Lung-specific expression of human mutant p53-273H is associated with a high frequency of lung adenocarcinoma in transgenic mice.
To investigate the tumorigenic potential of mutant p53 when selectively expressed in lung tissue, a transgenic mouse model was developed in which a mutant form of p53 (p53-273H) was placed under the transcriptional control of the lung-specific human surfactant protein C (SP-C) promoter. Two founder mice were identified, and a line of SP-C/p53-273H transgenic mice was established from one of the founders. Human p53-273H protein was detected specifically in lung tissue from transgenic mice. Malignant tumors, which were histologically characterized as adenocarcinomas, were observed in transgenic mice, with the earliest onset documented at 4 months of age. To further evaluate incidence and onset of tumor formation, transgenic mice (n=113) were sacrificed at age intervals ranging from 4-15 months. At 13-15 months of age, transgenic mice were significantly more likely to have lung tumors at necropsy than age-matched non-transgenic littermates (9 out of 39 (23%) versus 2 out of 35 (5.7%), chi(2) test, P=0.036). The SP-C/p53-273H transgenic mice described here thus represent a genetically defined model with which to study the role of p53 mutations in lung tumorigenesis, as well as the potential complementary contributions of other genetic alterations or environmental carcinogens to lung tumor development.
Duan
Wenrui
W
Comprehensive Cancer Center, The Ohio State University College of Medicine and Public Health, Columbus, Ohio, OH 43210, USA.
Ding
Haiming
H
Subler
Mark A
MA
Zhu
Wei-Guo
WG
Zhang
Huiming
H
Stoner
Gary D
GD
Windle
Jolene J
JJ
Otterson
Gregory A
GA
Villalona-Calero
Miguel A
MA
D000230:Adenocarcinoma / Q000235:genetics*; D017668:Age of Onset; D019943:Amino Acid Substitution; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D016158:Genes, p53; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009928:Organ Specificity; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D013045:Species Specificity; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*
D037721:Pulmonary Surfactant-Associated Protein C; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53