Structure of the Ki-ras gene of the human lung carcinoma cell line Calu-1

Shimizu, Kenji; Birnbaum, Daniel; Ruley, M. A.; Fasano, Ottavio; Suard, Y.; Edlund, Louise; Taparowsky, Elizabeth J.; Goldfarb, Mitchell; Wigler, Michael

doi:10.1038/304497a0

Cited by 374 publications

(198 citation statements)

References 23 publications

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“…In the present study we have examined the PLD activity in two human cancer cell lines that have activating mutations to H-Ras or K-Ras. We report here that there are very high levels of PLD activity in both T24 bladder and Calu-1 lung cancer cells that harbor mutations in H-Ras and K-Ras, respectively [19][20][21]. The PLD activity stimulated by Ras in these cells provided a survival signal that prevented apoptosis in the absence of serum.…”

Section: Introductionmentioning

confidence: 88%

“…Since activating Ras mutations are present in a large number of human cancers we investigated whether there is elevated PLD activity in human cancer cells with activated H-Ras and K-Ras genes. The T-24 bladder carcinoma expresses an activated H-Ras gene [19,20] and Calu-1 lung carcinoma cells express an activated K-Ras gene [21]. The PLD activity in these two cell lines was evaluated and compared with the PLD activity in two breast cancer cell lines (MDA-MB-231 and MCF7), which express relatively high and low PLD activity respectively [23,24].…”

Section: Pld Activity Is Elevated In T24 Bladder and Calu-1 Lung Cancmentioning

confidence: 99%

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Phospholipase D provides a survival signal in human cancer cells with activated H-Ras or K-Ras

et al. 2007

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Phospholipase D (PLD) is elevated in rodent fibroblasts expressing activated H-Ras mutants. We therefore examined the PLD activity in human cancer cells with activating Ras mutations. T24 bladder carcinoma cells express an activated H-Ras gene and Calu-1 lung carcinoma cells express an activated K-Ras gene. We report here that both of these cancer cell lines express highly elevated levels of PLD activity and that the PLD activity is dependent upon Ras. We also show that the PLD activity is dependent upon the Ras effector molecules RalA and phosphatidylinositol-3-kinase (PI3K). PLD activity has been shown to provide a survival signal in breast cancer cell lines that suppressed stress-induced apoptosis. Suppression of PLD activity in the T24 and Calu-1 cells resulted in apoptotic cell death in the absence of serum, indicating that the elevated PLD activity provided a survival signal in these cancer cell lines. Suppression of Ras, RalA, or PI3K also led to apoptosis in the absence of serum. These data indicate that a critical component of Ras signaling in human cancer cells is the activation of PLD and that targeting PLD survival signals in cancer cells could be an effective strategy to induce apoptosis in human cancers with activating Ras mutations.

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Section: Introductionmentioning

confidence: 88%

Section: Pld Activity Is Elevated In T24 Bladder and Calu-1 Lung Cancmentioning

confidence: 99%

Phospholipase D provides a survival signal in human cancer cells with activated H-Ras or K-Ras

et al. 2007

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“…Alternative splicing of a non-homologous ®fth (`IDX') exon between exons 3 and 4 in the H-ras gene may have a regulatory role (Cohen et al, 1989). As illustrated in Figure 1, the Kras gene has two alternative 3' exons designated 4A and 4B George et al, 1985;Shimizu et al, 1983). p21 K-rasA and p21 K-rasB are similar, but di er in the 24/25 C-terminal residues.…”

Section: Introductionmentioning

confidence: 99%

Developmentally-regulated expression of murine K-ras isoforms

et al. 1997

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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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Structure of the Ki-ras gene of the human lung carcinoma cell line Calu-1

Cited by 374 publications

References 23 publications

Phospholipase D provides a survival signal in human cancer cells with activated H-Ras or K-Ras

Phospholipase D provides a survival signal in human cancer cells with activated H-Ras or K-Ras

Developmentally-regulated expression of murine K-ras isoforms

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

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