Disruption of integrin-dependent adhesion and survival of endothelial cells by recombinant adenovirus expressing isolated β integrin cytoplasmic domains

Oguey, Delphine; Pw, George; Rüegg, Curzio

doi:10.1038/sj.gt.3301236

Cited by 23 publications

(19 citation statements)

References 46 publications

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“…The rapid degradation of integrin ␤1 suggests that the trigger for endothelial cell death induced by gingipains might be the loss of integrin signaling, which occurs prior to cell detachment and apoptosis. This would be consistent with a recent report demonstrating that disruption of focal adhesions and the actin cytoskeleton by overexpression of integrin ␤1 cytoplasmic domains preceded cell detachment and was, therefore, the cause rather than a consequence of endothelial cell detachment (53). Furthermore, it has been demonstrated that ligation of integrin ␤1 by antibodies protected fibroblasts from apoptosis through upregulation of phosphatidylinositol 3-kinase and Akt/protein kinase B activity (66) and that Akt is deactivated in both caspase-dependent and caspase-independent cell death in several cell types (46).…”

Section: Discussionsupporting

confidence: 80%

Gingipains fromPorphyromonas gingivalisW83 Induce Cell Adhesion Molecule Cleavage and Apoptosis in Endothelial Cells

Sheets¹,

et al. 2005

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The presence of Porphyromonas gingivalis in the periodontal pocket and the high levels of gingipain activity detected in gingival crevicular fluid could implicate a role for gingipains in the destruction of the highly vascular periodontal tissue. To explore the effects of these proteases on endothelial cells, we exposed bovine coronary artery endothelial cells and human microvascular endothelial cells to gingipain-active extracellular protein preparations and/or purified gingipains from P. gingivalis. Treated cells exhibited a rapid loss of cell adhesion properties that was followed by apoptotic cell death. Cleavage of N-and VE-cadherin and integrin ␤1 was observed in immunoblots of cell lysates. There was a direct correlation between the kinetics of cleavage of N-and VE-cadherin and loss of cell adhesion properties. Loss of cell adhesion, as well as N-and VE-cadherin and integrin ␤1 cleavage, could be inhibited or significantly delayed by preincubation of P. gingivalis W83 gingipain-active extracellular extracts with the cysteine protease inhibitor N␣-p-tosyl-L-lysine chloromethylketone. Furthermore, purified gingipains also induced endothelial cell detachment and apoptosis. Apoptosisassociated events, including annexin V positivity, caspase-3 activation, and cleavage of the caspase substrates poly(ADP-ribose) polymerase and topoisomerase I (Topo I), were observed in endothelial cells after detachment. All of the effects observed were correlated with the different levels of cysteine-dependent proteolytic activity of the extracts tested. Taken together, these results indicate that gingipains from P. gingivalis can alter cell adhesion molecules and induce endothelial cell death, which could have implications for the pathogenicity of this organism.

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Section: Discussionsupporting

confidence: 80%

Gingipains fromPorphyromonas gingivalisW83 Induce Cell Adhesion Molecule Cleavage and Apoptosis in Endothelial Cells

Sheets¹,

et al. 2005

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“…Established in adhesion-suspension assays for the examination of the cell detachment-related cell death type, termed anoikis (Martin and Vuori, 2004), the prosurvival function of specific integrin subunits such as b1 and b3 is well known (Oguey et al, 2000). In contrast to these acute and transient adhesion-and spreading-related processes, the role of b1-integrin and its downstream signaling in matrix adhered and exponentially growing cells is still unsolved in detail.…”

Section: Discussionmentioning

confidence: 99%

β1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury

et al. 2005

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Integrin-mediated adhesion to extracellular matrix proteins confers resistance to radiation-or drug-induced genotoxic injury. To analyse the underlying mechanisms specific for b1-integrins, wild-type b1A-integrin-expressing GD25b1A cells were compared to GD25b1B cells, which express signaling-incompetent b1B variants. Cells grown on fibronectin, collagen-III, b1-integrin-IgG or poly-l-lysine were exposed to 0-6 Gy X-rays in presence or depletion of growth factors and phosphatidylinositol-3 kinase (PI3K) inhibitors (LY294002, wortmannin). In order to test the relevance of these findings in tumor cells, human A-172 glioma cells were examined under the same conditions after siRNA-mediated silencing of b1-integrins. We found that b1A-integrin-mediated adhesion to fibronectin, collagen-III or b1-IgG was essential for cell survival after radiation-induced genotoxic injury. Mediated by PI3K, pro-survival b1A-integrin/Akt signaling was critically involved in this process. Additionally, the b1-integrin downstream targets p130Cas and paxillinimpaired survival-regulating PI3K-dependent JNK. In A-172 glioma cells, b1-integrin knockdown and PI3K inhibition confirmed the central role of b1-integrins in Akt-and p130Cas/paxillin-mediated prosurvival signaling. These findings suggest b1-integrins as critical regulators of cell survival after radiation-induced genotoxic injury. Elucidation of the molecular circuitry of prosurvival b1-integrin-mediated signaling in tumor cells may promote the development of innovative moleculartargeted therapeutic antitumor strategies.

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“…Additional targets of this type may explain why such a striking detachment phenotype was observed with such modest decreases in surface ␣3␤1. The degradation of integrins followed by cell detachment may cause some form of apoptosis, a phenomenon observed with integrin ␣5 subunit (39). This detachment-mediated apoptosis, termed anoikis (12,16,46), has been observed in other types of virus infections (45,52,54).…”

Section: Discussionmentioning

confidence: 99%

Identification of Integrin α3 as a New Substrate of the Adenovirus E4orf6/E1B 55-Kilodalton E3 Ubiquitin Ligase Complex

Dallaire¹,

Blanchette²,

Groitl

et al. 2009

J Virol

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The human adenovirus E4orf6 and E1B55K proteins promote viral replication by targeting several cellular proteins for degradation. The E4orf6 product has been shown by our group and others to form an E3 ubiquitin ligase complex that contains elongins B and C and cullin family member Cul5. E1B55K associates with this complex, where it is believed to function primarily to introduce bound substrates for degradation via proteasomes. In addition to p53, its first known substrate, the E4orf6/E1B 55-kDa complex (E4orf6/E1B55K) was shown to promote the degradation of Mre11 and DNA ligase IV; however, additional substrates are believed to exist. This notion is strengthened by the fact that none of these substrates seems likely to be associated with additional functions shown to be mediated by the E4orf6-associated E3 ubiquitin ligase complex, including export of late viral mRNAs and blockage of export of the bulk cellular mRNAs from the nucleus. In an attempt to identify new E4orf6/E1B55K substrates, we undertook a proteomic screen using human p53-null, non-smallcell lung carcinoma H1299 cells expressing either E4orf6 protein alone or in combination with E1B55K through infection by appropriate adenovirus vectors. One cellular protein that appeared to be degraded by E1B55K in combination with the E4orf6 protein was a species of molecular mass ϳ130 kDa that was identified as the integrin ␣3 subunit (i.e., very late activation antigen 3 alpha subunit). Preliminary analyses suggested that degradation of ␣3 may play a role in promoting release and spread of progeny virions.Viruses are well known to promote replication by inhibiting or enhancing endogenous cellular machinery or, in some cases, by reprogramming key cellular pathways. Human adenoviruses have developed effective ways to modulate the immune response, apoptosis, double-strand break repair, mRNA export, and translation to optimize virus replication and the spreading of progeny virions. The expression of adenovirus E1A proteins stabilizes p53 and induces apoptosis (8, 33); however, this effect is reversed in infected cells by the action of two early products: the E1B 55-kDa (E1B55K) and E4orf6 proteins (35, 36). We and others have shown that these proteins act through the formation of an E3 ubiquitin ligase complex analogous to the SCF and VBC complexes but which contains, in addition to elongins B and C and the RING protein Rbx1, the cullin family member Cul5 (18,41,43). This E4orf6-mediated E3 ligase complex blocks p53-induced apoptosis (35, 36) by promoting the ubiquitination of p53, followed by its degradation by proteasomes (41, 43). E4orf6 protein mediates the assembly of the complex by its interaction with elongin C through its three BC boxes (11,41,43). E1B55K, which appears to associate with the E4orf6 protein only when present in the ligase complex (4), is thought to function as a substrate recognition factor that brings substrates to the complex because, although both E4orf6 and E1B55K bind p53 independently, interaction of E1B55K with p53 is essential for ...

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Disruption of integrin-dependent adhesion and survival of endothelial cells by recombinant adenovirus expressing isolated β integrin cytoplasmic domains

Cited by 23 publications

References 46 publications

Gingipains fromPorphyromonas gingivalisW83 Induce Cell Adhesion Molecule Cleavage and Apoptosis in Endothelial Cells

Gingipains fromPorphyromonas gingivalisW83 Induce Cell Adhesion Molecule Cleavage and Apoptosis in Endothelial Cells

β1-integrin-mediated signaling essentially contributes to cell survival after radiation-induced genotoxic injury

Identification of Integrin α3 as a New Substrate of the Adenovirus E4orf6/E1B 55-Kilodalton E3 Ubiquitin Ligase Complex

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