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Defective p53 Response and Apoptosis Associated with an Ataxia-Telangiectasia–like Phenotype

¹ Queensland Institute of Medical Research; ² Central Clinical School, University of Queensland, Brisbane, Queensland, Australia; ³ Laboratorio Nazionale CIB, Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole, Trieste, Italy; ⁴ Radiation Oncology Research Laboratory, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland; and ⁵ Sydney Children's Hospital, Randwick, New South Wales, Australia

Requests for reprints: Martin F. Lavin, Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia. Phone: 61-7-33-62-0335; Fax: 61-7-33-62-0106; E-mail: martinL{at}qimr.edu.au.

Ataxia-telangiectasia mutated (ATM), the protein defective in ataxia-telangiectasia, plays a central role in DNA damage response and signaling to cell cycle checkpoints. We describe here a cell line from a patient with an ataxia-telangiectasia–like clinical phenotype defective in the p53 response to radiation but with normal ATM activation and efficient downstream phosphorylation of other ATM substrates. No mutations were detected in ATM cDNA. A normal level of interaction between p53 and peptidyl-prolyl-isomerase Pin1 suggests that posttranslational modification was intact in these cells but operating at reduced level. Defective p53 stabilization was accompanied by defective induction of p53 effector genes and failure to induce apoptosis in response to DNA-damaging agents. Continued association between p53 and murine double minute-2 (Mdm2) occurred in irradiated ATL2ABR cells in response to DNA damage, and incubation with Mdm2 antagonists, nutlins, increased the stabilization of p53 and its transcriptional activity but failed to induce apoptosis. These results suggest that ATM-dependent stabilization of p53 and induction of apoptosis by radiation involve an additional factor(s) that is defective in ATL2ABR cells. (Cancer Res 2006; 66(6): 2907-12)