High susceptibility of nullizygous p53 knockout mice to colorectal tumor induction by 1,2-dimethylhydrazine

Sakai, Hiroki; Tsukamoto, Tetsuya; Yamamoto, Masami; Shirai, Norimitsu; Iidaka, Takeshi; Hirata, Akihiro; Yanai, Tokuma; Masegi, Toshiaki; Donehower, Lawrence A.; Tatematsu, Masae

doi:10.1007/s00432-003-0443-9

Cited by 15 publications

(14 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(174), only 2% of p53 +/− mice developed intestinal adenocarcinomas and p53 −/− mice failed to develop intestinal tumors. p53 null mice do develop increased numbers of intestinal tumors when treated with carcinogens, such as AOM (175,176,177) and DMH (178). In addition, p53 null genotypes increase susceptibility to intestinal tumorigenesis driven by inflammation (179) or Apc mutation (180).…”

Section: Animal Models Of Human Colorectal Cancermentioning

confidence: 99%

Animal models of colorectal cancer

Johnson

Fleet

2012

Cancer Metastasis Rev

102

View full text Add to dashboard Cite

Colorectal cancer is a heterogeneous disease that afflicts a large number of people in the United States. The use of animal models has the potential to increase our understanding of carcinogenesis, tumor biology, and the impact of specific molecular events on colon biology. In addition, animal models with features of specific human colorectal cancers can be used to test strategies for cancer prevention and treatment. In this review we provide an overview of the mechanisms driving human cancer, we discuss the approaches one can take to model colon cancer in animals, and we describe a number of specific animal models that have been developed for the study of colon cancer. We believe that there are many valuable animal models to study various aspects of human colorectal cancer. However, opportunities for improving upon these models exist.

show abstract

Section: Animal Models Of Human Colorectal Cancermentioning

confidence: 99%

Animal models of colorectal cancer

Johnson

Fleet

2012

Cancer Metastasis Rev

102

View full text Add to dashboard Cite

show abstract

“…Mice that are homozygous for either of these knockout alleles are viable but develop tumors that are similar to those commonly seen in LFS patients (Donehower et al 1992;Jacks et al 1994;De Vries et al 2002). These mouse models have been treated with carcinogens and bred to other mice each predisposed to a particular cancer to understand more fully the role of p53 in suppressing tumorigenesis in particular tissues (Kemp et al 1993;Clarke et al 1995;Nacht et al 1996;Xu et al 1998;Reilly et al 2000;Yamamoto et al 2000;Halberg et al 2000;Shirai et al 2002;Sakai et al 2003;Hirata et al 2005).…”

Section: H Ighly Penetrant Familial Cancers Including 200mentioning

confidence: 99%

The Pleiotropic Phenotype of Apc Mutations in the Mouse: Allele Specificity and Effects of the Genetic Background

et al. 2008

View full text Add to dashboard Cite

Familial adenomatous polyposis (FAP) is a human cancer syndrome characterized by the development of hundreds to thousands of colonic polyps and extracolonic lesions including desmoid fibromas, osteomas, epidermoid cysts, and congenital hypertrophy of the pigmented retinal epithelium. Afflicted individuals are heterozygous for mutations in the APC gene. Detailed investigations of mice heterozygous for mutations in the ortholog Apc have shown that other genetic factors strongly influence the phenotype. Here we report qualitative and quantitative modifications of the phenotype of Apc mutants as a function of three genetic variables: Apc allele, p53 allele, and genetic background. We have found major differences between the Apc alleles Min and 1638N in multiplicity and regionality of intestinal tumors, as well as in incidence of extracolonic lesions. By contrast, Min mice homozygous for either of two different knockout alleles of p53 show similar phenotypic effects. These studies illustrate the classic principle that functional genetics is enriched by assessing penetrance and expressivity with allelic series. The mouse permits study of an allelic gene series on multiple genetic backgrounds, thereby leading to a better understanding of gene action in a range of biological processes.

show abstract

“…However, p53 (+/-) mice have not been shown to have increased susceptibility to induction of hepatocellular tumors by diethylnitrosamine (DEN) 15 or breast tumors by 7,12-dimethyl[a]benzanthracene (DMBA) 16 . We have also shown only a minimal increment of sensitivity in p53 (+/-) mice to stomach tumors induced by N-methyl-N-nitrosourea (MNU) 17 , colon tumors after treatment with 1,2-dimethylhydrazine (DMH) 18 , and liver t u m o r s i n d u c e d w i t h a h e t e r o c y c l i c a m i n e , aminophenylnorharman (APNH) 19 . Furthermore, utilization of N-bis (2-hydroxypropyl)nitrosamine (BHP) for the induction of tumors in multiple organs, pointed to tissue specificity regarding susceptibility (Hirata et al, manuscript submitted).…”

Section: Introductionmentioning

confidence: 99%

“…p53 (+/+), (+/-), and (-/-) mice were treated with subcutaneous injections of DMH at a dose of 20 mg/kg body weight, once a week for 5 or 15/16 weeks in short-and midterm experiments, then sacrificed two weeks after the final injection 18 . Colonic lesions were classified into focal atypias, adenomas, and adenocarcinomas.…”

Section: Colon Carcinogenesismentioning

confidence: 99%

Susceptibility of Heterozygous and Nullizygous p53 Knockout Mice to Chemical Carcinogens: Tissue Dependence and Role of p53 Gene Mutations

2005

Self Cite

View full text Add to dashboard Cite

Abstract:Mutations of the p53 tumor suppressor gene constitute one of the most frequent molecular changes in a wide variety of human cancers and mice deficient in p53 have recently attracted attention for their potential to identify chemical genotoxins. In this article, we review the data on the susceptibility of p53 nullizygote (-/-), heterozygote (+/ -), and wild type (+/+) mice to various carcinogens. Induction of esophageal and tongue squamous cell carcinomas (SCCs) by methyl-n-amylnitrosamine was shown to be increased in p53 (+/-) mice, in addition to the high sensitivity shown by p53 (-/-) littermates. N,N-dibutylnitrosamine (DBN) treatment also caused more tumor development in p53 (+/-) than wild-type mice, as with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the urinary bladder. In addition, p53 (+/-) heterozygotes proved more sensitive than wild type littermates to the induction of stromal cell tumors like hemangiomas/hemangiosarcomas by N-bis(2-hydroxypropyl)nitrosamine (BHP) or lymphomas and fibrosarcomas with other carcinogens. Analysis of exons 5-8 of the p53 gene demonstrated mutations in approximately one half of the lesions. With N-methyl-N-nitrosourea, preneoplastic lesions of the stomach, pepsinogen altered pyloric glands (PAPG), and a gastric adenocarcinoma, were found after only 15 weeks in p53 (-/-) mice, although there was no significant difference in the incidence of gastric tumors between p53 (+/+) and (+/-) mice in the longer-term. Regarding colon carcinogenicity, adenocarcinomas were observed limited to 1, 2-dimethylhydrazine treated p53 (-/-) mice in the short term, but again, no significant difference was evident between the p53 (+/+) and (+/-) cases at the end of the study. Furthermore, diethylnitrosamine or aminophenylnorharman treated p53 (+/-) mice did not demonstrate elevated susceptibility to tumors in the liver. With BHP, which induces tumors in multiple organs, p53 (+/-) mice were not more statistically sensitive with regard to lung tumor development than p53 (+/+). Of the malignant tumors examined in p53 (+/+) and (+/-) mice, as many as 10% demonstrated mutations in the p53 gene. These results suggest that p53 may not be a direct target for mouse adenomas/adenocarcinomas, but rather plays an important role as a gatekeeper in their genesis. In contrast p53 itself is frequently mutated in squamous, urothelial, or stromal tumors with a clear order of susceptibility: p53 (-/-) > p53 (+/-) > p53 (+/+) mice. p53 (-/-) mice are versatile animals for carcinogenicity testing, despite their disadvantage of a high background of spontaneous tumor development, and tissue dependence must be taken into account when exposing p53 (+/-) mice to chemical carcinogens. (J Toxicol Pathol 2005; 18: 121-134)

show abstract

High susceptibility of nullizygous p53 knockout mice to colorectal tumor induction by 1,2-dimethylhydrazine

Abstract: These results suggest that p53 might not be a direct target of DMH but complete loss of p53 might elevate susceptibility to DMH-induced colorectal carcinogenesis.

Cited by 15 publications

References 18 publications

Animal models of colorectal cancer

Animal models of colorectal cancer

The Pleiotropic Phenotype of Apc Mutations in the Mouse: Allele Specificity and Effects of the Genetic Background

Susceptibility of Heterozygous and Nullizygous p53 Knockout Mice to Chemical Carcinogens: Tissue Dependence and Role of p53 Gene Mutations

Contact Info

Product

Resources

About