Inactivation of both alleles of a gene by mutation or loss of heterozygosity due to genomic instability in the development of a cancer is required for that gene to be characterized as a tumor suppressor gene. This observation has become a hallmark for human cancers; particularly for the p53 tumor suppressor gene. The wild type p53 tumor suppressor protein suppresses the development of cancer in human and mice and is critical to the normal cell functions of cell cycle and maintenance of genomic stability. The mechanisms of p53 inactivation in human or mouse cancers are poorly understood. Exposure to endogenous or exogenous carcinogens under conditions of susceptiblity are believed to be involved and significantly increase risk for the development of cancer. Prospective identification of naturally occuring or synthetic environmental chemicals with carcinogenic potential of presumed risk to humans has primarily been carried out using two year rodent cancer bioassays. We, and others, have recently demonstrated that genetically altered mice heterozygous for a functional p53 allele rapidly develop cancer when exposed to chemical and physical carcinogens. These new short term cancer bioassays offer the promise of both reducing the resources required for prospective identification of potential carcinogens and providing a mechanistic basis for cancer induction. Demonstration of a mechanistic basis for cancer induction in mice similar to that observed in human cancer greatly strengthens the premise that a rodent chemical carcinogen may also be a potential human carcinogen. Using a series of rodent carcinogens (benzene, p-cresidine, phenolpthalein)and the human carcinogens (benzene and mephalan) we have been able to demonstrate that tumors of mesenchymal origin (lymphoma, sarcoma, etc.) primarily show a high frequency of the rapid loss of the remaining p53 functional allele, wheras carcinomas of the epidermis and bladder primarily show potential inactivating mutations in exon 5 of the functional p53 allele. These observations are critical to the argument that rapid short term cancer bioassays can rapidly prospectively identify carcinogens of potential significance to exposed humans. Thus, public health strategies for intervention and prevention may be developed to minimize exposure and risk.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES021207-04
Application #
6106597
Study Section
Special Emphasis Panel (ECP)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Cullen, John M; Brown, Danielle L; Kissling, Grace E et al. (2009) Aflatoxin B1 and/or hepatitis B virus induced tumor spectrum in a genetically engineered hepatitis B virus expression and Trp53 haploinsufficient mouse model system for hepatocarcinogenesis. Toxicol Pathol 37:333-42
Qu, Wei; Ke, Hengning; Pi, Jingbo et al. (2007) Acquisition of apoptotic resistance in cadmium-transformed human prostate epithelial cells: Bcl-2 overexpression blocks the activation of JNK signal transduction pathway. Environ Health Perspect 115:1094-100
Donehower, Lawrence A; French, John E; Hursting, Stephen D (2005) The utility of genetically altered mouse models for cancer research. Mutat Res 576:1-3
MacDonald, James; French, John E; Gerson, Ronald J et al. (2004) The utility of genetically modified mouse assays for identifying human carcinogens: a basic understanding and path forward. The Alternatives to Carcinogenicity Testing Committee ILSI HESI. Toxicol Sci 77:188-94
Martin, Keith R; Jokinen, Micheal P; Honeycutt, Hayden P et al. (2004) Tumor profile of novel p53 heterozygous Tg.AC (v-Ha-ras) bitransgenic mice treated with benzo(a)pyrene and fed dietary N-acetyl-L-cysteine (NAC). Toxicol Sci 81:293-301
Martin, Keith R; Jokinen, Michael P; Honeycutt, Hayden P et al. (2004) Tumor spectrum in the p53 heterozygous zeta globin-promoted Tg.AC (v-Ha-ras) bitransgenic mouse model. Toxicol Pathol 32:418-25
French, John E (2004) Identification and characterization of potential human carcinogens using B6.129tm1Trp53 heterozygous null mice and loss of heterozygosity at the Trp53 locus. IARC Sci Publ :271-87
Nwosu, Veronica C; Kissling, Grace E; Trempus, Carol S et al. (2004) Exposure of Tg.AC transgenic mice to benzene suppresses hematopoietic progenitor cells and alters gene expression in critical signaling pathways. Toxicol Appl Pharmacol 196:37-46
Pritchard, John B; French, John E; Davis, Barbara J et al. (2003) The role of transgenic mouse models in carcinogen identification. Environ Health Perspect 111:444-54
Hulla, J E; French, J E; Dunnick, J K (2001) Chromosome 11 allelotypes reflect a mechanism of chemical carcinogenesis in heterozygous p53-deficient mice. Carcinogenesis 22:89-98

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