Expression of a p53 mutant in the epidermis of transgenic mice accelerates chemical carcinogenesis.
To develop an in vivo model for studying the role of the p53 tumor suppressor in skin carcinogenesis, a murine p53(172H) mutant (equivalent to human p53(175H)) was expressed in the epidermis of transgenic mice, utilizing a targeting vector based on the human keratin 1 gene (HK1.p53m). HK1.p53m mice developed normally and did not exhibit an obvious epidermal phenotype or develop spontaneous tumors. However, these mice demonstrated an increased susceptibility to a two-stage chemical carcinogenesis protocol, with the rate of formation and number of papillomas being dramatically increased as compared to non-transgenic controls. The majority of papillomas in control mice regressed after termination of 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, whereas p53m papillomas progressed to carcinomas and metastases. In addition, more advanced malignancy, i.e., undifferentiated spindle cell carcinomas, were exclusively observed in p53m mice. Increased bromodeoxyuridine (BrdU) labeling, accompanied by decreased expression of p21, was observed in HK1.p53m papillomas. In situ examination of centrosomes in HK1.p53m papillomas also revealed marked abnormalities, with 75% of the cells containing > or = 3 centrosomes/cell, whereas centrosome numbers in papillomas from control animals remained normal. These data suggest that the accelerated tumorigenesis observed in chemically-treated p53m mice is most likely due to increased genomic instability resulting from an inhibition of G1 arrest and abnormal amplification of centrosomes.
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
X J
XJ
Wang
D A
DA
Greenhalgh
A
A
Jiang
D
D
He
L
L
Zhong
D
D
Medina
B R
BR
Brinkley
D R
DR
Roop
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D001973:Bromodeoxyuridine; D002273:Carcinogens / Q000633:toxicity; D018385:Centrosome; D004198:Disease Susceptibility; D004817:Epidermis / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007633:Keratins / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000096:biosynthesis
D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; D007633:Keratins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D001973:Bromodeoxyuridine; D013755:Tetradecanoylphorbol Acetate