Lung-specific expression of dominant-negative mutant p53 in transgenic mice increases spontaneous and benzo(a)pyrene-induced lung cancer.
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.
Tchou-Wong
Kam-Meng
KM
Department of Medicine, Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York 10016, USA. tchouk02@endeavor.med.nyu.edu
Jiang
Yixing
Y
Yee
Herman
H
LaRosa
Jennifer
J
Lee
Theodore C
TC
Pellicer
Angel
A
Jagirdar
Jaishree
J
Gordon
Terry
T
Goldberg
Judith D
JD
Rom
William N
WN
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D004195:Disease Models, Animal; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution; D014598:Uteroglobin; D000097642:GADD45 Proteins
D001564:Benzo(a)pyrene; D002273:Carcinogens; D047908:Intracellular Signaling Peptides and Proteins; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; D014598:Uteroglobin; D000097642:GADD45 Proteins; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse