ORIGIN
At the Hubrecht Institute a nonsense mutation at amino acid position 273 (Cys to stop) within the DNA binding domain of the rat p53 gene was isolated, which resulted in a full knockout mutation. Systematic generation of the p53 TGEM® knockout rats was carried out by random mutagenesis of Wistar rats followed by PCR amplification and capillary sequencing. Transferred to Charles River under exclusive license from Transposagen in 2010.
STRAIN CODE
499 (HOMOZYGOUS)
500 (HETEROZYGOUS)
501 (WILD-TYPE)
COAT COLOR
White (Albino)
MUTATION INFORMATION
The p53 TGEM® Rat Model harbors a premature stop codon (nonsense mutation at amino acid position C273 in the middle of the DNA binding domain). The DNA binding domain is essential for proper function of all p53 protein isoforms and up to 80% of p53 mutations in rodent and human tumors reside in this domain1. The p53 TGEM® Rat Model mutation results in a full knockout phenotype that recapitulates the human condition producing a wide variety of tumors. Homozygous p53 TGEM® Rats develop a condition similar to human Li-Fraumeni Syndrome.
The Tumor Protein 53 (Tp53, p53) is the most studied tumor suppressor. p53 plays a role in cell cycle control, apoptosis, angiogenesis, carcinogenesis, senescence, DNA repair, and changes in metabolism1. Homozygous and heterozygous p53 TGEM® Rats develop a wide variety of malignant tumors, including sarcomas and lymphomas.
Homozygous p53 TGEM® Rats develop tumors at 3-4 months, and heterozygotes develop tumors at 9 months. The p53 TGEM® Rat Model tumor onset and mortality statistics offer an ideal model for improved carcinogenicity testing timelines. Many tumors that develop in heterozygous p53 TGEM® Rats are found to be caused by loss of heterozygosity (LOH) for p53. This is a very important phenotype, as p53 is inactivated by somatic mutations in most human cancers. For example, 47% and 43% of all human ovary and colorectal cancers, respectively, are caused by p53 somatic mutations which result in LOH2.
p53 activates many genes that are thought to produce a comprehensive antioxidant effect. p53 expression controls the level of aging-associated oxidative damage3. The p53 TGEM® Rat Model may be useful for aging and antioxidant effect.
When p53 is upregulated in adipose tissue it causes an inflammatory response that results in insulin resistance. Animal models on high-fat diets often exhibit oxidative stress in the adipose tissue, leading to overexpression of p53 and subsequently insulin resistance4. The p53 TGEM® Rat Model provides an animal model for studying p53 expression, inflammatory response, insulin resistance and type II diabetes.
The p53 pathway is a suppressor of tumorigenicity and also induced pluripotent stem (iPS) cell generation. Many rodent embryonic fibroblasts lacking p53 expression generate iPS cells more efficiently than wild-type fibroblasts, and siRNA p53 knockdown promotes human iPS cell formation. There are many p53 regulated genes in embryonic fibroblasts that are common to both humans and rodents5. The p53 TGEM® Rat Model serves as a model to study iPS cell formation mechanisms.
References
1. Petitjean et al. (2007) Hum. Mutat. 28 (6): 622-9
2. Bourdon et al. (2007) Brit. J. Cancer. 97: 277-282
3. Matheu et al. (2009) Nature. 448 (7151): 375-9
4. Minamino et al. (2009) Nat. Med. 15 (9): 1082-7
5. Zhao et al. (2008) Cell Stem Cell. 3 (5): 475-9
RESEARCH APPLICATION
Oncology, Toxicology, Carcinogenicity
ORDERING INFORMATION
Please call 1.800.LAB.RATS if you would like to place an order.
For additional information about the p53 TGEM® rats, please contact us at 1.877.CRIVER.1 or askcharlesriver@crl.com.