| First Author | Gonzalez D | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 12 | Pages | e52964 |
| PubMed ID | 23285236 | Mgi Jnum | J:195743 |
| Mgi Id | MGI:5485127 | Doi | 10.1371/journal.pone.0052964 |
| Citation | Gonzalez D, et al. (2012) iNOS activation regulates beta-catenin association with its partners in endothelial cells. PLoS One 7(12):e52964 |
| abstractText | BACKGROUND: Signals that disrupt beta-catenin association to cadherins may influence the translocation of beta-catenin to the nucleus to regulate transcription. Post-translational modification of proteins is a signalling event that may lead to changes in structural conformation, association or function of the target proteins. NO and its derivatives induce nitration of proteins during inflammation. It has been described that animals treated with NO donors showed increased permeability due to modulation of VE-cadherin/catenin complex. We, therefore, aim to evaluate the effect of iNOS activation on the expression, nuclear localisation and function of beta-catenin in endothelial cells. METHODOLOGY/PRINCIPAL FINDINGS: Expression, nuclear localisation, post-translational modifications and function of beta-catenin was analysed by cell fractionation, immunoprecipitation, immunoblots, QRT-PCR and permeability assays in murine endothelial cells (H5V). Influence of macrophage activation on expression of VE-cadherin/p120-catenin/beta-catenin complex in co-cultured H5V cells was also assessed. Activation of macrophages to produce NO provoked a decrease in VE-cadherin/p120-catenin/beta-catenin expression in H5V cells. Phosphorylation of beta-catenin, p120-catenin and VE-cadherin, and reduction in the barrier properties of the cell monolayer was associated with iNOS induction. Moreover, high NO levels provoked nitration of beta-catenin, and induced its translocation to the nucleus. In the nucleus of NOS activated cells, nitration levels of beta-catenin influenced its association with TCF4 and p65 proteins. High levels of NO altered beta-catenin mediated gene expression of NFkappaB and Wnt target genes without affecting cell viability. CONCLUSIONS: NOS activity modulates beta-catenin post-translational modifications, function and its association with different partners to promote endothelial cell survival. Therapeutic manipulation of iNOS levels may remove a critical cytoprotective mechanism of importance in tumour angiogenesis. |
