Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells

Autores
Lo Ré, Andrea Emilia; Fernández Barrena, Maite G.; Almada, Luciana L.; Mills, Lisa D.; Elsawa, Sherine F.; Lund, George; Ropolo, Alejandro Javier; Molejon, Maria Ines; Vaccaro, Maria Ines; Fernandez Zapico, Martin Ernesto
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Autophagy is an evolutionarily conserved degradation process of cytoplasmic cellular constituents. It has been suggested that autophagy plays a role in tumor promotion and progression downstream oncogenic pathways; however, the molecular mechanisms underlying this phenomenon have not been elucidated. Here, we provide both in vitro and in vivo evidence of a novel signaling pathway whereby the oncogene KRAS induces the expression of VMP1, a molecule needed for the formation of the authophagosome and capable of inducing autophagy, even under nutrient-replete conditions. RNAi experiments demonstrated that KRAS requires VMP1 to induce autophagy. Analysis of the mechanisms identified GLI3, a transcription factor regulated by the Hedgehog pathway, as an effector of KRAS signaling. GLI3 regulates autophagy as well as the expression and promoter activity of VMP1 in a Hedgehog-independent manner. Chromatin immunoprecipitation assays demonstrated that GLI3 binds to the VMP1 promoter and complexes with the histone acetyltransferase p300 to regulate promoter activity. Knockdown of p300 impaired KRAS- and GLI3-induced activation of this promoter. Finally, we identified the PI3K-AKT1 pathway as the signaling pathway mediating the expression and promoter activity ofVMP1upstream of the GLI3-p300 complex. Together, these data provide evidence of a new regulatory mechanism involved in autophagy that integrates this cellular process into the molecular network of events regulating oncogene-induced autophagy.
Fil: Lo Ré, Andrea Emilia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Fernández Barrena, Maite G.. No especifíca;
Fil: Almada, Luciana L.. No especifíca;
Fil: Mills, Lisa D.. No especifíca;
Fil: Elsawa, Sherine F.. No especifíca;
Fil: Lund, George. No especifíca;
Fil: Ropolo, Alejandro Javier. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Molejon, Maria Ines. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Vaccaro, Maria Ines. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fernandez Zapico, Martin Ernesto. No especifíca;
Materia
VMP1
Autophagy
Pancreatic cancer
k-ras
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/195219
Acceder
id CONICETDig_e1b1819a2e6e0aaed51eebaf872a8e42
oai_identifier_str oai:ri.conicet.gov.ar:11336/195219
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cellsLo Ré, Andrea EmiliaFernández Barrena, Maite G.Almada, Luciana L.Mills, Lisa D.Elsawa, Sherine F.Lund, GeorgeRopolo, Alejandro JavierMolejon, Maria InesVaccaro, Maria InesFernandez Zapico, Martin ErnestoVMP1AutophagyPancreatic cancerk-rashttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Autophagy is an evolutionarily conserved degradation process of cytoplasmic cellular constituents. It has been suggested that autophagy plays a role in tumor promotion and progression downstream oncogenic pathways; however, the molecular mechanisms underlying this phenomenon have not been elucidated. Here, we provide both in vitro and in vivo evidence of a novel signaling pathway whereby the oncogene KRAS induces the expression of VMP1, a molecule needed for the formation of the authophagosome and capable of inducing autophagy, even under nutrient-replete conditions. RNAi experiments demonstrated that KRAS requires VMP1 to induce autophagy. Analysis of the mechanisms identified GLI3, a transcription factor regulated by the Hedgehog pathway, as an effector of KRAS signaling. GLI3 regulates autophagy as well as the expression and promoter activity of VMP1 in a Hedgehog-independent manner. Chromatin immunoprecipitation assays demonstrated that GLI3 binds to the VMP1 promoter and complexes with the histone acetyltransferase p300 to regulate promoter activity. Knockdown of p300 impaired KRAS- and GLI3-induced activation of this promoter. Finally, we identified the PI3K-AKT1 pathway as the signaling pathway mediating the expression and promoter activity ofVMP1upstream of the GLI3-p300 complex. Together, these data provide evidence of a new regulatory mechanism involved in autophagy that integrates this cellular process into the molecular network of events regulating oncogene-induced autophagy.Fil: Lo Ré, Andrea Emilia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Fernández Barrena, Maite G.. No especifíca;Fil: Almada, Luciana L.. No especifíca;Fil: Mills, Lisa D.. No especifíca;Fil: Elsawa, Sherine F.. No especifíca;Fil: Lund, George. No especifíca;Fil: Ropolo, Alejandro Javier. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Molejon, Maria Ines. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Vaccaro, Maria Ines. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernandez Zapico, Martin Ernesto. No especifíca;American Society for Biochemistry and Molecular Biology2012-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/195219Lo Ré, Andrea Emilia; Fernández Barrena, Maite G.; Almada, Luciana L.; Mills, Lisa D.; Elsawa, Sherine F.; et al.; Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 287; 30; 4-2012; 25325-253340021-9258CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0021925820736975info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M112.370809info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:43:42Zoai:ri.conicet.gov.ar:11336/195219instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:43:42.337CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells
title Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells
spellingShingle Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells
Lo Ré, Andrea Emilia
VMP1
Autophagy
Pancreatic cancer
k-ras
title_short Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells
title_full Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells
title_fullStr Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells
title_full_unstemmed Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells
title_sort Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells
dc.creator.none.fl_str_mv Lo Ré, Andrea Emilia
Fernández Barrena, Maite G.
Almada, Luciana L.
Mills, Lisa D.
Elsawa, Sherine F.
Lund, George
Ropolo, Alejandro Javier
Molejon, Maria Ines
Vaccaro, Maria Ines
Fernandez Zapico, Martin Ernesto
author Lo Ré, Andrea Emilia
author_facet Lo Ré, Andrea Emilia
Fernández Barrena, Maite G.
Almada, Luciana L.
Mills, Lisa D.
Elsawa, Sherine F.
Lund, George
Ropolo, Alejandro Javier
Molejon, Maria Ines
Vaccaro, Maria Ines
Fernandez Zapico, Martin Ernesto
author_role author
author2 Fernández Barrena, Maite G.
Almada, Luciana L.
Mills, Lisa D.
Elsawa, Sherine F.
Lund, George
Ropolo, Alejandro Javier
Molejon, Maria Ines
Vaccaro, Maria Ines
Fernandez Zapico, Martin Ernesto
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv VMP1
Autophagy
Pancreatic cancer
k-ras
topic VMP1
Autophagy
Pancreatic cancer
k-ras
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Autophagy is an evolutionarily conserved degradation process of cytoplasmic cellular constituents. It has been suggested that autophagy plays a role in tumor promotion and progression downstream oncogenic pathways; however, the molecular mechanisms underlying this phenomenon have not been elucidated. Here, we provide both in vitro and in vivo evidence of a novel signaling pathway whereby the oncogene KRAS induces the expression of VMP1, a molecule needed for the formation of the authophagosome and capable of inducing autophagy, even under nutrient-replete conditions. RNAi experiments demonstrated that KRAS requires VMP1 to induce autophagy. Analysis of the mechanisms identified GLI3, a transcription factor regulated by the Hedgehog pathway, as an effector of KRAS signaling. GLI3 regulates autophagy as well as the expression and promoter activity of VMP1 in a Hedgehog-independent manner. Chromatin immunoprecipitation assays demonstrated that GLI3 binds to the VMP1 promoter and complexes with the histone acetyltransferase p300 to regulate promoter activity. Knockdown of p300 impaired KRAS- and GLI3-induced activation of this promoter. Finally, we identified the PI3K-AKT1 pathway as the signaling pathway mediating the expression and promoter activity ofVMP1upstream of the GLI3-p300 complex. Together, these data provide evidence of a new regulatory mechanism involved in autophagy that integrates this cellular process into the molecular network of events regulating oncogene-induced autophagy.
Fil: Lo Ré, Andrea Emilia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Fernández Barrena, Maite G.. No especifíca;
Fil: Almada, Luciana L.. No especifíca;
Fil: Mills, Lisa D.. No especifíca;
Fil: Elsawa, Sherine F.. No especifíca;
Fil: Lund, George. No especifíca;
Fil: Ropolo, Alejandro Javier. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Molejon, Maria Ines. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Vaccaro, Maria Ines. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fernandez Zapico, Martin Ernesto. No especifíca;
description Autophagy is an evolutionarily conserved degradation process of cytoplasmic cellular constituents. It has been suggested that autophagy plays a role in tumor promotion and progression downstream oncogenic pathways; however, the molecular mechanisms underlying this phenomenon have not been elucidated. Here, we provide both in vitro and in vivo evidence of a novel signaling pathway whereby the oncogene KRAS induces the expression of VMP1, a molecule needed for the formation of the authophagosome and capable of inducing autophagy, even under nutrient-replete conditions. RNAi experiments demonstrated that KRAS requires VMP1 to induce autophagy. Analysis of the mechanisms identified GLI3, a transcription factor regulated by the Hedgehog pathway, as an effector of KRAS signaling. GLI3 regulates autophagy as well as the expression and promoter activity of VMP1 in a Hedgehog-independent manner. Chromatin immunoprecipitation assays demonstrated that GLI3 binds to the VMP1 promoter and complexes with the histone acetyltransferase p300 to regulate promoter activity. Knockdown of p300 impaired KRAS- and GLI3-induced activation of this promoter. Finally, we identified the PI3K-AKT1 pathway as the signaling pathway mediating the expression and promoter activity ofVMP1upstream of the GLI3-p300 complex. Together, these data provide evidence of a new regulatory mechanism involved in autophagy that integrates this cellular process into the molecular network of events regulating oncogene-induced autophagy.
publishDate 2012
dc.date.none.fl_str_mv 2012-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/195219
Lo Ré, Andrea Emilia; Fernández Barrena, Maite G.; Almada, Luciana L.; Mills, Lisa D.; Elsawa, Sherine F.; et al.; Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 287; 30; 4-2012; 25325-25334
0021-9258
CONICET Digital
CONICET
url http://hdl.handle.net/11336/195219
identifier_str_mv Lo Ré, Andrea Emilia; Fernández Barrena, Maite G.; Almada, Luciana L.; Mills, Lisa D.; Elsawa, Sherine F.; et al.; Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 287; 30; 4-2012; 25325-25334
0021-9258
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0021925820736975
info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.M112.370809
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1844613375318818816
score 13.070432

Publicaciones similares