdm2) proteins.

MeSH Terms (21)

Antineoplastic Agents Apoptosis bcl-2-Associated X Protein Cisplatin Cyclin-Dependent Kinase Inhibitor p21 Cyclin G Cyclin G1 Cyclins DNA Damage Gene Expression Regulation Humans Intracellular Signaling Peptides and Proteins Mitogen-Activated Protein Kinases Nuclear Proteins Protein Biosynthesis Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Proto-Oncogene Proteins c-mdm2 Tumor Cells, Cultured Tumor Suppressor Protein p53

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