Search for novel modulators of NIS abundance and retention at the plasma membrane to enhance iodide uptake

Detalhes bibliográficos
Autor(a) principal: Vareda, José António Gonçalves
Data de Publicação: 2023
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/61728
Resumo: Tese de mestrado, Bioquímica e Biomedicina, 2023, Universidade de Lisboa, Faculdade de Ciências
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spelling Search for novel modulators of NIS abundance and retention at the plasma membrane to enhance iodide uptakeSimportador de sódio-iodo (NIS)Junções aderentes (AJs)iodo radioativo (RAI)Depleção de cálcioTeses de mestrado - 2023Departamento de Química e BioquímicaTese de mestrado, Bioquímica e Biomedicina, 2023, Universidade de Lisboa, Faculdade de CiênciasThe sodium–iodide symporter (NIS) is responsible for the active transport of iodide into thyroid cells, being present in most differentiated thyroid carcinomas (DTCs). NIS is frequently downregulated in malignant thyroid tissues, and about 30% of metastatic DTCs become refractory to radioiodine (RAI) treatment, the current gold-standard therapeutic option for metastatic disease of thyroid cancers (TCs). However, many RAI-refractory DTCs still show relatively abundant NIS protein levels despite failing to uptake sufficient iodide to enable RAI therapy. NIS deficiency in these tumours is the main reason for impaired iodide uptake, which reflects a transcriptional impairment, but also a defective targeting and retention at the cells’ plasma membrane (PM). In previous works, we identified NIS interactors involved in the regulation of the actin cytoskeleton, from which it was possible to characterize the SRC/RAC1/EZRIN signaling pathway that regulates NIS anchoring and retention at the PM. Through reanalysis of the previous datasets, we identified the regulation of adherens junctions (AJs) dynamics to be another overrepresented pathway. The current work is to better understand the signaling mechanisms that underlie SRC activation that leads to RAC1 activation and evaluate the influence of AJs on the abundance and retention of NIS at the PM. We showed that by interacting with NIS at the PM, AJ-associated P120-catenin recruits and is phosphorylated by SRC at the PM, allowing it to recruit RAC1 to the complex. This allows SRCphosphorylated VAV2 exchange factor to activate RAC1 GTPase, enhancing NIS retention at the PM and hence its abundance and activity at the surface of thyroid cells. Also, our findings indicate that loss of epithelial cell–cell adhesion may contribute to a decrease in functional NIS expression, which leads to RAI refractoriness. Therefore, successful resensitization therapies might require agents that improve cell–cell adhesion and NIS PM retention in refractory TC cells.Silva, Ana LuísaCarvalho, Margarida Henriques da Gama, 1972-Repositório da Universidade de LisboaVareda, José António Gonçalves2024-01-11T10:01:22Z202320232023-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/61728enginfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-01-15T01:19:06Zoai:repositorio.ul.pt:10451/61728Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T01:44:37.051969Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Search for novel modulators of NIS abundance and retention at the plasma membrane to enhance iodide uptake
title Search for novel modulators of NIS abundance and retention at the plasma membrane to enhance iodide uptake
spellingShingle Search for novel modulators of NIS abundance and retention at the plasma membrane to enhance iodide uptake
Vareda, José António Gonçalves
Simportador de sódio-iodo (NIS)
Junções aderentes (AJs)
iodo radioativo (RAI)
Depleção de cálcio
Teses de mestrado - 2023
Departamento de Química e Bioquímica
title_short Search for novel modulators of NIS abundance and retention at the plasma membrane to enhance iodide uptake
title_full Search for novel modulators of NIS abundance and retention at the plasma membrane to enhance iodide uptake
title_fullStr Search for novel modulators of NIS abundance and retention at the plasma membrane to enhance iodide uptake
title_full_unstemmed Search for novel modulators of NIS abundance and retention at the plasma membrane to enhance iodide uptake
title_sort Search for novel modulators of NIS abundance and retention at the plasma membrane to enhance iodide uptake
author Vareda, José António Gonçalves
author_facet Vareda, José António Gonçalves
author_role author
dc.contributor.none.fl_str_mv Silva, Ana Luísa
Carvalho, Margarida Henriques da Gama, 1972-
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Vareda, José António Gonçalves
dc.subject.por.fl_str_mv Simportador de sódio-iodo (NIS)
Junções aderentes (AJs)
iodo radioativo (RAI)
Depleção de cálcio
Teses de mestrado - 2023
Departamento de Química e Bioquímica
topic Simportador de sódio-iodo (NIS)
Junções aderentes (AJs)
iodo radioativo (RAI)
Depleção de cálcio
Teses de mestrado - 2023
Departamento de Química e Bioquímica
description Tese de mestrado, Bioquímica e Biomedicina, 2023, Universidade de Lisboa, Faculdade de Ciências
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023-01-01T00:00:00Z
2024-01-11T10:01:22Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/61728
url http://hdl.handle.net/10451/61728
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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