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 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.
Houghtaling
Scott
S
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA. houghtal@ohsu.edu
Granville
Laura
L
Akkari
Yassmine
Y
Torimaru
Yumi
Y
Olson
Susan
S
Finegold
Milton
M
Grompe
Markus
M
D000782:Aneuploidy; D000818:Animals; D002277:Carcinoma / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004249:DNA Damage; D005199:Fanconi Anemia / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein; D015321:Gene Rearrangement; D016158:Genes, p53; D006580:Genetic Carrier Screening; D005816:Genetic Complementation Test; D020022:Genetic Predisposition to Disease; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics*
C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; D009687:Nuclear Proteins