ras gene Amplification and malignant transformation.

Pulciani, Simonetta; Santos, Eugenio; Long, Linda K.; Sorrentino, Vincenzo; Barbacid, Mariano

doi:10.1128/mcb.5.10.2836

Cited by 189 publications

(100 citation statements)

References 31 publications

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“…Normal mouse fibroblasts (obtained from the ATCC, Manassas, VA, USA) and a K-Ras-transformed normal-derived cell line, 226.4.1 (Pulciani et al, 1985), were routinely grown in Dulbecco's modified Eagle's medium (Invitrogen, Carlsbad, CA, USA) containing 10% newborn calf serum, 2 mM glutamine, 100 U/ml penicillin and 100 mg/ml streptomycin (normal growth medium), at 371C in a humidified atmosphere of 5% CO 2 . The reverted cell line, stably and constitutively expressing the dominant mutant Cdc25 W1056E (GEF-DN) (Bossu`et al, 2000) was maintained in normal growth medium supplemented with 0.7 mg/ml geneticin (G418; Sigma-Aldrich Inc., St Louis, MO, USA).…”

Section: Cell Culturementioning

confidence: 99%

Ras-dependent carbon metabolism and transformation in mouse fibroblasts

et al. 2006

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Mutational activation of ras genes is required for the onset and maintenance of different malignancies. Here we show, using a combination of molecular physiology, nutritional perturbations and transcriptional profiling, that full penetrance of phenotypes related to oncogenic Ras activation, including the shift of carbon metabolism towards fermentation and upregulation of key cell cycle regulators, is dependent upon glucose availability. These responses are induced by Ras activation, being specifically reverted by downregulation of the Ras pathway obtained through the expression of a dominant-negative Rasspecific guanine nucleotide exchange protein. Our data allow to link directly to ras activation the alteration in energy metabolism of cancer cells, their fragility towards glucose shortage and ensuing apoptotic death.

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Section: Cell Culturementioning

confidence: 99%

Ras-dependent carbon metabolism and transformation in mouse fibroblasts

et al. 2006

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“…It is known that overexpression of the Hras protooncogene is able to transform NIH 3T3 cells and produce low numbers of foci. 49 Ras proteins are in equilibrium between GDP and GTP, but if the absolute number of Ras-GTP increases, then this may produce an oncogenic effect. 49 Since we observe a reduction in the number of foci when cotransfecting the wild-type with the oncogenic Ras (Fig.…”

Section: Biochemical Competition Between Wild-type and Oncogenic Ras mentioning

confidence: 99%

“…49 Ras proteins are in equilibrium between GDP and GTP, but if the absolute number of Ras-GTP increases, then this may produce an oncogenic effect. 49 Since we observe a reduction in the number of foci when cotransfecting the wild-type with the oncogenic Ras (Fig. 6), this favors our hypothesis that wild-type Ras inhibits the transforming activity of the oncogene.…”

Section: Biochemical Competition Between Wild-type and Oncogenic Ras mentioning

confidence: 99%

Inhibition of Ras oncogenic activity by Ras protooncogenes

Díaz

Lue

Mathews

et al. 2004

Intl Journal of Cancer

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Point mutations in ras genes have been found in a large number and wide variety of human tumors. These oncogenic Ras mutants are locked in an active GTP-bound state that leads to a constitutive and deregulated activation of Ras function. The dogma that ras oncogenes are dominant, whereby the mutation of a single allele in a cell will predispose the host cell to transformation regardless of the presence of the normal allele, is being challenged. We have seen that increasing amounts of Ras protooncogenes are able to inhibit the activity of the N-Ras oncogene in the activation of Elk in NIH 3T3 cells and in the formation of foci. We have been able to determine that the inhibitory effect is by competition between Ras protooncogenes and the N-Ras oncogene that occurs first at the effector level at the membranes, then at the processing level and lastly at the effector level in the cytosol. In addition, coexpression of the N-Ras protooncogene in thymic lymphomas induced by the N-Ras oncogene is associated with increased levels of p107, p130 and cyclin A and decreased levels of Rb. In the present report, we have shown that the N-Ras oncogene is not truly dominant over Ras protooncogenes and their competing activities might be depending on cellular context. Key words: oncogene inhibition; N-Ras; protooncogene; Ras processing; Ras effectors ras genes play an important role in a variety of differentiation processes and signal transduction, including the regulation of cell proliferation, vesicle movement, cell survival, T-cell activation, apoptosis and cytoskeleton. 1,2 The 3 ras genes encode 4 highly related proteins of 21 kd in size that are ubiquitously expressed: N-Ras, H-Ras, K-RasA and K-RasB. 2,3 Ras is synthesized on free ribosomes as a soluble inactive protein that requires several posttranslational modifications in order to reach the cell membranes where it exhibits its biologic activity. These modifications include prenylation, proteolysis, carboxymethylation and palmitoylation. 4 -7 Once activated by ligand-mediated extracellular stimuli, Ras induces the activation of effector molecules to propagate downstream signals in the cytoplasm and nucleus of the cell. Ras effectors preferentially bind to Ras-GTP through the effector domain loop found in amino acids 32-40. There are several different mammalian proteins that have been described as Ras effectors: Raf, phosphatidylinositol 3-kinase (PI3K), Ral GDP dissociation stimulator (RalGDS), members of the Rho family, mitogen-activating protein kinase 1 (MEKK1), Nore1, among others. 2,3,8 Specific point mutations in ras genes at codons 12, 13 and 61 have been found in a large number and wide variety of human tumors. 9 These mutations render Ras as an oncogene since it is constitutively active (in the GTP-bound form), leading to a deregulated activation of Ras function. 2,3,5,9 -11 In order to dissect the effects of the different downstream pathways of Ras, oncogenic mutants in the effector domain of Ras have been characterized. Thus, Ras/V12/E38 binds Raf and not PI3...

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“…1,2 In addition to activating point mutations, the oncogenic potential of KRAS can be achieved by increase in copy number of the KRAS gene. 3,4 Recent studies have shown that in a subset of cases, KRAS mutations were strongly associated with higher KRAS gene copy number. [5][6][7] The combination of these genetic events may result in an imbalance between the wild-type allele and the mutant allele.…”

mentioning

confidence: 99%

KRAS mutant allele-specific imbalance in lung adenocarcinoma

et al. 2011

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The significance of KRAS mutant allele-specific imbalance (MASI) in lung adenocarcinomas is unknown. KRAS MASI was defined as predominance of the mutant allele over the wild-type allele. We assessed the frequency of KRAS MASI by comparing peak heights of mutant and wild-type alleles on sequencing electropherograms and by KRAS fluorescence in situ hybridization (FISH). A review of sequencing electropherograms of 207 KRAS-mutated lung adenocarcinomas demonstrated 23 (11%) cases with the mutant allele peak higher than the wild-type allele peak and 15 (7%) cases with the mutant allele peak equal to the wild-type allele peak. Of 17 cases with the mutant allele peak higher or equal to the wild-type allele peak, 8 (47%) showed KRAS amplification by FISH. KRAS FISH analysis of 36 KRAS-mutated lung adenocarcinomas with the mutant allele peak lower than the wild-type allele peak, 21 KRAS and EGFR wild-type and 16 EGFR-mutated adenocarcinomas showed no KRAS amplification. KRAS MASI was associated with selective amplification of the KRAS mutant allele (Po0.001). Patients with KRAS MASI showed worse overall survival. The cumulative proportion surviving at 17 months for KRAS MASI group was 35% compared with 84.1% for patients with KRAS mutant allele peak lower than wild-type allele peak (P ¼ 0.012). The adverse prognostic significance of KRAS MASI was independent of clinical stage and was maintained among stage I patients. The detection of KRAS MASI in lung adenocarcinomas by sequencing electropherograms may identify patients with more aggressive disease.

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ras gene Amplification and malignant transformation.

Cited by 189 publications

References 31 publications

Ras-dependent carbon metabolism and transformation in mouse fibroblasts

Ras-dependent carbon metabolism and transformation in mouse fibroblasts

Inhibition of Ras oncogenic activity by Ras protooncogenes

KRAS mutant allele-specific imbalance in lung adenocarcinoma

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