GTP Loading of Farnesylated p21Ras by Insulin at the Plasma Membrane

Goalstone, Marc L.; Jw, Leitner; Draznin, Boris

doi:10.1006/bbrc.1997.7413

Cited by 12 publications

(7 citation statements)

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“…Next, we measured by a western blot analysis the level of the KRAS protein in the treated Panc-1 cells, to rule out the possibility that the observed mRNA repression was the result of a temporary fluctuation unable to effectively impact on translation. As the half-life of human p21 RAS proteins has been found to vary from 20 (50) to 36 h (51), the western blots were carried out at 48 and 72 h after treatment. Panc-1 cells, 48 and 72 h after transfection with decoys 32R-3n, 2998, 3044, 5153 and 5154, were lysed, and the protein extract was analyzed by immunoblotting with a KRAS-specific antibody.…”

Section: Resultsmentioning

confidence: 99%

MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice

Cogoi

Zorzet

Rapozzi

et al. 2013

Nucleic Acids Research

100

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KRAS mutations are primary genetic lesions leading to pancreatic cancer. The promoter of human KRAS contains a nuclease-hypersensitive element (NHE) that can fold in G4-DNA structures binding to nuclear proteins, including MAZ (myc-associated zinc-finger). Here, we report that MAZ activates KRAS transcription. To knockdown oncogenic KRAS in pancreatic cancer cells, we designed oligonucleotides that mimic one of the G-quadruplexes formed by NHE (G4-decoys). To increase their nuclease resistance, two locked nucleic acid (LNA) modifications were introduced at the 3′-end, whereas to enhance the folding and stability, two polycyclic aromatic hydrocarbon units (TINA or AMANY) were inserted internally, to cap the quadruplex. The most active G4-decoy (2998), which had two para-TINAs, strongly suppressed KRAS expression in Panc-1 cells. It also repressed their metabolic activity (IC50 = 520 nM), and it inhibited cell growth and colony formation by activating apoptosis. We finally injected 2998 and control oligonucleotides 5153, 5154 (2 nmol/mouse) intratumorally in SCID mice bearing a Panc-1 xenograft. After three treatments, 2998 reduced tumor xenograft growth by 64% compared with control and increased the Kaplan–Meier median survival time by 70%. Together, our data show that MAZ-specific G4-decoys mimicking a KRAS quadruplex are promising for pancreatic cancer therapy.

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Section: Resultsmentioning

confidence: 99%

MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice

Cogoi

Zorzet

Rapozzi

et al. 2013

Nucleic Acids Research

100

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“…p21Ras is among the most prominent of these enzymes and prenylation of p21Ras with a farnesyl moiety by the enzyme farnesyl transferase is an essential step in anchoring p21Ras to the plasma membrane in readiness for GTP loading and signalling via the MAPK pathway. Insulin can activate farnesyl transferase by phosphorylation of its regulatory α subunit [121], and insulin-induced increases in p21Ras farnesylation have indeed been shown to be associated with increased GTP loading of membrane-bound p21Ras [122]. Activation of farnesyl transferase appears to be mediated via the insulin receptor, as shown by increased levels of farnesylated p21Ras in cells overexpressing insulin receptors and reduced levels in cells expressing a mutant insulin receptor with impaired function [123].…”

Section: Mitogenic and Anti-apoptotic Effects Of Insulinmentioning

confidence: 99%

Insulin resistance and hyperinsulinaemia in the development and progression of cancer

2009

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Experimental, epidemiological and clinical evidence implicates insulin resistance and its accompanying hyperinsulinaemia in the development of cancer, but the relative importance of these disturbances in cancer remains unclear. There are, however, theoretical mechanisms by which hyperinsulinaemia could amplify such growth-promoting effects as insulin may have, as well as the growth-promoting effects of other, more potent, growth factors. Hyperinsulinaemia may also induce other changes, particularly in the IGF (insulin-like growth factor) system, that could promote cell proliferation and survival. Several factors can independently modify both cancer risk and insulin resistance, including subclinical inflammation and obesity. The possibility that some of the effects of hyperinsulinaemia might then augment pro-carcinogenic changes associated with disturbances in these factors emphasizes how, rather than being a single causative factor, insulin resistance may be most usefully viewed as one strand in a network of interacting disturbances that promote the development and progression of cancer.

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“…ras is translocated to the plasma membrane where it can be activated by GTP loading in response to other growth factors and growth-promoting agents (1,2,6). Thus, by its stimulatory influence of FTase, insulin increases the size of the cellular pool of farnesylated p21 ras that is available for activation.…”

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confidence: 99%

Effect of Insulin on Farnesyltransferase

Goalstone

Leitner

Wall

et al. 1998

Journal of Biological Chemistry

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We have previously demonstrated that insulin activates farnesyltransferase (FTase) and augments the amounts of farnesylated p21 ras (Goalstone, M. L., and Draznin, B. (1996) J. Biol. Chem. 271, 27585-27589). We postulated that this aspect of insulin action might explain the "priming effect" of insulin on the cellular response to other growth factors. In the present study, we show the specificity of the effect of insulin on FTase. Insulin, but not insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), or platelet-derived growth factor (PDGF), stimulated the phosphorylation of the ␣-subunit of FTase and the amounts of farnesylated p21ras . Even though all four growth factors utilized the Ras pathway to stimulate DNA synthesis, only insulin used this pathway to influence FTase. Insulin failed to stimulate FTase in cells expressing the chimeric insulin/ IGF-1 receptor and in cells derived from the insulin receptor knock-out animals. Insulin potentiated the effects of IGF-1, EGF, and PDGF on DNA synthesis in cells expressing the wild type insulin receptor, but this potentiation was inhibited in the presence of the FTase inhibitor, ␣-hydroxyfarnesylphosphonic acid. We conclude that the effect of insulin on FTase is specific, requires the presence of an intact insulin receptor, and serves as a conduit for the "priming" influence of insulin on the nuclear effects of other growth factors.

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GTP Loading of Farnesylated p21Ras by Insulin at the Plasma Membrane

Cited by 12 publications

References 0 publications

MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice

MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice

Insulin resistance and hyperinsulinaemia in the development and progression of cancer

Effect of Insulin on Farnesyltransferase

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