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Chromosome 11 loss from thymic lymphomas induced in heterozygous Trp53 mice by phenolphthalein
J E Hulla1, J E French, J K Dunnick
1University of North Dakota School of Medicine, Grand Forks, ND, USA. hulla@niehs.nih.gov
Abstract:
C57BL/6 p53 (+/-) N5 mice heterozygous for a null p53 allele were given phenolphthalein to learn more about mechanisms of carcinogenesis and to evaluate the p53-deficient mouse as a tool for identifying potential human carcinogens. DNA samples isolated from 10 phenolphthalein-induced thymic lymphomas were analyzed for loss of heterozygosity (LOH) at the Trp53 locus and simple sequence length polymorphic (SSLP) loci. The initial screening revealed remarkable results from only chromosome 11. Allelotyping at approximately five centiMorgan intervals, we found SSLP heterozygosity for C57BL/6 and 129Sv over much of chromosome 11. In the tumors, treatment-related LOH was apparent on chromosome 11 at each of the 28 informative loci examined. The strain-specific polymorphism lost from individual tumors allowed us to deduce the distribution of alleles along the length of the maternal and paternal chromosomes 11. The allelic patterns indicate that mitotic homologous recombination occurred during embryogenesis if breeding protocols were carried out as described. The mitotic recombination observed may be attributable to p53 haploinsufficiency for normal suppression of mitotic recombination.
Insights
This study used p53-deficient mice to investigate carcinogenesis mechanisms. Phenolphthalein exposure revealed significant loss of heterozygosity on chromosome 11, suggesting a role for p53 in suppressing mitotic recombination.
Area of Science:
- Genetics
- Molecular Biology
- Toxicology
Background:
- The tumor suppressor gene p53 plays a critical role in maintaining genomic stability.
- p53 haploinsufficiency can impair its tumor-suppressive functions.
- Understanding carcinogenesis mechanisms is crucial for identifying human carcinogens.
Purpose of the Study:
- To investigate the role of p53 in carcinogenesis using a mouse model.
- To evaluate the utility of p53-deficient mice for carcinogen identification.
- To elucidate the mechanisms underlying phenolphthalein-induced tumorigenesis.
Main Methods:
- C57BL/6 mice heterozygous for a null p53 allele (p53 (+/-)) were administered phenolphthalein.
- DNA from induced thymic lymphomas was analyzed for loss of heterozygosity (LOH) at the Trp53 locus and other polymorphic loci.
- Allelotyping was performed at approximately five centiMorgan intervals across chromosome 11.
Main Results:
- Phenolphthalein induced thymic lymphomas in p53 (+/-) mice.
- Significant LOH was observed on chromosome 11 in all 28 informative loci examined.
- Allelic patterns indicated mitotic homologous recombination during embryogenesis.
- Mitotic recombination was linked to p53 haploinsufficiency.
Conclusions:
- p53 haploinsufficiency may lead to increased mitotic recombination.
- The p53-deficient mouse model is valuable for studying carcinogenesis.
- Phenolphthalein's carcinogenic mechanism involves alterations on chromosome 11.