p53 transgenic mice are highly susceptible to 1, 2-dimethylhydrazine-induced uterine sarcomas.
p53 Transgenic mice were crossed with C57BL/6J mice to investigate whether a germ-line mutation in the p53 gene predisposes for tumorigenesis in mice. (C57BL/6J x UL53-3) F(1) mice were treated with 1,2-dimethylhydrazine (DMH), a colon carcinogen. The presence of a mutant p53 led to an increased incidence or multiplicity of uterine sarcomas, colon carcinomas, lung adenomas, and hepatomas in DMH-treated mice. The most significant effect of mutant p53 was the increased incidence of uterine sarcomas, which were found in approximately 90% of p53(val135/wt) mice but only seen in approximately 10% of p53(wt/wt) mice. After examination of 15 known p53 downstream target genes in uterine sarcomas and normal uteri, we found that expression of the Reprimo gene was significantly increased in normal uteri of p53(wt/wt) mice but not in either normal uterus or uterine sarcomas of p53(val135/wt) mice. In DMH-treated animals, long-term treatment with this chemopreventive agent, piroxicam, reduced colon carcinoma incidence and multiplicity in both p53(val135/wt) or p53(wt/wt) mice but did not affect the formation of uterine sarcomas, lung adenomas, or hepatomas. These results demonstrate a tissue-specific enhancement of tumorigenesis in multiple organs by the mutant p53 transgene and additionally support the utility of (C57BL/6J x UL53-3) F(1) mice for chemoprevention studies.
Zhang
Zhongqiu
Z
Division of Human Cancer Genetics, The Ohio State University Comprehensive Cancer Center, 514 Medical Research Facility, 420 West 12th Avenue, Columbus, OH 43210, USA.
Li
Jie
J
Lantry
Laura E
LE
Wang
Yian
Y
Wiseman
Roger W
RW
Lubet
Ronald A
RA
You
Ming
M
D019813:1,2-Dimethylhydrazine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002273:Carcinogens; D018797:Cell Cycle Proteins / Q000235:genetics*; D003043:Cocarcinogenesis; D005260:Female; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006023:Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010894:Piroxicam / Q000494:pharmacology; D012509:Sarcoma / Q000139:chemically induced* / Q000235:genetics* / Q000517:prevention & control; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014594:Uterine Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000517:prevention & control
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002273:Carcinogens; D018797:Cell Cycle Proteins; D006023:Glycoproteins; C575025:REPRIMO protein, mouse; D016159:Tumor Suppressor Protein p53; D010894:Piroxicam; D019813:1,2-Dimethylhydrazine