Alterations of G-protein coupling function in phosphoinositide signaling pathways of cells transformed by ras and other membrane-associated and cytoplasmic oncogenes.

Alonso, Teresa; Srivastava, S; Santos, Eugenio

doi:10.1128/mcb.10.6.3117

Cited by 17 publications

(11 citation statements)

References 27 publications

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“…Activation of mAChRs may transform NIH 3T3 cells by coupling to arachidonic acid release and prostaglandin synthesis or by altering the behavior of ion channels (13)(14)(15)17). Alternatively, the ras oncogene product (a GTP-binding protein) has been suggested to alter G protein-coupled receptor functioning (30)(31)(32), including m2 mAChR-mediated activation of cardiac K+ channels (33). If so, a provocative linkage may exist between G proteincoupled receptors and p2lras.…”

Section: Discussionmentioning

confidence: 99%

Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes.

Gutkind

Novotny²,

Brann³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

280

219

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We have evaluated the muscarinic acetylcholine family of G protein-coupled receptors (mAChRs) for their oncogenic potential. These receptors are preferentially expressed in postmitotic cells, transducing signals specified by their endogenous agonist, the neurotransmitter acetylcholine. Cells transfected with individual human mAChR genes were morphologically indistinguishable from parental NIH 3T3 cells in the absence of agonist. In contrast, when cultures were supplemented with carbachol, a stable analog of acetylcholine, foci of transformation readily appeared in ml, m3, or m5 but not in m2 or m4 mAChRs transfectants. Receptor expression was verified by ligand binding and was similar for each transfected culture. Transformation was dose-dependent and required only low levels of receptor expression. In transformation-competent cells, agonist induced phosphatidylinositol hydrolysis, whereas in m2 or m4 transfectants, receptors were coupled to the inhibition of adenylyl cyclase. These findings demonstrate that mAChRs linked to phosphatidylinositol hydrolysis can act as conditional oncogenes when expressed in cells capable of proliferation.Receptors for polypeptides, such as epidermal growth factor and platelet-derived growth factor, can induce cellular transformation when constitutively activated (1-4). Structural mutations or unregulated availability of ligand are mechanisms known to account for their transforming activity. These receptors are prototypes of a class that mediate signal transduction by virtue of an intrinsic protein-tyrosine kinase activity (2,5,6). When the mas oncogene was discovered, a class of cell-surface receptors lacking protein-tyrosine kinase domains was also implicated in cellular transformation. The mas oncogene product has a structural motif characteristic of receptors that mediate signal transduction by coupling to GTP-binding proteins (G proteins) (7). Although mas has a weak focus-inducing activity in vitro, cells transfected with this gene are highly tumorigenic in nude mice (7). More recently, G protein-coupled serotonin receptors have been shown to convert fibroblasts to a tumorigenic state (8). Because in these latter cases exogenous ligand is not required for transformation, either these genes encode aberrant receptors or endogenous ligands are responsible for their activation. Thus, ligand independence has limited the study of the mechanism by which these receptors mediate transformation.In the present study, we have directly tested the hypothesis that normal G-protein-coupled receptors can induce agonistdependent neoplastic transformation. We chose a family of cell-surface neurotransmitter receptors, human muscarinic acetylcholine receptors (mAChRs), which possess sequence homology with both mas and the serotonin receptor (9-12). Muscarinic receptors are preferentially expressed in neurons and other postmitotic cells, and they transduce signals specified by their endogenous agonist, the neurotransmitter acetylcholine. The mAChR family consists of five distinct but high...

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Section: Discussionmentioning

confidence: 99%

Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes.

Gutkind

Novotny²,

Brann³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

280

219

View full text Add to dashboard Cite

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“…Altered p21 protein also affects the GTPase activating protein, which mediates the signal transducing effect of p21 (94)(95)(96) thereby inactivating the signaling switch (Fig. Altered p21 protein also affects the GTPase activating protein, which mediates the signal transducing effect of p21 (94)(95)(96) thereby inactivating the signaling switch (Fig.…”

Section: Gene Expression By Nicotinementioning

confidence: 99%

“…Altered p21 protein also affects the GTPase activating protein, which mediates the signal transducing effect of p21 (94)(95)(96) thereby inactivating the signaling switch (Fig. Activation of the ras gene is known to trigger the release of inositol phosphates through receptor-mediated Gprotein coupling (94,95), and also stimulate phospholipase C (PLC), which generates "second messengers'' such as DAG and IP,. Thus, the H-rus gene mediated signal transduction pathway might be one of the mechanistic sites by which nicotine induces pancreatic injury.…”

Section: Gene Expression By Nicotinementioning

confidence: 99%

Pathophysiological Effects of Nicotine on the Pancreas

Chowdhury

Rayford

Chang

1998

Experimental Biology and Medicine

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icotine, a smoking N acterized major component of tobacco and cigarette is an addictive agent and has been charas a drug of abuse by the US Surgeon General (1-3). The economic burden due to abuse of this drug is substantial because of the well-documented pathophysiological effects of nicotine on organs in the cardiovascular, respiratory, hepatic, renal, and nervous systems (3).Association of nicotine through cigarette smoking with the increased incidence of pancreatitis and pancreatic cancer has also been reported (4-18). A survey on the association between cigarette smoking and pancreatic cancer showed that cigarette smokers had a significant 70% higher risk of pancreatic cancer in comparison to nonsmokers (8-1 6). When compared with nonsmokers, subjects who smoke filtered cigarettes had a 50% elevated risk. The proportion of pancreatic cancer attributable to cigarette smoking was 29% in blacks and 26% in whites (10). Most of the data that link cigarette smokehicotine to pancreatic diseases were gathered in humans. Recent studies with animals have also shown that nicotine or its metabolites could induce pathological and functional changes in the pancreas (17)(18)(19)(20)(21)(22)(23)(24)(25). This review will present and discuss the current understanding of the pathophysiology induced by nicotine in the exocrine pancreas and the possible mechanism of action of nicotine.Cotinine and nornicotine are natural metabolites of nicotine. About 80%-90% of the dose of nicotine consumed

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“…The relative importance of the Ras-GAP pathway is probably increased in tumour cells possibly because of the loss of functionality of some survival pathways, or because Ras-GAP has an antiapoptotic function. It is known for instance that the coupling of growth factor receptors to second messengers is largely blunted in cancer cells (Alonso et al, 1990), and that cancer cells are less sensitive to death signals.…”

Section: Mab200 Speci®cally Induces Apoptosis Of Tumour But Not Of Nmentioning

confidence: 99%

Ras-GTPase activating protein inhibition specifically induces apoptosis of tumour cells

1999

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Oncogenes and tumour suppressor genes control the balance between apoptotic death and anti-apoptotic survival signals determining whether a cell proliferates or dies. Through which eectors might oncoproteins generate sensitivity to apoptosis remains to be determined. Ras GTPase activating protein (Ras-GAP) is a key element in the Ras signalling pathway, being both a negative regulator and possibly an eector of Ras. Ras-GAP acts as a regulator of transcription, and possibly connects Ras to stress-activated protein kinases. A role for Ras-GAP in cell survival has been suspected from the study of knock-out mouse embryos. In search for selective killing of tumour cells, we asked whether Ras-GAP inhibition by other means would lead to apoptosis in established cell lines. We injected a monoclonal antibody directed against the SH3 domain of Ras-GAP (mAb200) that has been shown to block Ras-GAP downstream signalling into various human normal and tumour cell lines. We show that inhibition of Ras-GAP induces apoptosis speci®cally in tumour, but not in normal cells, therefore pointing at a speci®c role for Ras-GAP in tumour cell survival. MAb200-induced apoptosis is largely prevented by coinjection of activated RhoA or Cdc42 proteins, by injection of a constitutively activated mutant of phosphoinositide 3-OH kinase (PI3-K), but not by injection of v-Raf. These results show that targeting of Ras-GAP could represent a novel anticancer approach.

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Alterations of G-protein coupling function in phosphoinositide signaling pathways of cells transformed by ras and other membrane-associated and cytoplasmic oncogenes.

Cited by 17 publications

References 27 publications

Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes.

Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes.

Pathophysiological Effects of Nicotine on the Pancreas

Ras-GTPase activating protein inhibition specifically induces apoptosis of tumour cells

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