Ras protein signalling

Olson, Michael F.; Marais, Richard

doi:10.1006/smim.2000.0208

Cited by 97 publications

(58 citation statements)

References 94 publications

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“…Naturally occurring mutations in the Ki-ras gene have been localised to codon 12 (most frequently), 13 and 61. Owing to an associated inappropriate stimulation signal, the mutant ras transmits a constitutive growth signal to the nucleus (Gansauge et al, 1996;Olson and Marais, 2000). The incidence of ras gene mutations varies among different kinds of tumours, but was found mutated predominantly in pancreatic adenocarcinomas with a frequency of 80 -90% (Sirivatanauksorn et al, 1998;Ghaneh et al, 2002).…”

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confidence: 99%

Detection of Ki-ras mutations in tissue and plasma samples of patients with pancreatic cancer using PNA-mediated PCR clamping and hybridisation probes

et al. 2005

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In the present study, we combined the PCR-clamping approach with melting curve analysis using mutant specific hybridisation probes and wild-type specific peptide nucleic acids (PNAs) to determine the genotypes of the most frequent point mutation in codon 12 of the proto-oncogene Ki-ras in tissue and plasma samples of patients with pancreatic cancer. The sensitivity of our assay was 1 -5 Â 10 À5 . The melting curve analysis of tissue samples of four patients revealed two valine mutations, one none-valine mutation and one wild-type sequence. Ki-ras alterations were found in 28% of DNAs (18 out of 64) of nonrelated plasma samples of 10 patients with ductal adenocarcinoma of the pancreas. The valine mutation was the predominantly detected gene alteration (83%). Out of ten patients investigated, four patients (40%) became positive during clinical observation with respect to Ki-ras mutation. All four patients exhibited progressive disease and high levels of tumour marker CA 19-9. In conclusion, the one-step procedure discribed may be a useful clinical tool for analysing Ki-ras point mutations in tissue and plasmas samples. In addition, this method can be adapted for simultanous detection of multiple mutations and quantitation.

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confidence: 99%

Detection of Ki-ras mutations in tissue and plasma samples of patients with pancreatic cancer using PNA-mediated PCR clamping and hybridisation probes

et al. 2005

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“…Ras proteins, consisting of H-Ras, K-Ras, and N-Ras, are important transmitters in cell-surface receptor signaling for cellular proliferation, differentiation, and apoptosis (15)(16)(17). TCR stimulation causes rapid activation of Ras (18), which causes Th2 cell differentiation (19).…”

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confidence: 99%

Blockade of Airway Inflammation and Hyperresponsiveness by HIV-TAT-Dominant Negative Ras

Myou

Zhu

Myo

et al. 2003

The Journal of Immunology

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We have reported previously that HIV-TAT-dominant negative (dn) Ras inhibits eosinophil adhesion to ICAM-1 after activation by IL-5 and eotaxin. In this study, we evaluated the role of Ras in Ag-induced airway inflammation and hyperresponsiveness by i.p. administration into mice of dnRas, which was fused to an HIV-TAT protein transduction domain (TAT-dnRas). Uptake of TAT-dnRas (t1/2 = 12 h) was demonstrated in leukocytes after i.p. administration. OVA-sensitization significantly increased eosinophil and lymphocyte numbers in bronchoalveolar lavage fluid 24 h after final challenge. Treatment of animals with 3–10 mg/kg TAT-dnRas blocked the migration of eosinophils from 464 ± 91 × 103/ml to 288 ± 79 × 103/ml with 3 mg/kg of TAT-dnRas (p < 0.05), and further decreased to 116 ± 63 × 103/ml after 10 mg/kg TAT-dnRas (p < 0.01). Histological examination demonstrated that inflammatory cell infiltration (largely eosinophils and mononuclear cells) and mucin production around the airways caused by OVA were blocked by TAT-dnRas. OVA challenge also caused airway hyperresponsiveness to methacholine, which was dose dependently blocked by treatment with TAT-dnRas. TAT-dnRas also blocked Ag-induced IL-4 and IL-5, but not IFN-γ, production in lung tissue. Intranasal administration of IL-5 caused eosinophil migration into the airway lumen, which was attenuated by pretreatment with TAT-dnRas. By contrast, TAT-green fluorescent protein or dnRas lacking the TAT protein transduction domain did not block airway inflammation, cytokine production, or airway hyperresponsiveness. We conclude that Ras mediates Th2 cytokine production, airway inflammation, and airway hyperresponsiveness in immune-sensitized mice.

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“…5,16 The accumulation and activation of tumor suppressor genes, like p53, is part of the fail-safe mechanism of a normal cell against the uncontrolled proliferation elicited by oncogenic stimuli. 8 Although the crosstalk between Ras signaling pathway and p53 activation is well established, it remains unclear how the Ras/MEK/ERK pathway induces growth arrest in the absence of p53.…”

Section: Discussionmentioning

confidence: 99%

“…The orchestration of a variety of signaling pathways to produce diverse and specific cellular outcomes requires the ability of Ras to activate a particular responsive module for each specific stimulus. 5 Upon external stimuli, Ras becomes transiently activated relaying its signal to downstream effectors. The signaling intensity by the Raf/MEK/ ERK module is known to play an important role in Rasinduced cell cycle arrest and cellular differentiation.…”

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p73 cooperates with Ras in the activation of MAP kinase signaling cascade

et al. 2006

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The p73 gene is capable of inducing cell cycle arrest, apoptosis, senescence, differentiation and to cooperate with oncogenic Ras in cellular transformation. Ras can be considered as a branch point in signal transduction, where diverse extracellular stimuli converge. The intensity of the mitogen-activated protein kinase (MAPK) cascade activation influences the cellular response to Ras. Despite the fundamental role of p53 in Ras-induced growth arrest and senescence, it remains unclear how the Ras/MEK/ERK pathway induces growth arrest in the absence of p53. We report here that oncogenic Ras stabilizes p73 resulting in p73 accumulation and enhancement of its activity. p73, in turn, induces a sustained activation of the MAP kinase cascade synergizing with oncogenic Ras. We also found that inhibition of p73 function modifies the cellular outcome to Ras activation inhibiting Ras-dependent differentiation. Here, we show for the first time that there is a signaling loop between Ras-dependent MAPK cascade activation and p73 function.

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Ras protein signalling

Cited by 97 publications

References 94 publications

Detection of Ki-ras mutations in tissue and plasma samples of patients with pancreatic cancer using PNA-mediated PCR clamping and hybridisation probes

Detection of Ki-ras mutations in tissue and plasma samples of patients with pancreatic cancer using PNA-mediated PCR clamping and hybridisation probes

Blockade of Airway Inflammation and Hyperresponsiveness by HIV-TAT-Dominant Negative Ras

p73 cooperates with Ras in the activation of MAP kinase signaling cascade

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