Unraveling the molecular mechanisms involved in RCAN-peptide mediated inhibition of calcineurin-NFAT signaling and its potential as an inhibitor of tumor progressions

The calcineurin-NFATc signaling pathway is involved in many aspects of the development and function of the immune, neural, skeletal, cardiovascular and muscular system of vertebrates. Regulators of Calcineurin (RCAN) proteins constitute a family of endogenous regulators of calcineurin, which play an...

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Detalles Bibliográficos
Autor: Martínez Høyer, Sergio
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2012
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/123913
Acceso en línea:http://hdl.handle.net/10803/123913
Access Level:acceso abierto
Palabra clave:Calcineurin
NFATc
Angiogenesis
Immunosupression
Mechanism of signal transduction
Regulator of Calcineurin (RCAN)
Calcineurina
CK2
Angiogénesis
Inmunosupresión
Mecanismos de transducción de señales
577
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spelling Unraveling the molecular mechanisms involved in RCAN-peptide mediated inhibition of calcineurin-NFAT signaling and its potential as an inhibitor of tumor progressionsMartínez Høyer, SergioCalcineurinNFATcAngiogenesisImmunosupressionMechanism of signal transductionRegulator of Calcineurin (RCAN)CalcineurinaCK2AngiogénesisInmunosupresiónMecanismos de transducción de señales577The calcineurin-NFATc signaling pathway is involved in many aspects of the development and function of the immune, neural, skeletal, cardiovascular and muscular system of vertebrates. Regulators of Calcineurin (RCAN) proteins constitute a family of endogenous regulators of calcineurin, which play an important role in the modulation of the calcineurin-NFATc pathway. Here, we identifiy a novel protein kinase CK2 dependent mechanism by which the CIC motif of RCAN proteins modulate the final signaling output of the pathway. Moreover, we show that the functional CIC motif of RCANs responsible for Cn-NFATc regulation is sufficient to inhibit tumor progression producing a strong anti-angiogenic phenotype in an orthotopic human breast cancer mouse model. Therefore, a CIC-derived peptide has potent immunosuppressive and antitumoral activities by itself. Finally, the results here presented provide important insights for the rational design of potent and specific NFATc inhibitory drugs, which could be of use in autoimmune diseases and cancer.La vía de señalización calcineurina-NFATc desempeña diversos roles en el desarrollo y function en el sistema, immune, nervioso, esqueletico, cardiovascular y muscular de veretebrados. Las proteínas RCAN (Regulators of Calcineurin), constitutyen una familia de reguladores endógenos de la calcineurina (Cn) que juegan un papel importante en la modulación de dicha vía. En el presente trabajo, hemos identificado un nuevo mecanismo de regulación, dependiente de la proteína quinasa CK2, por el cual el motivo CIC de las RCAN regula la vía Cn-NFATc. Además, demostramos que el motivo CIC de las RCAN responsable de la regulación de la vía Cn-NFATc, es suficiente para inhibir la progresión tumoral, produciendo un fuerte efecto angiogénico en un modelo ortotópico murino de tumor de mama. Por tanto, un péptido derivado del motivo CIC posee actividad inmunosupresora y antitumoral por sí mismo. Finalmente, este trabajo proporciona nuevos conocimientos que pueden ser de aplicación en el desarrollo racional de nuevos fármacos, especificos y potentes inhibidores de NFATc con posibles aplicaciones en la terapia immunosupresora y del cáncer.Programa de doctorat en BiomedicinaUniversitat Pompeu FabraPérez Riba, MercèUniversitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut201320132012info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion226 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/123913TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/1239132026-06-14T12:46:07Z
dc.title.none.fl_str_mv Unraveling the molecular mechanisms involved in RCAN-peptide mediated inhibition of calcineurin-NFAT signaling and its potential as an inhibitor of tumor progressions
title Unraveling the molecular mechanisms involved in RCAN-peptide mediated inhibition of calcineurin-NFAT signaling and its potential as an inhibitor of tumor progressions
spellingShingle Unraveling the molecular mechanisms involved in RCAN-peptide mediated inhibition of calcineurin-NFAT signaling and its potential as an inhibitor of tumor progressions
Martínez Høyer, Sergio
Calcineurin
NFATc
Angiogenesis
Immunosupression
Mechanism of signal transduction
Regulator of Calcineurin (RCAN)
Calcineurina
CK2
Angiogénesis
Inmunosupresión
Mecanismos de transducción de señales
577
title_short Unraveling the molecular mechanisms involved in RCAN-peptide mediated inhibition of calcineurin-NFAT signaling and its potential as an inhibitor of tumor progressions
title_full Unraveling the molecular mechanisms involved in RCAN-peptide mediated inhibition of calcineurin-NFAT signaling and its potential as an inhibitor of tumor progressions
title_fullStr Unraveling the molecular mechanisms involved in RCAN-peptide mediated inhibition of calcineurin-NFAT signaling and its potential as an inhibitor of tumor progressions
title_full_unstemmed Unraveling the molecular mechanisms involved in RCAN-peptide mediated inhibition of calcineurin-NFAT signaling and its potential as an inhibitor of tumor progressions
title_sort Unraveling the molecular mechanisms involved in RCAN-peptide mediated inhibition of calcineurin-NFAT signaling and its potential as an inhibitor of tumor progressions
dc.creator.none.fl_str_mv Martínez Høyer, Sergio
author Martínez Høyer, Sergio
author_facet Martínez Høyer, Sergio
author_role author
dc.contributor.none.fl_str_mv Pérez Riba, Mercè
Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut
dc.subject.none.fl_str_mv Calcineurin
NFATc
Angiogenesis
Immunosupression
Mechanism of signal transduction
Regulator of Calcineurin (RCAN)
Calcineurina
CK2
Angiogénesis
Inmunosupresión
Mecanismos de transducción de señales
577
topic Calcineurin
NFATc
Angiogenesis
Immunosupression
Mechanism of signal transduction
Regulator of Calcineurin (RCAN)
Calcineurina
CK2
Angiogénesis
Inmunosupresión
Mecanismos de transducción de señales
577
description The calcineurin-NFATc signaling pathway is involved in many aspects of the development and function of the immune, neural, skeletal, cardiovascular and muscular system of vertebrates. Regulators of Calcineurin (RCAN) proteins constitute a family of endogenous regulators of calcineurin, which play an important role in the modulation of the calcineurin-NFATc pathway. Here, we identifiy a novel protein kinase CK2 dependent mechanism by which the CIC motif of RCAN proteins modulate the final signaling output of the pathway. Moreover, we show that the functional CIC motif of RCANs responsible for Cn-NFATc regulation is sufficient to inhibit tumor progression producing a strong anti-angiogenic phenotype in an orthotopic human breast cancer mouse model. Therefore, a CIC-derived peptide has potent immunosuppressive and antitumoral activities by itself. Finally, the results here presented provide important insights for the rational design of potent and specific NFATc inhibitory drugs, which could be of use in autoimmune diseases and cancer.
publishDate 2012
dc.date.none.fl_str_mv 2012
2013
2013
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/123913
url http://hdl.handle.net/10803/123913
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 226 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat Pompeu Fabra
publisher.none.fl_str_mv Universitat Pompeu Fabra
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869404611080617984
score 15,300724

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