Radiation and Chemical Activation of ras Oncogenes in Different Mouse Strains

Newcomb, Elizabeth W.; Diamond, Lisa E.; Sloan, Steve R.; Corominas, Montserrat; Guerrerro, Isabel; Pellicer, A.

doi:10.2307/3430801

Cited by 4 publications

(6 citation statements)

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“…Activated ras proto-oncogenes have also been detected in spontaneous and chemical-induced tumors generated in numerous rodent model systems (Table 3) (3,19,(73)(74)(75)(76)(77)(78)(79). The reproducible activation of ras oncogenes in chemicalinduced rodent tumors has made it possible to correlate the activating mutations with the promutagenic adducts formed either directly or by metabolic activation of the carcinogen.…”

Section: Ras Oncogenes In Human and Rodent Tumorsmentioning

confidence: 99%

“…The reproducible activation of ras oncogenes in chemicalinduced rodent tumors has made it possible to correlate the activating mutations with the promutagenic adducts formed either directly or by metabolic activation of the carcinogen. For example, mutational spectra have been determined in ras oncogenes detected in tumors generated in mouse lymphocytes (78), mouse liver (20,96), mouse and rat skin (76,93), mouse and rat lung (81,82,89), and rat mammary gland (84,85). In most of these cases, the observed mutational spectrum in the ras oncogenes is consistent with the pattern of DNA adducts induced by the genotoxic carcinogen and is also consistent with in-vitro mutation patterns, such as those generated in the lacI gene of Escherichia coli by methylating agents and benzo[a]pyrene (81).…”

Section: Ras Oncogenes In Human and Rodent Tumorsmentioning

confidence: 99%

“…liver 96, and mouse lung (81) tumors; however, the only reported adduct to date is a deoxyguanosine adduct (98-100). Detailed discussions of the relationship between ras mutational spectra observed in chemical-induced tumors, and the known DNA binding properties of the chemical are presented in some of the above-mentioned references (20,76,78,81,84,85,93,96). Many chemicals that induce tumors in rodents have no detectable DNA damaging activity in genotoxicity assays in vitro (101).…”

Section: Ras Oncogenes In Human and Rodent Tumorsmentioning

confidence: 99%

“…B-raf oncogenes were also detected in two mouse hepatocellular carcinomas (20). fl Several potentially new types of oncogenes that await characterization have been detected in human lung tumors (45), mouse lung tumors (80,90), rat nasal squamous carcinomas (169), mouse lymphomas (78,170), and rabbit SCC (91).…”

Section: Non-ras Oncogenes In Human and Rodent Tumorsmentioning

confidence: 99%

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Role of proto-oncogene activation in carcinogenesis.

Anderson

Reynolds

You

et al. 1992

Environ Health Perspect

124

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The accumulation of genetic damage in the forms of activated proto-oncogenes and inactivated tumor-suppressor genes is the driving force in the evolution of a normal cell to a malignant cell. For example, both the activation of ras oncogenes and the inactivation of several suppressor genes, including p53, have been observed in the development of human colon and lung tumors. Point mutations in key codons can activate ras proto-oncogenes and inactivate the p53 suppressor gene. Thus, several critical genes for tumorigenesis are potential targets for carcinogens and radiation that can induce point mutations at low doses. The ras proto-oncogenes are targets for many genotoxic carcinogens. Activation of the ras gene is an early event--probably the "initiating" step--in the development of many chemical-induced rodent tumors. ras Oncogenes are observed in more human tumors and at a higher frequency than any other oncogene, and activation of the proto-oncogene may occur at various stages of the carcinogenic process. Numerous proto-oncogenes other than the ras genes have been shown to be activated in human tumors and to a lesser extent in rodent tumors. Mechanisms that induce aberrant expression of proto-oncogenes are gene amplification and chromosomal translocation or gene rearrangement. Amplification of proto-oncogenes and possibly gene overexpression during the absence of gene amplification occur in the development of many human tumors. For a specific tumor type, amplification of any one proto-oncogene may occur at a low frequency, but the frequency of tumors in which at least one proto-oncogene is amplified can be much higher. Proto-oncogene amplification is usually associated with late stages of tumor progression; however, amplified HER2/neu has been observed in early clinical stages of mammary neoplasia. Activation of proto-oncogenes by chromosomal translocation has been detected at a high frequency in several hematopoietic tumors. Non-ras genes have been detected by DNA transfection assays in both human and rodent tumors. For example, ret and trk genes were found to be activated by gene rearrangements in human papillary thyroid carcinomas. Several potentially new types of oncogenes have also been detected by DNA transfection assays. The etiology of the genetic alterations observed in most human tumors is unclear at present. Examples of ras gene activation and those documented for mutations in the p53 gene demonstrate that exogenous conditions can induce oncogenic mutants of normal genes. The genetic alterations observed in most human tumors are probably generated by both spontaneous events and exogenous conditions.

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Section: Ras Oncogenes In Human and Rodent Tumorsmentioning

confidence: 99%

Section: Ras Oncogenes In Human and Rodent Tumorsmentioning

confidence: 99%

Section: Ras Oncogenes In Human and Rodent Tumorsmentioning

confidence: 99%

Section: Non-ras Oncogenes In Human and Rodent Tumorsmentioning

confidence: 99%

See 2 more Smart Citations

Role of proto-oncogene activation in carcinogenesis.

Anderson

Reynolds

You

et al. 1992

Environ Health Perspect

124

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“…Species and strain genetic factors are important in determining which (if any) oncogene will be part of the transformation pathway. This was shown most notably by Pellicer and co-workers, who found that in radiation-induced thymomas from RF/J mice, both K-and N-ras genes were mutated, while in C57B1/6J mice, these tumors contained mostly N-ras and novel non-ras oncogenes (13,14). In canine leukemia induced by exposure to gamma radiation from a cobalt source, the N-ras oncogene was found to be activated (15).…”

Section: Ras Gene Activationmentioning

confidence: 89%

Oncogenes and radiation carcinogenesis.

Garte

Burns

1991

Environ Health Perspect

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Current research indicates a role for several oncogenes in radiation-induced carcinogenesis in vivo and cell transformation in vitro. Certain oncogenes are probably also involved in some cases of human cancer caused by exposure to nonionizing radiation and may play a mechanistic role in the phenomenon of radioresistance seen in later stages of tumor progression. The mechanisms of oncogene activation seen in radiation-induced tumors include point mutations, gene amplification, and changes in gene expression. Genetic factors associated with target species, strain, and tissue type play an important role in determining the specific nature of oncogene activation by radiation exposure. Using the rat skin as a model for cancer induction by ionizing radiation, we found concurrent activation of K-ras and c-myc oncogenes in end-stage tumors. Amplification of the myc gene proved to occur during a late stage of tumor progression and is not an early initiating event resulting from the direct action of radiation on target cells. The importance of tissue specificity, tumor cell heterogeneity, and physical characteristics of the radiation exposure are discussed.

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129-derived Strains of Mice Are Deficient in DNA Polymerase ι and Have Normal Immunoglobulin Hypermutation

McDonald

Frank

Plosky

et al. 2003

The Journal of Experimental Medicine

169

160

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Recent studies suggest that DNA polymerase η (polη) and DNA polymerase ι (polι) are involved in somatic hypermutation of immunoglobulin variable genes. To test the role of polι in generating mutations in an animal model, we first characterized the biochemical properties of murine polι. Like its human counterpart, murine polι is extremely error-prone when catalyzing synthesis on a variety of DNA templates in vitro. Interestingly, when filling in a 1 base-pair gap, DNA synthesis and subsequent strand displacement was greatest in the presence of both pols ι and η. Genomic sequence analysis of Poli led to the serendipitous discovery that 129-derived strains of mice have a nonsense codon mutation in exon 2 that abrogates production of polι. Analysis of hypermutation in variable genes from 129/SvJ (Poli −/−) and C57BL/6J (Poli +/+) mice revealed that the overall frequency and spectrum of mutation were normal in polι-deficient mice. Thus, either polι does not participate in hypermutation, or its role is nonessential and can be readily assumed by another low-fidelity polymerase.

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Radiation and Chemical Activation of ras Oncogenes in Different Mouse Strains

Cited by 4 publications

References 0 publications

Role of proto-oncogene activation in carcinogenesis.

Role of proto-oncogene activation in carcinogenesis.

Oncogenes and radiation carcinogenesis.

129-derived Strains of Mice Are Deficient in DNA Polymerase ι and Have Normal Immunoglobulin Hypermutation

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