Heterozygosity for p53 (Trp53+/-) accelerates epithelial tumor formation in Fanconi anemia complementation group D2 (Fancd2) knockout mice

Fanconi anemia (FA) is an autosomal recessive disease characterized by progressive bone marrow failure and an increased susceptibility to cancer. FA is genetically heterogeneous, consisting of at least 11 complementation groups, FA-A through L, including FA-D1 (BRCA2) and D2. We have previously repo...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2005, Vol.65 (1), p.85-91
Main Authors: HOUGHTALING, Scott, GRANVILLE, Laura, AKKARI, Yassmine, TORIMARU, Yumi, OLSON, Susan, FINEGOLD, Milton, GROMPE, Markus
Format: Article
Language:English
Subjects:
Aneuploidy
Animals
Antineoplastic agents
Biological and medical sciences
Carcinoma - genetics
Cell Transformation, Neoplastic - genetics
Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...)
DNA Damage
Fanconi Anemia - genetics
Fanconi Anemia Complementation Group D2 Protein
Gene Rearrangement
Genes, p53
Genetic Carrier Screening
Genetic Complementation Test
Genetic Predisposition to Disease
Medical genetics
Medical sciences
Mice
Mice, Knockout
Nuclear Proteins - deficiency
Nuclear Proteins - genetics
Pharmacology. Drug treatments
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Summary:Fanconi anemia (FA) is an autosomal recessive disease characterized by progressive bone marrow failure and an increased susceptibility to cancer. FA is genetically heterogeneous, consisting of at least 11 complementation groups, FA-A through L, including FA-D1 (BRCA2) and D2. We have previously reported an increased incidence of epithelial tumors in Fancd2 knockout mice. To further investigate the role of the FA pathway in tumor prevention, Fancd2 mutant mice were crossed to mice with a null mutation in the tumor suppressor gene, Trp53. The tumor spectrum in Fancd2(-/-)/Trp53(+/-) mice included sarcomas expected in Trp53 heterozygotes, as well as mammary and lung adenocarcinomas that occur rarely in Trp53 heterozygotes. These tumors occurred earlier than in Fancd2(-/-) control mice. Therefore, the Fancd2(-/-)/Trp53(+/-) mice represent an improved model for the study of adenocarcinoma in FA. In addition, it was found that Fancd2(-/-) mouse embryonic fibroblasts but not Fancd2(-/-)/Trp53(-/-) mouse embryonic fibroblasts arrest following DNA damage. Therefore, Trp53 is required for the S phase checkpoint activation observed in Fancd2 mutant cells. Fancd2(-/-)/Trp53(-/-) cells showed an increase in aneuploidy and had multiple gross chromosomal rearrangements.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.85.65.1