TRIB2 confers resistance to MAPK and TOR1 inhibitors

Detalhes bibliográficos
Autor(a) principal: Silva, Neuton Pedro Gorjão da
Data de Publicação: 2015
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.1/9833
Resumo: Dissertação de mestrado, Oncobiologia, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2016
id RCAP_c07591ebc4c4e1d1d212c719492c749b
oai_identifier_str oai:sapientia.ualg.pt:10400.1/9833
network_acronym_str RCAP
network_name_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository_id_str 7160
spelling TRIB2 confers resistance to MAPK and TOR1 inhibitorsMelanomaInibidores MEKInibidores mTORFármaco-resistênciaTRIB2Domínio/Área Científica::Ciências Médicas::Biotecnologia MédicaDissertação de mestrado, Oncobiologia, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2016Malignant melanoma is the deadliest form of skin cancer that leads to a median survival time of only 6 to 9 months. Besides the patients in early stages that could be successfully treated by surgery alone, actually, there is no efficient diagnostic procedure. It is imperative to find alternatives and better methods of diagnosis for metastatic melanoma. Acquisition of resistance to chemotherapy agents, namely cytotoxic drugs such as dacarbazine, remains a major problem in melanoma therapy. Since TRIB2 (tribbles2) protein has recently been implicated as a biomarker for melanoma, and as a mediator in the process of resistance to conventional chemotherapeutics or PI3K (Phosphoinositide 3-kinase) inhibitors, we hypothesised that resistance to the inhibition of different components of this and other signalling pathways such as mTOR (mammalian target of rapamycin) and MEK (MAPK/ERK Kinase) is mediated by TRIB2. In this study, we examined the impact of ectopic expression of TRIB2 in the presence of mTOR or MEK inhibitors. We demonstrated that in the presence of rapamycin, a potent inhibitor of mTORC1 (mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1), TRIB2 confers resistance to this kind of treatment. However, when we exposed cells to a mTOR2 inhibitor, TORIN1, resistance is not observed. We demonstrated that TRIB2 acts as an adaptor, recruits the mTOR complex 1 that phosphorylates AKT (also known as Protein Kinase B, PKB) on residue Serine 473. Furthermore, we investigated the effect of TRIB2 expression, when cells where exposed to pharmaceutical inhibition of MEK. We found that TRIB2 expression protects cells against the effect of the MEK inhibitor BAY 766. We have seen that TRIB2 and MEK co-localize, interact and form a protein-protein complex. We also observed that the inhibition of MEK/ERK and PI3K pathways regulated by TRIB2, represses FOXO3 (Forkhead box O3a) a binding to p27 promoter, a well-known and studied transcription factor. On the other hand, high levels of TRIB2 leads to an increase of NF-κB (factor nuclear K B) affinity for promotor. NF-κB enhances the transcription of different genes crucial for melanoma cells proliferation and survival. This study suggests that TRIB2 is a meaningful component of a drug resistance mechanism in melanoma cells. This molecular process determines and modulates important cell decisions which include cell growth, proliferation and survival.Link, WolfgangHill, RichardSapientiaSilva, Neuton Pedro Gorjão da2017-06-03T11:53:26Z2016-09-0920152016-09-09T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10400.1/9833TID:201702495enginfo: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:RCAAP2023-07-24T10:21:23Zoai:sapientia.ualg.pt:10400.1/9833Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:01:40.270095Repositório 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 TRIB2 confers resistance to MAPK and TOR1 inhibitors
title TRIB2 confers resistance to MAPK and TOR1 inhibitors
spellingShingle TRIB2 confers resistance to MAPK and TOR1 inhibitors
Silva, Neuton Pedro Gorjão da
Melanoma
Inibidores MEK
Inibidores mTOR
Fármaco-resistência
TRIB2
Domínio/Área Científica::Ciências Médicas::Biotecnologia Médica
title_short TRIB2 confers resistance to MAPK and TOR1 inhibitors
title_full TRIB2 confers resistance to MAPK and TOR1 inhibitors
title_fullStr TRIB2 confers resistance to MAPK and TOR1 inhibitors
title_full_unstemmed TRIB2 confers resistance to MAPK and TOR1 inhibitors
title_sort TRIB2 confers resistance to MAPK and TOR1 inhibitors
author Silva, Neuton Pedro Gorjão da
author_facet Silva, Neuton Pedro Gorjão da
author_role author
dc.contributor.none.fl_str_mv Link, Wolfgang
Hill, Richard
Sapientia
dc.contributor.author.fl_str_mv Silva, Neuton Pedro Gorjão da
dc.subject.por.fl_str_mv Melanoma
Inibidores MEK
Inibidores mTOR
Fármaco-resistência
TRIB2
Domínio/Área Científica::Ciências Médicas::Biotecnologia Médica
topic Melanoma
Inibidores MEK
Inibidores mTOR
Fármaco-resistência
TRIB2
Domínio/Área Científica::Ciências Médicas::Biotecnologia Médica
description Dissertação de mestrado, Oncobiologia, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2016
publishDate 2015
dc.date.none.fl_str_mv 2015
2016-09-09
2016-09-09T00:00:00Z
2017-06-03T11:53:26Z
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/10400.1/9833
TID:201702495
url http://hdl.handle.net/10400.1/9833
identifier_str_mv TID:201702495
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
repository.mail.fl_str_mv
_version_ 1799133247187189760

Registros relacionados