ATR-Chk2 Signaling in p53 Activation and DNA Damage Response during Cisplatin-induced Apoptosis

• DOI: 10.1074/jbc.m707568200
• Publication Date: 2007-12-28T01:12:51Z
• Authors: Navjotsingh Pabla; Shuang Huang; Qing-Sheng Mi; Rene Daniel; Zheng Dong
• Keywords: 0301 basic medicine; Proteasome Endopeptidase Complex; Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; Ataxia Telangiectasia Mutated Proteins; Protein Serine-Threonine Kinases; 3. Good health; DNA-Binding Proteins; Histones; Kidney Tubules, Proximal; Checkpoint Kinase 2; 03 medical and health sciences; Neoplasms; Checkpoint Kinase 1; Animals; Humans; Kidney Diseases; Cisplatin; Protein Kinases; Gene Deletion; Cell Line, Transformed; DNA Damage

Cisplatin is one of the most effective anti-cancer drugs; however, use cisplatin limited by its toxicity in normal tissues, particularly injury kidneys. The mechanisms underlying therapeutic effects cancers and side tissues are largely unclear. Recent work has suggested a role for p53 cisplatin-induced renal cell apoptosis kidney injury; signaling pathway leading to activation unknown. Here we demonstrate an early DNA damage response during treatment cells tissues. Importantly, response, critical ATR, but not ATM (ataxia telangiectasia mutated) or DNA-PK (DNA-dependent protein kinase), apoptosis. We show that ATR specifically activated co-localizes with H2AX, forming nuclear foci at site damage. Blockade dominant-negative mutant inhibits Consistently, suppressed ATR-deficient fibroblasts. Downstream both Chk1 Chk2 phosphorylated ATR-dependent manner. Interestingly, following phosphorylation, degraded via proteosomal pathway, whereas activated. Inhibition gene deficiency attenuates In vivo C57BL/6 mice, treatment. Together, results suggest important mediated ATR-Chk2 nephrotoxicity.