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

R. van Boxtel; R. Kuiper; P.W. Toonen; S. van Heesch; R. Hermsen; A. de Bruin; E. Cuppen

doi:10.1016/j.ajpath.2011.06.036

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

R. van Boxtel, R. Kuiper, P.W. Toonen, S. van Heesch, R. Hermsen, A. de Bruin, E. Cuppen

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1616-1622
Journal	American Journal of Pathology
Volume	179
Issue number	4
DOIs	https://doi.org/10.1016/j.ajpath.2011.06.036
Publication status	Published - 2011

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title = "Homozygous and heterozygous p53 knockout rats develop metastasizing sarcomas with high frequency",

abstract = "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.",

author = "{van Boxtel}, R. and R. Kuiper and P.W. Toonen and {van Heesch}, S. and R. Hermsen and {de Bruin}, A. and E. Cuppen",

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doi = "10.1016/j.ajpath.2011.06.036",

language = "English",

volume = "179",

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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

VL - 179

SP - 1616

EP - 1622

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 4

ER -

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

Abstract

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