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

Citation
Rd. Dehaan et al., Regulation of p53 target gene expression by cisplatin-induced extracellular signal-regulated kinase, CANC CHEMOT, 48(5), 2001, pp. 383-388
Citations number
37
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER CHEMOTHERAPY AND PHARMACOLOGY
ISSN journal
0344-5704 → ACNP
Volume
48
Issue
5
Year of publication
2001
Pages
383 - 388
Database
ISI
SICI code
0344-5704(200111)48:5<383:ROPTGE>2.0.ZU;2-E
Abstract
The extracellular signal-regulated kinase (ERK) pathway is among several si gnal transduction pathways that are activated in response to exposure to th e DNA damage-inducing chemotherapeutic agent cisplatin. We have previously reported that inhibition of cisplatin-induced ERK activity enhances sensiti vity 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 investi gations to examine the effect of cisplatin-induced ERK activation on the ex pression 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, G add45, p21(WAF1), and Mdm.2. In the ovarian carcinoma cell line A2780, cisp latin was shown to induce expression of p21(WAF1), Gadd45 and Mdm2, but cis platin had no effect on expression of Bax, Bcl-2, Bcl-(xl), or Cyclin G. In hibition 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, t hese cell cycle control (p21(WAF1), Gadd45), DNA repair (Gadd45) and p53-re gulatory (Mdm2) proteins.