Activation of cellular oncogenes by environmental carcinogens may represent a critical process in the mechanism of carcinogenesis. Animal tumor models using defined carcinogenic protocols are necessary tools to understand the precise molecular relationships between the effects of carcinogens and the biological end point of cancer. In this proposal, rat skin tumors induced by ionizing radiation will be examined for activation of the ras family of transforming oncogenes as well as activating alterations of the myc oncogene. The frequency and nature of point mutations, gene amplification, chromosomal translocations, and enhanced transcriptional activity of active oncogenes will be compared in a large panel of tumors of various histologic type. Preliminary results have indicated that both K-ras and myc are activated in some of these tumors. Active oncogenes will be examined on a molecular level by Southern and Northern analysis, gene cloning and sequencing, and in situ hybridization. Studies on the temporal aspects of oncogene activation as a function of radiation exposure will be done using the C3H10T 1/2 cell culture system, as well as rat skin in vivo. A new clonal cell hybridization technique will be used to screen monoclonal populations of irradiated cells for gene amplification and gene expression at sequential times after irradiation. One hypothesis to be addressed by the proposed research is that radiation effects on target DNA leads directly to activation of myc. A more general issue that will be studied in this model system relates to the significance of multiple oncogene activation in primary epithelial tumors. A greater understanding of the molecular mechanisms by which environmental carcinogens such as radiation produce neoplastic transformation will be relevant to the design of strategies for detection, prevention and control of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043199-02
Application #
3185229
Study Section
Radiation Study Section (RAD)
Project Start
1986-07-01
Project End
1989-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Jin, Y; Burns, J; Garte, S J et al. (1996) Infrequent alterations of the p53 gene in rat skin cancers induced by ionizing radiation. Carcinogenesis 17:873-6
Burns, F J; Jin, Y; Garte, S J et al. (1994) Estimation of risk based on multiple events in radiation carcinogenesis of rat skin. Adv Space Res 14:507-19
Felber, M; Burns, F J; Garte, S J (1994) DNA fingerprinting analysis of radiation-induced rat skin tumors. Cancer Biochem Biophys 14:163-70
Roy, N K; Ballesteros, A; Garte, S J (1993) Cloning and sequence of the rat retinoblastoma (Rb) gene cDNA. Nucleic Acids Res 21:170
Burns, F J; Jin, Y; Koenig, K L et al. (1993) The low carcinogenicity of electron radiation relative to argon ions in rat skin. Radiat Res 135:178-88
Garte, S J (1993) The c-myc oncogene in tumor progression. Crit Rev Oncog 4:435-49
Jin, Y; Burns, F J; Garte, S J (1992) Oncogene amplification detected by in situ hybridization in radiation-induced skin cancers in rats. Radiat Res 132:193-9
Felber, M; Burns, F J; Garte, S J (1992) Amplification of the c-myc oncogene in radiation-induced rat skin tumors as a function of linear energy transfer and dose. Radiat Res 131:297-301
Burns, F J; Hosselet, S; Jin, Y et al. (1991) Progression and multiple events in radiation carcinogenesis of rat skin. J Radiat Res (Tokyo) 32 Suppl 2:202-16
Garte, S J; Burns, F J (1991) Oncogenes and radiation carcinogenesis. Environ Health Perspect 93:45-9

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