Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of Harvey murine sarcoma virus

Chang, Esther H.; Furth, Mark E.; Scolnick, Edward M.; Lowy, Douglas R.

doi:10.1038/297479a0

Cited by 553 publications

(212 citation statements)

References 29 publications

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“…There is increasing evidence that such quantitative changes may also be involved in ras activation. Experimentally, elevation of expression can be sufficient to permit a normal Ha-ras gene to transform NIH3T3 cells (Chang et al, 1982) and to immortalise primary fibroblasts (Spandidos & Wilkie, 1984). Direct observations on human material have revealed apparent increases in ras mRNA or p21 protein content in tumour versus normal cells in colon (Thor et al, 1984;Spandidos & Kerr, 1984;Gallick et al, 1985), as well as breast (Ohuchi et al, 1986) and lung cancers (Kurzrock et al, 1986).…”

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confidence: 99%

Ha-ras restriction fragment length polymorphisms in colorectal cancer

Wyllie

Wynford-Thomas²,

Lemoine³

et al. 1988

Br J Cancer

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Summary The possibility of an association between restriction fragment length polymorphisms (RFLPs) at the Ha-ras gene locus and susceptibility to develop colorectal cancer has been investigated. Leucocyte DNA from 46 carcinoma patients and 49 controls was analysed by Southern blotting to determine the size distribution of restriction fragments containing the variable tandem repeat 3' to the Ha-ras gene. Four predominant allelic fragments were found in both groups (in AvalI digests having sizes of 1.55, 2.0, 2.65 and 3.15 kilobases [kb]), together with a variety of 'rare' alleles (with individual frequencies <5%). The overall prevalence of rare alleles was not significantly different between cancer and control groups. The distribution of the common alleles, however, differed significantly. The combined frequency of the two larger alleles (a3 and a4) was approximately twice as high in the cancer group (34%) as in controls (18%) (P<0.025), which was reflected in a highly significant increase in the proportion of individuals carrying an a3 or a4 allele.

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confidence: 99%

Ha-ras restriction fragment length polymorphisms in colorectal cancer

Wyllie

Wynford-Thomas²,

Lemoine³

et al. 1988

Br J Cancer

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“…In mammals, they comprise a family of at least three members (H-, K-, and N-ras) which share structural and functional properties. They were first identified, in their mutant forms, as potent oncogenes (4,5,7,12,22,26,29,33,36,38,39). Although the normal ras genes are not oncogenic, they too can cause the malignant transformation of cells when expressed at abnormally high levels (7).…”

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confidence: 99%

Guanine nucleotide activation of, and competition between, RAS proteins from Saccharomyces cerevisiae.

Field¹,

Broek²,

Kataoka³

et al. 1987

Mol. Cell. Biol.

111

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In the yeast Saccharomyces cerevisiae, yeast RAS proteins are potent activators of adenylate cyclase. In the present work we measured the activity of adenylate cyclase in membranes from Saccharomyces cerevisiae which overexpress this enzyme. The response of the enzyme to added RAS2 proteins bound with various guanine nucleotides and their analogs suggests that RAS2 proteins are active in their GTP-bound form and are virtually inactive in their GDP-bound form. Also, active RAS2 protein is not inhibited by inactive RAS2, suggesting that the inactive form does not compete with the active form in binding to its effector.ras genes are ubiquitous in eucaryotes (9,24,27,32). In mammals, they comprise a family of at least three members (H-, K-, and N-ras) which share structural and functional properties. They were first identified, in their mutant forms, as potent oncogenes (4,5,7,12,22,26,29,33,36,38,39). Although the normal ras genes are not oncogenic, they too can cause the malignant transformation of cells when expressed at abnormally high levels (7). In mammals, Ras proteins are 21,000-dalton molecules that are localized to the cytoplasmic side of the cell membrane (44). They bind GTP and GDP (30) and have an intrinsic GTPase activity (14,21,35). Moreover, some oncogenic forms of Ras protein are deficient in GTPase activity (14,21,35). Based on these properties, and reasoning by analogy to other known guanine nucleotide-binding proteins, the G proteins (reviewed in reference 15), most investigators think that Ras proteins act as transducers to convey extracellular signals to an intracellular effector pathway. According to this model, Ras protein bound to GTP activates its effector, and then shuts itself off through its intrinsic GTPase activity. Mutant Ras proteins which are defective in GTPase would thus cause abnormally prolonged stimulation of the effector system, explaining their oncogenicity.The RAS1 and RAS2 proteins of the yeast Saccharomyces cerevisiae provide an ideal system for testing aspects of this model. They are structurally, biochemically, and functionally similar to the mammalian Ras proteins, and at least one of their effector systems is known (3,9,10,18,24,37,41,42). The yeast RAS genes were originally isolated by using mammalian ras genes as probes to screen libraries of S. cerevisiae genomic DNA. They encode proteins which are highly homologous to the mammalian Ras proteins, particularly at their amino termini (9, 24). They undergo processing events very similar to those of their mammalian counterparts and localize to membrane fractions (8,13,25,31,44). Like the mammalian proteins, they bind guanine nucleotides; they have an intrinsic GTPase activity, and this activity is reduced in the mutant (17), and that has enabled us to create yeast strains which greatly overexpress that enzyme. As a result, we have been able to develop a more sensitive biochemical assay for Ras proteins. Using this system we have reexamined the guanine nucleotide dependence of RAS2 protein and conclude that RAS2 may b...

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“…Furthermore, similarity in molecular size between the major low mol. wt component (23 Kd) and the ras gene product p21 (Chang et al, 1982) known to be well expressed in some TCC cells, raised the question whether the two molecules might be identical. However, radiolabelled TCC cell extracts precipitated by antibodies to either the p21 or the 23 Kd molecules showed distinct migration profiles (G.M.…”

Section: Discussionmentioning

confidence: 99%