Chromosome 11 allelotypes reflect a mechanism of chemical carcinogenesis in heterozygous p53-deficient mice.
Mice heterozygous for a null p53 allele were administered three well-characterized carcinogens to learn more about mechanisms of carcinogenesis and to evaluate the p53-deficient mouse as a tool for identifying potential human carcinogens. Benzene-induced sarcomas, p-cresidine-induced bladder carcinomas and phenolphthalein-induced thymic lymphomas were allelotyped at the Trp53 locus and chromosome 11 simple sequence length polymorphic (SSLP) loci. Loss of Trp53 and loss of one copy of chromosome 11 occurred in each of 10 lymphomas examined and each of the eight sarcomas examined. Loss of Trp53 and loss of heterozygosity (LOH) at SSLP loci were sporadic in the bladder carcinomas. However, LOH was detected at two or more SSLP loci in six of the eight bladder tumors examined. Loss of one complete copy of chromosome 11 was implicated in three of the bladder tumors where LOH occurred at seven or more widely dispersed SSLP loci. Loss of one copy of chromosome 11 likely occurred through a p53-mediated selection process since Trp53 is located on mouse chromosome 11 and only one copy harbored a functional gene. The data suggest that loss occurred through a mechanism common among the three tumor types. Allelotype patterns of the maternal chromosome 11 were inconsistent with those expected from a nullizygous C57BL/6-Trp53 (N4) x inbred C57BL/6 cross which was reported for production of the mice under investigation. However, comparison with individual control tissues still allowed deduction of maternal chromosome loss. If the breeding protocols were carried out as described, the unexpected allelotype patterns observed in histologically normal tissues might be due to mitotic homologous recombination during embryogenesis.
Hulla
J E
JE
University of North Dakota School of Medicine, Grand Forks, ND, USA. hulla@niehs.nih.gov
French
J E
JE
Dunnick
J K
JK
D000483:Alleles; D000814:Aniline Compounds / Q000633:toxicity; D000818:Animals; D001554:Benzene / Q000633:toxicity; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D002875:Chromosomes / Q000235:genetics; D003433:Crosses, Genetic; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006579:Heterozygote; D019656:Loss of Heterozygosity; D008223:Lymphoma / Q000139:chemically induced / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics*; D020113:Phenolphthalein / Q000633:toxicity; D011110:Polymorphism, Genetic; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000235:genetics; D013953:Thymus Neoplasms / Q000139:chemically induced / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics
D000814:Aniline Compounds; D002273:Carcinogens; D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53; C013453:cresidine; D020113:Phenolphthalein; D001554:Benzene