Please use this identifier to cite or link to this item:
https://hdl.handle.net/10316/109922
DC Field | Value | Language |
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dc.contributor.author | Simões-Correia, Joana | - |
dc.contributor.author | Figueiredo, Joana | - |
dc.contributor.author | Lopes, Rui | - |
dc.contributor.author | Stricher, François | - |
dc.contributor.author | Oliveira, Carla | - |
dc.contributor.author | Serrano, Luís | - |
dc.contributor.author | Seruca, Raquel | - |
dc.date.accessioned | 2023-11-07T10:29:41Z | - |
dc.date.available | 2023-11-07T10:29:41Z | - |
dc.date.issued | 2012 | - |
dc.identifier.issn | 1932-6203 | pt |
dc.identifier.uri | http://hdl.handle.net/10316/109922 | - |
dc.description.abstract | E-cadherin is critical for the maintenance of tissue architecture due to its role in cell-cell adhesion. E-cadherin mutations are the genetic cause of Hereditary Diffuse Gastric Cancer (HDGC) and missense mutations represent a clinical burden, due to the uncertainty of their pathogenic role. In vitro and in vivo, most mutations lead to loss-of-function, although the causal factor is unknown for the majority. We hypothesized that destabilization could account for the pathogenicity of E-cadherin missense mutations in HDGC, and tested our hypothesis using in silico and in vitro tools. FoldX algorithm was used to calculate the impact of each mutation in E-cadherin native-state stability, and the analysis was complemented with evolutionary conservation, by SIFT. Interestingly, HDGC patients harbouring germline E-cadherin destabilizing mutants present a younger age at diagnosis or death, suggesting that the loss of native-state stability of E-cadherin accounts for the disease phenotype. To elucidate the biological relevance of E-cadherin destabilization in HDGC, we investigated a group of newly identified HDGC-associated mutations (E185V, S232C and L583R), of which L583R is predicted to be destabilizing. We show that this mutation is not functional in vitro, exhibits shorter half-life and is unable to mature, due to premature proteasome-dependent degradation, a phenotype reverted by stabilization with the artificial mutation L583I (structurally tolerated). Herein we report E-cadherin structural models suitable to predict the impact of the majority of cancer-associated missense mutations and we show that E-cadherin destabilization leads to loss-of-function in vitro and increased pathogenicity in vivo. | pt |
dc.language.iso | eng | pt |
dc.publisher | Public Library of Science | pt |
dc.relation | This work was supported by Fundac¸a˜o para a Cieˆncia e Tecnologia, Portugal (PTDC/SAU-OBD/64319/2006, PTDC/SAU-OBD/104017/2008, SFRH/BPD/ 48765/2008), EMBO (short-term fellowship ASTF 60-2009) and EU grant Prospects (HEALTH-F4-2008-201648). | pt |
dc.rights | openAccess | pt |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | pt |
dc.subject.mesh | Algorithms | pt |
dc.subject.mesh | Amino Acid Sequence | pt |
dc.subject.mesh | Animals | pt |
dc.subject.mesh | CHO Cells | pt |
dc.subject.mesh | Cadherins | pt |
dc.subject.mesh | Cricetinae | pt |
dc.subject.mesh | Cricetulus | pt |
dc.subject.mesh | Humans | pt |
dc.subject.mesh | Models, Molecular | pt |
dc.subject.mesh | Molecular Sequence Data | pt |
dc.subject.mesh | Stomach Neoplasms | pt |
dc.subject.mesh | Mutation, Missense | pt |
dc.title | E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer | pt |
dc.type | article | - |
degois.publication.firstPage | e33783 | pt |
degois.publication.issue | 3 | pt |
degois.publication.title | PLoS ONE | pt |
dc.peerreviewed | yes | pt |
dc.identifier.doi | 10.1371/journal.pone.0033783 | pt |
degois.publication.volume | 7 | pt |
dc.date.embargo | 2012-01-01 | * |
uc.date.periodoEmbargo | 0 | pt |
item.grantfulltext | open | - |
item.cerifentitytype | Publications | - |
item.languageiso639-1 | en | - |
item.openairetype | article | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.fulltext | Com Texto completo | - |
crisitem.author.orcid | 0000-0003-2623-5628 | - |
Appears in Collections: | I&D IBILI - Artigos em Revistas Internacionais |
Files in This Item:
File | Description | Size | Format | |
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E-Cadherin Destabilization Accounts for the Pathogenicity of Missense Mutations in Hereditary Diffuse Gastric Cancer.pdf | 2.61 MB | Adobe PDF | View/Open |
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This item is licensed under a Creative Commons License