© 2002 American Thoracic Society Lung-Specific Expression of Dominant-Negative Mutant p53 in Transgenic Mice Increases Spontaneous and Benzo(a)pyrene-Induced Lung CancerDepartments of Medicine, Microbiology, Pathology, and Environmental Medicine, Division of Pulmonary and Critical Care Medicine, and Department of Environmental Medicine, Division of Biostatistics, New York University School of Medicine, New York, New York Address correspondence to: Kam-Meng Tchou-Wong, Ph.D., New York University School of Medicine, 550 First Avenue, MSB 147, New York, NY 10016. E-mail: tchouk02{at}endeavor.med.nyu.edu Mutations in the p53 gene have been implicated to play an important role in the development of various human cancers. To evaluate the importance of p53 in lung cancer, a transgenic mouse model was established by utilizing the Clara cell secretory protein (CCSP) promoter to target the expression of a dominant-negative mutant form of p53 (dnp53) in the lung. In two transgenic CCSP-dnp53 founder lines, the dnp53 protein was expressed exclusively in the lungs. The incidence of spontaneous lung cancer in 18-month-old transgenic mice was 45%, whereas that in age-matched control mice was 20%. The relative risk of lung tumors in CCSP-dnp53 mice was 2.3 times that of wild-type mice (exact confidence limits of 0.69, 17.5). In addition to the increased incidence of spontaneous lung tumor, these mice were more susceptible to the development of lung adenocarcinoma after exposure to benzo(a)pyrene (BaP). Six months after intratracheal instillation of benzo(a)pyrene, the tumor incidence in wild-type and CCSP-dnp53 mice was 39% and 73%, respectively. The risk of lung tumors was 25.3 times greater in BaP-treated mice adjusted for transgene expression (95% confidence limits of 3.29, 678, mid-p corrected). These results suggest that p53 function is important for protecting mice from both spontaneous and BaP-induced lung cancers.
Abbreviations: Clara cell secretory protein, CCSP • cytomegalovirus, CMV • dominant-negative mutant p53, dnp53 • ß-galactosidase, ß-gal • Li-Fraumeni syndrome, LFS • murine CCSP, mCCSP • polymerase chain reaction, PCR • retinoblastoma, Rb • T antigen, TAg This article has been cited by other articles:
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