Homozygous and heterozygous p53 knockout rats develop metastasizing sarcomas with high frequency

TY - JOUR

T1 - Homozygous and heterozygous p53 knockout rats develop metastasizing sarcomas with high frequency

AU - van Boxtel, R.

AU - Kuiper, R.

AU - Toonen, P.W.

AU - van Heesch, S.

AU - Hermsen, R.

AU - de Bruin, A.

AU - Cuppen, E.

N1 - Reporting year: 2011 Metis note: 3181367;

PY - 2011

Y1 - 2011

N2 - The TP53 tumor suppressor gene is mutated in the majority of human cancers. Inactivation of p53 in a variety of animal models results in early-onset tumorigenesis, reflecting the importance of p53 as a gatekeeper tumor suppressor. We generated a mutant Tp53 allele in the rat using a target-selected mutagenesis approach. Here, we report that homozygosity for this allele results in complete loss of p53 function. Homozygous mutant rats predominantly develop sarcomas with an onset of 4 months of age with a high occurrence of pulmonary metastases. Heterozygous rats develop sarcomas starting at 8 months of age. Molecular analysis revealed that these tumors exhibit a loss-of-heterozygosity of the wild-type Tp53 allele. These unique features make this rat highly complementary to other rodent p53 knockout models and a versatile tool for investigating tumorigenesis processes as well as genotoxic studies.

AB - The TP53 tumor suppressor gene is mutated in the majority of human cancers. Inactivation of p53 in a variety of animal models results in early-onset tumorigenesis, reflecting the importance of p53 as a gatekeeper tumor suppressor. We generated a mutant Tp53 allele in the rat using a target-selected mutagenesis approach. Here, we report that homozygosity for this allele results in complete loss of p53 function. Homozygous mutant rats predominantly develop sarcomas with an onset of 4 months of age with a high occurrence of pulmonary metastases. Heterozygous rats develop sarcomas starting at 8 months of age. Molecular analysis revealed that these tumors exhibit a loss-of-heterozygosity of the wild-type Tp53 allele. These unique features make this rat highly complementary to other rodent p53 knockout models and a versatile tool for investigating tumorigenesis processes as well as genotoxic studies.

U2 - 10.1016/j.ajpath.2011.06.036

DO - 10.1016/j.ajpath.2011.06.036

M3 - Article

SN - 0002-9440

VL - 179

SP - 1616

EP - 1622

JO - American Journal of Pathology

JF - American Journal of Pathology

IS - 4

ER -