SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/62529 |
Resumo: | Background Half of human cancers harbour TP53 mutations that render p53 inactive as a tumor suppressor. As such, reactivation of mutant (mut)p53 through restoration of wild-type (wt)-like function represents one of the most promising therapeutic strategies in cancer treatment. Recently, we have reported the (S)-tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a new reactivator of wt and mutp53 R280K with in vitro and in vivo p53-dependent antitumor activity. The present work aimed a mechanistic elucidation of mutp53 reactivation by SLMP53-1. Methods and results By cellular thermal shift assay (CETSA), it is shown that SLMP53-1 induces wt and mutp53 R280K thermal stabilization, which is indicative of intermolecular interactions with these proteins. Accordingly, in silico studies of wt and mutp53 R280K DNA-binding domain with SLMP53-1 unveiled that the compound binds at the interface of the p53 homodimer with the DNA minor groove. Additionally, using yeast and p53-null tumor cells ectopically expressing distinct highly prevalent mutp53, the ability of SLMP53-1 to reactivate multiple mutp53 is evidenced. Conclusions SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53. General Significance This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status. |
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SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutationsp53MutantCancerChemotherapyReactivatorCiências Médicas::Biotecnologia MédicaScience & TechnologyBackground Half of human cancers harbour TP53 mutations that render p53 inactive as a tumor suppressor. As such, reactivation of mutant (mut)p53 through restoration of wild-type (wt)-like function represents one of the most promising therapeutic strategies in cancer treatment. Recently, we have reported the (S)-tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a new reactivator of wt and mutp53 R280K with in vitro and in vivo p53-dependent antitumor activity. The present work aimed a mechanistic elucidation of mutp53 reactivation by SLMP53-1. Methods and results By cellular thermal shift assay (CETSA), it is shown that SLMP53-1 induces wt and mutp53 R280K thermal stabilization, which is indicative of intermolecular interactions with these proteins. Accordingly, in silico studies of wt and mutp53 R280K DNA-binding domain with SLMP53-1 unveiled that the compound binds at the interface of the p53 homodimer with the DNA minor groove. Additionally, using yeast and p53-null tumor cells ectopically expressing distinct highly prevalent mutp53, the ability of SLMP53-1 to reactivate multiple mutp53 is evidenced. Conclusions SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53. General Significance This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status.European Union (FEDER funds through Programa Operacional Factores de Competitividade – COMPETE) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) through the projects UID/QUI/50006/2019, COMPETE 2020 (POCI-01-0145-FEDER-006684/POCI-01-0145-FEDER-007440) and the BioTecNorte operation (NORTE-01-0145-FEDER-000004), (3599-PPCDT) PTDC/DTP-FTO/1981/2014 – POCI-01-0145-FEDER-016581 and UID/QUI/0081/2013; the Italian Association for Cancer Research, AIRC (IG#5506 to G.F.), Compagnia S. Paolo, Turin, Italy (Project 2017.0526 to G.F.) and Ministry of Health, (Project 5 × 1000, 2013 and 2015; Current research 2016). We also thank FCT for the financial support through CEECIND/01772/2017 (M.M.M. Santos), PTDC/QUI-QOR/29664/2017, UID/DTP/04138/2013, IF/01272/2015 (A. Carvalho), IF/00780/2015 (F. Marcelo) and fellowships SFRH/BD/119144/2016 (H. Ramos), PD/BD/114046/2015 (A. S. Gomes), SFRH/BD/128673/2017 (J. B. Loureiro), SFRH/BD/96189/2013 (S. Gomes), SFRH/BPD/110640/2015 (C. Oliveira) and PD/BI/135334/2017 (V. Barcherini), and the Programa Operacional Potencial Humano (POCH), specifically the BiotechHealth Programme (PD/00016/2012)info:eu-repo/semantics/publishedVersionElsevierUniversidade do MinhoGomes, A. S.Ramos, HelenaGomes, S.Loureiro, Joana B.Soares, JoanaBarcherini, ValentinaMonti, PaolaFronza, GilbertoOliveira, Carla Cristina Marques deDomingues, LucíliaBastos, MargaridaDourado, Daniel F. A. R.Carvalho, Ana LuísaRomão, Maria JoãoPinheiro, BeneditaMarcelo, FilipaCarvalho, AlexandraSantos, Maria M. M.Saraiva, Lucília2020-012020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/62529engGomes, A. S.; Ramos, Helena; Gomes, S.; Loureiro, Joana B.; Soares, Joana; Barcherini, Valentina; Monti, Paola; Fronza, Gilberto; Oliveira, Carla; Domingues, Lucília; Bastos, Margarida; Dourado, Daniel F. A. R.; Carvalho, Ana Luísa; Romão, Maria João; Pinheiro, Benedita; Marcelo, Filipa; Carvalho, Alexandra; Santos, Maria M. M.; Saraiva, Lucília, SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations. Biochimica et Biophysica Acta-General Subjects, 1864(1), 129440, 20200304-416510.1016/j.bbagen.2019.12944031536751http://www.elsevier.com/locate/issn/03044165info: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:RCAAP2023-07-21T12:53:30Zoai:repositorium.sdum.uminho.pt:1822/62529Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:52:53.308003Repositório 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 |
SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations |
title |
SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations |
spellingShingle |
SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations Gomes, A. S. p53 Mutant Cancer Chemotherapy Reactivator Ciências Médicas::Biotecnologia Médica Science & Technology |
title_short |
SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations |
title_full |
SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations |
title_fullStr |
SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations |
title_full_unstemmed |
SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations |
title_sort |
SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations |
author |
Gomes, A. S. |
author_facet |
Gomes, A. S. Ramos, Helena Gomes, S. Loureiro, Joana B. Soares, Joana Barcherini, Valentina Monti, Paola Fronza, Gilberto Oliveira, Carla Cristina Marques de Domingues, Lucília Bastos, Margarida Dourado, Daniel F. A. R. Carvalho, Ana Luísa Romão, Maria João Pinheiro, Benedita Marcelo, Filipa Carvalho, Alexandra Santos, Maria M. M. Saraiva, Lucília |
author_role |
author |
author2 |
Ramos, Helena Gomes, S. Loureiro, Joana B. Soares, Joana Barcherini, Valentina Monti, Paola Fronza, Gilberto Oliveira, Carla Cristina Marques de Domingues, Lucília Bastos, Margarida Dourado, Daniel F. A. R. Carvalho, Ana Luísa Romão, Maria João Pinheiro, Benedita Marcelo, Filipa Carvalho, Alexandra Santos, Maria M. M. Saraiva, Lucília |
author2_role |
author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Gomes, A. S. Ramos, Helena Gomes, S. Loureiro, Joana B. Soares, Joana Barcherini, Valentina Monti, Paola Fronza, Gilberto Oliveira, Carla Cristina Marques de Domingues, Lucília Bastos, Margarida Dourado, Daniel F. A. R. Carvalho, Ana Luísa Romão, Maria João Pinheiro, Benedita Marcelo, Filipa Carvalho, Alexandra Santos, Maria M. M. Saraiva, Lucília |
dc.subject.por.fl_str_mv |
p53 Mutant Cancer Chemotherapy Reactivator Ciências Médicas::Biotecnologia Médica Science & Technology |
topic |
p53 Mutant Cancer Chemotherapy Reactivator Ciências Médicas::Biotecnologia Médica Science & Technology |
description |
Background Half of human cancers harbour TP53 mutations that render p53 inactive as a tumor suppressor. As such, reactivation of mutant (mut)p53 through restoration of wild-type (wt)-like function represents one of the most promising therapeutic strategies in cancer treatment. Recently, we have reported the (S)-tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a new reactivator of wt and mutp53 R280K with in vitro and in vivo p53-dependent antitumor activity. The present work aimed a mechanistic elucidation of mutp53 reactivation by SLMP53-1. Methods and results By cellular thermal shift assay (CETSA), it is shown that SLMP53-1 induces wt and mutp53 R280K thermal stabilization, which is indicative of intermolecular interactions with these proteins. Accordingly, in silico studies of wt and mutp53 R280K DNA-binding domain with SLMP53-1 unveiled that the compound binds at the interface of the p53 homodimer with the DNA minor groove. Additionally, using yeast and p53-null tumor cells ectopically expressing distinct highly prevalent mutp53, the ability of SLMP53-1 to reactivate multiple mutp53 is evidenced. Conclusions SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53. General Significance This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-01 2020-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/62529 |
url |
http://hdl.handle.net/1822/62529 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Gomes, A. S.; Ramos, Helena; Gomes, S.; Loureiro, Joana B.; Soares, Joana; Barcherini, Valentina; Monti, Paola; Fronza, Gilberto; Oliveira, Carla; Domingues, Lucília; Bastos, Margarida; Dourado, Daniel F. A. R.; Carvalho, Ana Luísa; Romão, Maria João; Pinheiro, Benedita; Marcelo, Filipa; Carvalho, Alexandra; Santos, Maria M. M.; Saraiva, Lucília, SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations. Biochimica et Biophysica Acta-General Subjects, 1864(1), 129440, 2020 0304-4165 10.1016/j.bbagen.2019.129440 31536751 http://www.elsevier.com/locate/issn/03044165 |
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.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
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 |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799133122554494976 |