FIGURE 8.

Model of DNA damage-triggered activation of SAPK/JNK at late times following cisplatin treatment. Apart from DNA damage-independent mechanisms that can cause an early activation of SAPK/JNK after cisplatin treatment, cisplatin-induced DNA damage is also able to trigger signaling to SAPK/JNK at late times (i.e. 16–24 h) after drug exposure. Late SAPK/JNK activation is pronounced in TC-NER- (i.e. CSB- and XPA-) and DNA-PKcs-defective cells. It is mitigated under the condition of XPC, ERCC1, and BRCA2 deficiency, indicating that these repair factors have additional functions as part of a signaling complex. Transcription blockage and DSBs are not sufficient for stimulating SAPK/JNK activity. The response appears to be specific for platinum compounds. Replication-associated ATR-regulated mechanisms are likely involved in signaling to SAPK/JNK triggered by cisplatin-induced DNA lesions. Furthermore, Rho GTPases (Rho) and tyrosine kinases (i.e. EGFR and c-Abl) seem to have a permissive function. Bearing in mind that c-Abl tyrosine kinase is activated by genotoxins, including cisplatin (84), is regulated in an ATM-dependent manner (86, 87), and furthermore regulates MEK kinase 1 (65), this kinase is a rational candidate to converge the DNA damage response with the SAPK/JNK pathway. Late activation of SAPK/JNK by cisplatin is suggested to promote survival. c-Abli, inhibitor of the c-Abl tyrosine kinase; GFR, growth factor receptor; PI3Ki, phosphatidylinositol 3-kinase-related kinase inhibitors (i.e. wortmannin and Ku55933); Rho, Ras-homologous GTPases; RTK, receptor tyrosine kinases; TKi, tyrosine kinase inhibitors (i.e. Iressa and c-Abl inhibitor); JNKi, JNK inhibitor type II; Pol, polymerase; Pt, platinum.