Adhesion‐dependent control of Akt/protein kinase B occurs at multiple levels

Gall, Maude Le; Chambard, Jean-Claude; Grall, Dominique; Obberghen-Schilling, Ellen Van

doi:10.1002/jcp.10276

Cited by 6 publications

(4 citation statements)

References 45 publications

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“…Decreased Akt activity has been reported in anoikis (3), and inhibition of Akt increases cell susceptibility to Fas-mediated apoptosis (1). Recent studies have demonstrated that there is activation of PI3-kinase following integrin engagement (23) and, conversely, that there is decreased Akt activity following disruption of cell anchorage (39). We observed decreased levels of phosphorylated epithelial Akt following neutrophil transmigration across epithelia as well as following epithelial incubation with leukocyte elastase for 18 h. These decreased levels may be partly attributable to disruption in cell adhesion.…”

Section: Discussionmentioning

confidence: 97%

Leukocyte elastase induces epithelial apoptosis: role of mitochondial permeability changes and Akt

Ginzberg

Shannon²,

Suzuki³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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During acute inflammation, neutrophil-mediated injury to epithelium may lead to disruption of epithelial function, including the induction of epithelial apoptosis. Herein, we report the effects of neutrophil transmigration and of purified leukocyte elastase on epithelial cell survival. Neutrophil transmigration induced apoptosis of epithelial cells [control monolayers: 5 ± 1 cells/25 high-power fields (HPF) vs. neutrophil-treated monolayers: 29 ± 10 cells/HPF, P < 0.05, n = 3 as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay] as did low concentrations (0.1 U/ml) of purified leukocyte elastase (control monolayers: 6.4 ± 2.5% apoptotic vs. elastase: 26.2 ± 2.9% apoptotic, P < 0.05, as determined by cytokeratin 18 cleavage). Treatment with elastase resulted in decreased mitochondrial membrane potential, release of cytochrome c to the cytosol, and cleavage of caspases-9 and -3 as determined by Western blot analysis, implicating altered mitochondrial membrane permeability as a primary mechanism for elastase-induced apoptosis. Additionally, incubation of epithelial cells with leukocyte elastase resulted in an early increase followed by a decrease in the phosphorylation of epithelial Akt, a serine/threonine kinase important in cell survival. Inhibition of epithelial Akt before elastase treatment potentiated epithelial cell apoptosis, suggesting that the initial activation of Akt represents a protective response by the epithelial cells to the proapoptotic effects of leukocyte elastase. Taken together, these observations suggest that epithelial cells exhibit a dual response to cellular stress imposed by leukocyte elastase with a proapoptotic response mediated via early alterations in mitochondrial membrane permeability countered by activation of the survival pathway involving Akt.

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Section: Discussionmentioning

confidence: 97%

Leukocyte elastase induces epithelial apoptosis: role of mitochondial permeability changes and Akt

Ginzberg

Shannon²,

Suzuki³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…These findings are consistent with our previous observations in fibroblasts that removing serum survival factors can potentiate anoikis. 45 …”

Section: Effects Of S 36578-2 On Nonimmortalized Microvascular-derivementioning

confidence: 99%

Blockade of αvβ3 and αvβ5 integrins by RGD mimetics induces anoikis and not integrin-mediated death in human endothelial cells

Maubant

Saint-Dizier

Boutillon

et al. 2006

Blood

Self Cite

103

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␣v integrins are thought to play an important role in tumor angiogenesis. However, discrepancies between findings with ArgGly-Asp (RGD) mimetics, which block angiogenesis in animal models, and knockout mice, in which loss of some ␣v integrins enhances tumor angiogenesis, raise questions concerning the function of these integrins and the precise role of ␣v substrate mimetics in antiangiogenic therapies. We have examined the effects of a novel non-peptide RGD mimetic, S 36578-2, on human endothelial cells to elucidate its antagonist activity and to identify possible agonist functions. S 36578-2 is highly selective for ␣v␤3 and ␣v␤5 integrins and induces detachment, caspase-8 activation, and apoptosis in human umbilical endothelial cells (HUVECs) plated on vitronectin. Importantly, the compound has no effect on the morphology or survival of cells plated on interstitial matrix components such as fibronectin, and it does not potentiate the apoptotic process in suspended cells. Identical results were obtained with a cyclic RGD peptide with similar target specificity. In microvascular endothelial cells, S 36578-2-induced death was also linked to its antiadhesive effect, with established lines markedly more resistant than primary cultures to the antiadhesive and proapoptotic effects. IntroductionThe formation of new blood vessels from existing vasculature, or angiogenesis, is essential for successful tumor growth and for the development of metastases. Previous work has suggested that certain endothelial cell integrins, including ␣v␤3 and ␣v␤5, actively contribute to the angiogenic process. 1,2 More recently, endogenous inhibitors of angiogenesis have been shown to target these integrins. 3 Integrins are transmembrane receptors for extracellular matrix (ECM) and basement membrane proteins that are composed of 2 noncovalently associated subunits, ␣ and ␤. 4 To date, 18 ␣ and 8 ␤ subunits have been identified in mammals, and their association in various combinations leads to the formation of at least 24 receptors with distinct ligand specificity. Besides mediating stable adhesion, integrins transmit signals that regulate cell survival, growth, motility, and remodeling of their extracellular environment. [4][5][6] The integrins ␣v␤3 and ␣v␤5 bind to ECM molecules through an Arg-Gly-Asp (RGD)-binding site. Based on the concept that they are proangiogenic receptors, specific inhibitors, including blocking monoclonal antibodies, RGD peptides, and RGD peptidomimetics, have been developed and evaluated in vivo. 7 Indeed, pharmacologic agents targeted to ␣v␤3, ␣v␤5, or both, have been reported to block tumor and retinal angiogenesis. [8][9][10][11][12][13][14] Some of these angiogenesis inhibitors, including a humanized monoclonal anti␣v␤3 (Vitaxin; MedImmune, Gaithersburg, MD) and an ␣v␤3/ ␣v␤5-selective RGD-based cyclic peptide (cilengitide), have entered clinical trials. 15,16 Early experiments show that a monoclonal antibody directed against ␣v␤3 inhibits angiogenesis by inducing the apoptosis of angiogenic blood vessels. 17...

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“…Upon b-estradiol stimulation, DRaf:ERs have been shown to specifically activate the downstream targets of Raf molecule, MEK1/2 and ERK1/2 (McCubrey et al, 1998;Hoyle et al, 2000). This system has been exploited successfully and extensively by others to study the roles of Raf in cancer biology (McCarthy et al, 1997;McCubrey et al, 1998;Hoyle et al, 2000;Chang and McCubrey, 2001;Le Gall et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Raf promotes human herpesvirus-8 (HHV-8/KSHV) infection

et al. 2004

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Human herpesvirus-8 (HHV-8/KSHV) is etiologically associated with Kaposi's sarcoma (KS) and other tumors. Constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway has been associated with a variety of tumors, including AIDS-related KS. The oncoprotein Raf is situated at a pivotal position in regulating the MAPK pathway. Hence, we analysed the effect of oncoprotein Raf on HHV-8 infectious entry into target cells. Here we report Raf expression to significantly enhance HHV-8 infection of target cells. These findings implicate a role for Raf not only in the infectious entry of HHV-8 but also in modulating KS pathogenesis.

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Adhesion‐dependent control of Akt/protein kinase B occurs at multiple levels

Cited by 6 publications

References 45 publications

Leukocyte elastase induces epithelial apoptosis: role of mitochondial permeability changes and Akt

Leukocyte elastase induces epithelial apoptosis: role of mitochondial permeability changes and Akt

Blockade of αvβ3 and αvβ5 integrins by RGD mimetics induces anoikis and not integrin-mediated death in human endothelial cells

Raf promotes human herpesvirus-8 (HHV-8/KSHV) infection

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