Distinctive transforming genes in x-ray-transformed mammalian cells.

Borek, Carmia; Ong, Augustinus; Mason, Howard S.

doi:10.1073/pnas.84.3.794

Cited by 76 publications

(38 citation statements)

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“…This model uses chemically initiated neoplastic hamster embryo cells as an alternative in vitro system the characteristics of which make it relevant for studies of the cellular and molecular biology of human carcinogenesis (DiPaolo et al, 1969a(DiPaolo et al, ,b, 1971(DiPaolo et al, , 1986. The treatment of Syrian hamster cells in vitro with chemical or physical carcinogens has been used as the experimental model in other laboratories, and proved to be e cient for the detection of non-ras transforming genes (Borek et al, 1987;Gilmer et al, 1988). We demonstrated that ras activation is a low frequency event in this system (Notario et al, 1990), and established the participation of oncogenes and tumor suppressor genes in the carcinogenesis process (Notario et al, 1990;Albor et al, 1994a,b).…”

Section: Introductionmentioning

confidence: 99%

The product of the cph oncogene is a truncated, nucleotide-binding protein that enhances cellular survival to stress

1999

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Cph was isolated from neoplastic Syrian hamster embryo ®broblasts initiated by 3-methylcholanthrene (MCA), and was shown to be a single copy gene in the hamster genome, conserved from yeast to human cells, expressed in fetal cells and most adult tissues, and acting synergistically with H-ras in the transformation of murine NIH3T3 ®broblasts. We have now isolated Syrian hamster full-length cDNAs for the cph oncogene and proto-oncogene. Nucleotide sequence analysis revealed that cph was activated in MCA-treated cells by a point-mutational deletion at codon 214, which caused a shift in the normal open reading frame (ORF) and brought a translation termination codon 33 amino acids downstream. While proto-cph encodes a protein (pcph) of 469 amino acids, cph encodes a truncated protein (cph) of 246 amino acids with a new, hydrophobic C-terminus. Similar mechanisms activated cph in other MCA-treated Syrian hamster cells. The cph and proto-cph proteins have partial sequence homology with two protein families: GDP/GTP exchange factors and nucleotide phosphohydrolases. In vitro translated, gel-puri®ed cph proteins did not catalyze nucleotide exchange for H-ras, but were able to bind nucleotide phosphates, in particular ribonucleotide diphosphates such as UDP and GDP. Steady-state levels of cph mRNA increased 6.7-fold in hamster neoplastic cells, relative to a 2.2-fold increase in normal cells, when they were subjected to a nutritional stress such as serum deprivation. Moreover, cphtransformed NIH3T3 cells showed increased survival to various forms of stress (serum starvation, hyperthermia, ionizing radiation), strongly suggesting that cph participates in cellular mechanisms of response to stress.

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Section: Introductionmentioning

confidence: 99%

The product of the cph oncogene is a truncated, nucleotide-binding protein that enhances cellular survival to stress

1999

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“…However, the presence of a mutated c-ras gene has not been demonstrated so far (Sawey et al, 1988). Borek et al (1987) have demonstrated the presence of a unique non-ras transforming gene in cell lines derived from irradiated hamster embryo cells and mouse C3H 10 T1/2 cells. This work was supported by a grant from the Medical Research Council.…”

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confidence: 99%

Oncogenic transformation of murine C3H 10T1/2 cells resulting from DNA double-strand breaks induced by a restriction endonuclease

Riches²

1989

Br J Cancer

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“…Other oncogenes must also be involved in the development of non-small-cell lung cancers. DNA from cells transformed in vitro by X-rays (28,29) (30)(31)(32)(33)(34)(35)(36)(37), with the exception of squamous cell carcinomas (38,39). Mutations in this gene are also infrequent in murine lung tumors (40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Alterations in the K-ras and p53 Genes in Rat Lung Tumors

Belinsky¹,

Swafford²,

Finch³

et al. 1997

Environmental Health Perspectives

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Activation of the K-ras protooncogene and inactivation of the p53 tumor suppressor gene are events common to many types of human cancers. Molecular epidemiology studies have associated mutational profiles in these genes with specific exposures. The purpose of this paper is to review investigations that have examined the role of the K-ras and p53 genes in lung tumors induced in the F344 rat by mutagenic and nonmutagenic exposures. Mutation profiles within the K-ras and p53 genes, if present in rat lung tumors, would help to define some of the molecular mechanisms underlying cancer induction by various environmental agents. Pulmonary adenocarcinomas or squamous cell carcinomas were induced by tetranitromethane (TNM), 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), beryllium metal, plutonium-239, X-ray, diesel exhaust, or carbon black. These agents were chosen because the tumors they produced could arise via different types of DNA damage. Mutation of the K-ras gene was determined by approaches that included DNA transfection, direct sequencing, mismatch hybridization, and restriction fragment length polymorphism analysis. The frequency for mutation of the K-ras gene was exposure dependent. Only two agents, TNM and plutonium, led to mutation frequencies of > 10%. In both cases, the transition mutations formed could have been derived from deamination of cytosine. The identification of non-ras transforming genes in rat lung tumors induced by mutagenic and nonmutagenic exposures such as NNK and beryllium would help define some of the mechanisms underlying cancer induction by different types of DNA damage. Alteration in the p53 gene was assessed by immunohistochemical analysis for p53 protein and single-strand conformation polymorphism (SSCP) analysis of exons 4 to 9. None of the 93 adenocarinomas examined was immunoreactive toward the anti-p53 antibody CM1. In contrast, 14 of 71 squamous cell carcinomas exhibited nuclear p53 immunoreactivity with no correlation to type of exposure. However, SSCP analysis only detected mutations in 2 of 14 squamous cell tumors that were immunoreactive, suggesting that protein stabilization did not stem from mutations within the p53 gene. Thus, the p53 gene does not appear to be involved in the genesis of most rat lung tumors-Environ Health Perspect 105(Suppl 4): 901-906 (1997)

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Distinctive transforming genes in x-ray-transformed mammalian cells.

Abstract: DNAs from hamster embryo cells and mouse C3H/lOT1/2 cells transformed in vitro by x-irradiation into malignant cells transmit the radiation transformation phenotype by producing transformed colonies (transfectants) in two mouse recipient lines, the NIH 3T3 and C3H/101/2 cells, and

Cited by 76 publications

References 38 publications

The product of the cph oncogene is a truncated, nucleotide-binding protein that enhances cellular survival to stress

The product of the cph oncogene is a truncated, nucleotide-binding protein that enhances cellular survival to stress

Oncogenic transformation of murine C3H 10T1/2 cells resulting from DNA double-strand breaks induced by a restriction endonuclease

Alterations in the K-ras and p53 Genes in Rat Lung Tumors

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