Ras binding to a C‐terminal region of GAP

Molloy, David P.; Owen, Darerca; Grand, Roger J. A.

doi:10.1016/0014-5793(95)00657-u

Cited by 4 publications

(3 citation statements)

References 24 publications

(33 reference statements)

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“…The GDP-bound form is converted to the active GTP-bound form through a GDP/ GTP exchange reaction that is facilitated by guanine nucleotide exchange factors (GEFs) (34,35). Similarly, the GTP-bound form is converted to the GDP-bound form by intrinsic GTPase activity, which is accelerated by GTPase-activating proteins (GAPs) (36). Oncogenic mutations at codon glycine 12 result in a loss of approximately 85% of the intrinsic GTPase activity of K-Ras and also greatly reduce the responsiveness of K-Ras to inactivation by GAPs (37).…”

Section: Figurementioning

confidence: 99%

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

et al. 2012

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Genetic mutations that give rise to active mutant forms of Ras are oncogenic and found in several types of tumor. However, such mutations are not clear biomarkers for disease, since they are frequently detected in healthy individuals. Instead, it has become clear that elevated levels of Ras activity are critical for Ras-induced tumorigenesis. However, the mechanisms underlying the production of pathological levels of Ras activity are unclear. Here, we show that in the presence of oncogenic Ras, inflammatory stimuli initiate a positive feedback loop involving NF-κB that further amplifies Ras activity to pathological levels. Stimulation of Ras signaling by typical inflammatory stimuli was transient and had no long-term sequelae in wild-type mice. In contrast, these stimuli generated prolonged Ras signaling and led to chronic inflammation and precancerous pancreatic lesions (PanINs) in mice expressing physiological levels of oncogenic K-Ras. These effects of inflammatory stimuli were disrupted by deletion of inhibitor of NF-κB kinase 2 (IKK2) or inhibition of Cox-2. Likewise, expression of active IKK2 or Cox-2 or treatment with LPS generated chronic inflammation and PanINs only in mice expressing oncogenic K-Ras. The data support the hypothesis that in the presence of oncogenic Ras, inflammatory stimuli trigger an NF-κB-mediated positive feedback mechanism involving Cox-2 that amplifies Ras activity to pathological levels. Because a large proportion of the adult human population possesses Ras mutations in tissues including colon, pancreas, and lung, disruption of this positive feedback loop may be an important strategy for cancer prevention.

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Section: Figurementioning

confidence: 99%

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

et al. 2012

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“…The sequenced region covers the SH2/SH3 domains and the catalytic domain (Adari et al 1988;Gideon et al 1992;Molloy et al 1995). No base difference was found between the two strains.…”

Section: Resultsmentioning

confidence: 95%

Analysis of candidate genes included in the mammary cancer susceptibility 1 (Mcs1) region

et al. 2001

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The rat strain COP is resistant to spontaneous and carcinogen-induced mammary cancer, whereas the strain WF is susceptible. Using genetic linkage analysis of (WF x COP) F1 x WF backcrosses, LC Hsu, LA Shepel and co-workers showed that a region at the centromeric end of Chromosome (Chr) 2 (2q1) segregates with the sensitivity to mammary cancer development. The responsible locus was named Mcs1 (for mammary cancer susceptibility 1). We have developed the chromosome map of the 2q1 region by localizing 18 genes, 4 ESTs, and several anonymous markers, using radiation hybrids and fluorescence in situ hybridization. The region containing Mcs1 was delineated to 2q12-q14. Five of the genes (Mef2c, Map1b, Ccnh, Rasa, Rasgrf2) were assigned to this region and were shown to be expressed in the rat mammary glands, while three possible functional candidate genes, Pi3kr1, Rad17, and Naip, were excluded from the critical region. Since cyclin H, encoded by Ccnh, plays an important role in the control of the cell cycle and since the proteins encoded by Rasa and Rasgrf2 control the activity of the RAS oncoprotein, the corresponding genes appeared as both functional and positional Mcs1 candidates. RT-PCR experiments on RNA extracted from mammary glands of the two rat strains (COP, WF) was done. No amino acid sequence difference was found between the two strains. These results argue against the hypothesis that any of these three genes is Mcs1.

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“…The GDP-bound form is converted to the GTP-bound form through a GDP/GTP exchange reaction that is facilitated by guanine nucleotide-releasing factors (Segal et al, 1993;Overbeck et al, 1995;Lin et al, 1996). On the other hand, the GTP-bound form is converted to the GDP-bound form by the intrinsic GTPase activity, which is accelerated by GTPase-activating proteins (GAPs) (Molloy et al, 1995;Miao et al, 1996;Wittinghofer et al, 1997). Since hydrolysis of GTP was an important event in regulation of p21 activity, it was suggested that mutation of ras gene might affect normal GTP hydrolysis.…”

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confidence: 99%

Decreased GTPase activity of K- ras mutants deriving from human functional adrenocortical tumours

et al. 2000

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Our previous studies have shown that seven out of 15 patients with adrenocortical tumours contained K- ras gene mutation. In addition, the mutation type was a multiple-site mutation, and the hot spots were located at codons 15, 16, 18 and 31, which were different from those reported before (codons 12, 13 and 61). To understand whether the mutation hot spots in human adrenocortical tumours were associated with activation of K- Ras oncogene and the alterations of its biocharacteristics, mutant K- Ras genes were cloned from tumour tissues and then constructed with expression vector pBKCMV. Mutant K- Ras genes were expressed at high levels in Escherichia coli and the resultant K- Ras proteins were shown to be functional with respect to their well-known specific, high-affinity, GDP/GTP binding. The purified K- Ras protein from E. coli were then measured for their intrinsic GTPase activity and the GTPase activity in the presence of GTPase-activating protein for Ras. The results showed that the wild-type cellular K- Ras protein (p21BN) exhibits about ten times higher intrinsic GTPase activity than the activated protein (p21BM3) encoded by mutant K- Ras gene, which mutated at codon 60. With regards to the codon 15, 16, 18 and 31 mutant K- Ras proteins (p21BM2), the GTPase activity in the presence of GAP is much lower than that of the normal K- Ras protein, whereas the intrinsic GTPase activity is nearly the same as that of the normal K- Ras protein. These results indicated that mutations at these hot spots of K- Ras gene were indeed activated K- Ras oncogene in adrenocortical tumours; however, their association with tumors needs further experiments to prove. © 2000 Cancer ResearchCampaign

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Ras binding to a C‐terminal region of GAP

Cited by 4 publications

References 24 publications

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

Analysis of candidate genes included in the mammary cancer susceptibility 1 (Mcs1) region

Decreased GTPase activity of K- ras mutants deriving from human functional adrenocortical tumours

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