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Formation of Covalent DNA Adducts by Enzymatically Activated Carcinogens and Drugs In Vitro and Their Determination by 32P-postlabeling
Published on: March 20, 2018
The role of non-ras transforming genes in chemical carcinogenesis
1Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey, UK.
Abstract:
DNA transfection experiments using the NIH 3T3 mouse fibroblast cell line have demonstrated that chemically induced tumors and chemically transformed cell lines frequently contain dominant transforming genes. Although many of the genes detected using the NIH 3T3 transfection-transformation assay are activated versions of H-ras, K-ras, and N-ras, in some experimental systems activated forms of genes such as met and neu that are unrelated to ras have been observed. The activated met gene was originally detected in a human cell line that had been transformed by exposure to N-methyl-N'-nitro-N-nitrosoguanidine. Subsequent studies demonstrated that the met proto-oncogene encodes a novel growth factor receptor and that gene activation involves the production of a chimeric gene in which the regions of met encoding the extracellular and transmembrane domains of the receptor are replaced by the 5'-region of an unrelated gene called trp. The activated neu gene was detected in tumors of the nervous system that arose in mice following transplacental exposure to N-ethyl-N-nitrosourea. The neu gene also encodes a novel growth factor receptor but, in contrast to met, its activation involves a single T:A----A:T point mutation in the region of the neu gene encoding the receptor transmembrane domain. The presence of genetic alterations in chemically induced malignancies has also been assessed in cytogenetic studies and by Southern analysis of DNA from neoplastic cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Chemically induced tumors often contain dominant transforming genes, including ras family members and other growth factor receptors like met and neu. These genes, activated by mutations or gene fusions, drive cancer development.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Chemically induced tumors and cell lines frequently harbor dominant transforming genes.
- The NIH 3T3 transfection-transformation assay is a key method for detecting these genes.
- While ras family genes (H-ras, K-ras, N-ras) are common, other genes like met and neu are also implicated.
Purpose of the Study:
- To identify and characterize dominant transforming genes in chemically induced malignancies.
- To investigate the mechanisms of activation for non-ras transforming genes, specifically met and neu.
Main Methods:
- DNA transfection experiments using NIH 3T3 mouse fibroblast cell line.
- Analysis of activated met gene in a human cell line transformed by N-methyl-N'-nitro-N-nitrosoguanidine.
- Characterization of activated neu gene in mouse nervous system tumors induced by N-ethyl-N-nitrosourea.
- Cytogenetic studies and Southern analysis of DNA from neoplastic cells.
Main Results:
- Activated met gene identified, encoding a growth factor receptor; activation involves a chimeric gene (met/trp).
- Activated neu gene identified, encoding a growth factor receptor; activation involves a point mutation.
- Demonstrated that genetic alterations are present in chemically induced malignancies.
Conclusions:
- Chemically induced tumors contain diverse dominant transforming genes, including ras and non-ras proto-oncogenes.
- Activation mechanisms for proto-oncogenes like met and neu involve gene fusion or point mutations.
- These findings highlight the genetic basis of chemical carcinogenesis and identify novel oncogenes.
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