Driven to Death: Inhibition of Farnesylation Increases Ras Activity and Promotes Growth Arrest and Cell Death

Geryk-Hall, Mandy; Yang, Yanwen; Hughes, Dennis P.M.

doi:10.1158/1535-7163.mct-09-0833

Cited by 29 publications

(23 citation statements)

References 46 publications

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“…8 A ). Studies in nonneuronal systems have shown that treatment with tipifarnib leads to unfarnesylation of Ras, which migrates more slowly on gel than farnesylated active Ras (F-Ras; Alcock et al 2002; Geryk-Hall et al 2010). Our analysis showed that tipifarnib treatment led to formation of two Ras-reactive bands, with one showing reduced mobility on gel, indicative of inactivated unfarnesylated Ras (U-Ras; Fig.…”

Section: Resultsmentioning

confidence: 99%

Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer’s Disease

Kirouac

Rajic

Cribbs

et al. 2017

eNeuro

179

111

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It is widely accepted that amyloid β (Aβ) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in Alzheimer’s disease (AD), yet little is known about the contribution of APP to intracellular signaling events preceding AD pathogenesis. The data presented here demonstrate that APP expression and neuronal exposure to oligomeric Aβ42 enhance Ras/ERK signaling cascade and glycogen synthase kinase 3 (GSK-3) activation. We find that RNA interference (RNAi)-directed knockdown of APP in B103 rat neuroblastoma cells expressing APP inhibits Ras-ERK signaling and GSK-3 activation, indicating that APP acts upstream of these signal transduction events. Both ERK and GSK-3 are known to induce hyperphosphorylation of tau and APP at Thr668, and our findings suggest that aberrant signaling by APP facilitates these events. Supporting this notion, analysis of human AD brain samples showed increased expression of Ras, activation of GSK-3, and phosphorylation of APP and tau, which correlated with Aβ levels in the AD brains. Furthermore, treatment of primary rat neurons with Aβ recapitulated these events and showed enhanced Ras-ERK signaling, GSK-3 activation, upregulation of cyclin D1, and phosphorylation of APP and tau. The finding that Aβ induces Thr668 phosphorylation on APP, which enhances APP proteolysis and Aβ generation, denotes a vicious feedforward mechanism by which APP and Aβ promote tau hyperphosphorylation and neurodegeneration in AD. Based on these results, we hypothesize that aberrant proliferative signaling by APP plays a fundamental role in AD neurodegeneration and that inhibition of this would impede cell cycle deregulation and neurodegeneration observed in AD.

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Section: Resultsmentioning

confidence: 99%

Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer’s Disease

Kirouac

Rajic

Cribbs

et al. 2017

eNeuro

179

111

View full text Add to dashboard Cite

show abstract

“…Double knock down of RSK2 and MSK1 showed the most significant inhibitory effect. Mutations in ras , particularly H-Ras , are frequent in SCCs (25, 26). To further examine the role of endogenous RSK2 and MSK1 signaling in Ras-induced cell transformation, we conducted a Ras G12V -mediated foci-formation assay in NIH3T3 cells.…”

Section: Resultsmentioning

confidence: 99%

Kaempferol Targets RSK2 and MSK1 to Suppress UV Radiation-Induced Skin Cancer

Yao

Chen

Liu

et al. 2014

Cancer Prevention Research

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Solar ultraviolet (SUV) irradiation is a major factor in skin carcinogenesis, the most common form of cancer in the USA. The mitogen-activated protein (MAP) kinase cascades are activated by SUV irradiation. The 90 kDa ribosomal S6 kinase (RSK) and mitogen and stress activated protein kinase (MSK) proteins constitute a family of protein kinases that mediate signal transduction downstream of the MAP kinase cascades. In this study, phosphorylation of RSK and MSK1 was up-regulated in human squamous cell carcinoma (SCC) and solar UV-treated mouse skin. Kaempferol, a natural flavonol, found in tea, broccoli, grapes, apples and other plant sources, is known to have anticancer activity, but its mechanisms and direct target(s) in cancer chemoprevention are unclear. Kinase array results revealed that kaempferol inhibited RSK2 and MSK1. Pull-down assay results, ATP competition and in vitro kinase assay data revealed that kaempferol interacts with RSK2 and MSK1 at the ATP-binding pocket and inhibits their respective kinase activities. Mechanistic investigations showed that kaempferol suppresses RSK2 and MSK1 kinase activities to attenuate solar UV-induced phosphorylation of CREB and histone H3 in mouse skin cells. Kaempferol was a potent inhibitor of solar UV-induced mouse skin carcinogenesis. Further analysis showed that skin from the kaempferol-treated group exhibited a substantial reduction in solar UV-induced phosphorylation of cAMP response element-binding protein (CREB), c-Fos and histone H3. Overall, our results identify kaempferol as a safe and novel chemopreventive agent against solar UV-induced skin carcinogenesis that acts by targeting RSK2 and MSK1.

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“…Further complicating matters, the nature of the posttranslational modifications of Ras can have a significant impact on its pro-apoptotic behavior. For example, treatment of cells expressing N-Ras or K-RasB with a farnesyltransferase inhibitor seems to switch Ras from a stimulator of cell proliferation to an inducer of apoptosis by promoting alternative prenylation of the carboxyl-terminal cysteine (normally farnesylated) with a geranylgeranyl group (87). One possible explanation for the switch to pro-apoptotic behavior might be that altering the lipid modification on Ras could affect its subcellular compartmentalization and/or change its range of potential effector interactions.…”

Section: Induction Of Apoptosis By Rasmentioning

confidence: 99%

Death pathways triggered by activated Ras in cancer cells

Overmeyer

Maltese²

2011

Front Biosci

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Ras GTPases are best known for their ability to serve as molecular switches regulating cell growth, differentiation and survival. Gene mutations that result in expression of constitutively active forms of Ras proteins have been clearly linked to oncogenesis in animal models and humans. However, over the past two decades, evidence has gradually accumulated to support a paradoxical role for Ras proteins in the initiation of cell death pathways. The balance between the opposing functions of Ras in cell proliferation/survival versus cell death can be critical for determining the overall fate of the cancer cell. In this review we will survey the body of literature that points to the ability of activated Ras proteins to tip the scales toward cell death under conditions where cancer cells encounter adverse environmental conditions or are subjected to apoptotic stimuli. In some cases the consequences of Ras activation are mediated through interactions with known effectors and well defined apoptotic death pathways. However, in other cases it appears that Ras operates by triggering novel non-apoptotic death mechanisms that are just beginning to be characterized. Understanding the details of these pathways, and the various factors that go into changing the nature of Ras signaling from pro-survival to pro-death, could potentially set the stage for the development of novel therapeutic approaches aimed at manipulating the pro-death Ras effector pathways in cancers.

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Driven to Death: Inhibition of Farnesylation Increases Ras Activity and Promotes Growth Arrest and Cell Death

Abstract: Introduction

Cited by 29 publications

References 46 publications

Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer’s Disease

Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer’s Disease

Kaempferol Targets RSK2 and MSK1 to Suppress UV Radiation-Induced Skin Cancer

Death pathways triggered by activated Ras in cancer cells

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