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Multiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear export

2022Journal article Open Access
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dc.contributor.authorJimenez, Lucia
dc.contributor.authorMayoral‐Varo, Victor
dc.contributor.authorAmenábar, Carlos
dc.contributor.authorOrtega, Judit
dc.contributor.authorSequeira, João G. N.
dc.contributor.authorMachuqueiro, Miguel
dc.contributor.authorMourato, Cristiana
dc.contributor.authorSilvestri, Romano
dc.contributor.authorAngeli, Andrea
dc.contributor.authorCarta, Fabrizio
dc.contributor.authorSupuran, Claudiu T.
dc.contributor.authorMegías, Diego
dc.contributor.authorFerreira, Bibiana
dc.contributor.authorLink, Wolfgang
dc.date.accessioned2023-02-11T11:01:33Z
dc.date.available2023-02-11T11:01:33Z
dc.date.issued2022
dc.description.abstractChromosomal region maintenance 1 (CRM1 also known as Xpo1 and exportin-1) is the receptor for the nuclear export controlling the intracellular localization and function of many cellular and viral proteins that play a crucial role in viral infections and cancer. The inhibition of CRM1 has emerged as a promising therapeutic approach to interfere with the lifecycle of many viruses, for the treatment of cancer, and to overcome therapy resistance. Recently, selinexor has been approved as the first CRM1 inhibitor for the treatment of multiple myeloma, providing proof of concept for this therapeutic option with a new mode of action. However, selinexor is associated with dose-limiting toxicity and hence, the discovery of alternative small molecule leads that could be developed as less toxic anticancer and antiviral therapeutics will have a significant impact in the clinic. Here, we report a CRM1 inhibitor discovery platform. The development of this platform includes reporter cell lines that monitor CRM1 activity by using red fluorescent protein or green fluorescent protein-labeled HIV-1 Rev protein with a strong heterologous nuclear export signal. Simultaneously, the intracellular localization of other proteins, to be interrogated for their capacity to undergo CRM1-mediated export, can be followed by co-culturing stable cell lines expressing fluorescent fusion proteins. We used this platform to interrogate the mode of nuclear export of several proteins, including PDK1, p110 alpha, STAT5A, FOXO1, 3, 4 and TRIB2, and to screen a compound collection. We show that while p110 alpha partially relies on CRM1-dependent nuclear export, TRIB2 is exported from the nucleus in a CRM1-independent manner. Compound screening revealed the striking activity of an organoselenium compound on the CRM1 nuclear export receptor.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1111/tra.12872pt_PT
dc.identifier.issn1398-9219
dc.identifier.urihttp://hdl.handle.net/10400.1/19058
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relationNot Available
dc.relationBiosystems and Integrative Sciences Institute
dc.relationBiosystems and Integrative Sciences Institute
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAnticancer drugspt_PT
dc.subjectAntiviral drugspt_PT
dc.subjectBiosensorspt_PT
dc.subjectCRM1pt_PT
dc.subjectNuclear exportpt_PT
dc.subjectOrganoselenium compoundspt_PT
dc.subjectSelinexorpt_PT
dc.titleMultiplexed cellular profiling identifies an organoselenium compound as an inhibitor of CRM1‐mediated nuclear exportpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleNot Available
oaire.awardTitleBiosystems and Integrative Sciences Institute
oaire.awardTitleBiosystems and Integrative Sciences Institute
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/CEEC IND 2017/CEECIND%2F02300%2F2017%2FCP1387%2FCT0031/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04046%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04046%2F2020/PT
oaire.citation.endPage599pt_PT
oaire.citation.issue12pt_PT
oaire.citation.startPage587pt_PT
oaire.citation.titleTrafficpt_PT
oaire.citation.volume23pt_PT
oaire.fundingStreamCEEC IND 2017
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
person.familyNameMourato Paulo
person.familyNameferreira
person.givenNameCristiana Isabel
person.givenNameBibiana
person.identifier.ciencia-id3B1A-A815-4188
person.identifier.ciencia-idA311-E925-09C5
person.identifier.orcid0000-0003-1402-9747
person.identifier.orcid0000-0003-4772-9395
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublicationc928b692-bf43-4e45-929b-cba3517a966d
relation.isAuthorOfPublication.latestForDiscovery04ebc7d1-46fc-4df7-82e0-8a39988736f4
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