E2F1-dependent oncogenic addiction of melanoma cells to MDM2.

One of the defining features of aggressive melanomas is their complexity. Hundreds of mutations and an ever increasing list of changes in the transcriptome and proteome distinguish normal from malignant melanocytic cells. Yet, despite this altered genetic background, a long-known attribute of melano...

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Detalhes bibliográficos
Autores: Verhaegen, M, Checinska, A, Riblett, M B, Wang, S, Soengas, MS
Formato: artículo
Fecha de publicación:2012
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/25449
Acesso em linha:https://hdl.handle.net/20.500.12105/25449
Access Level:acceso abierto
Palavra-chave:melanoma
senescence
oncogene dependency
MDM-2 INHIBITORS
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spelling E2F1-dependent oncogenic addiction of melanoma cells to MDM2.Verhaegen, MChecinska, ARiblett, M BWang, SSoengas, MSmelanomasenescenceoncogene dependencyMDM-2 INHIBITORSOne of the defining features of aggressive melanomas is their complexity. Hundreds of mutations and an ever increasing list of changes in the transcriptome and proteome distinguish normal from malignant melanocytic cells. Yet, despite this altered genetic background, a long-known attribute of melanomas is a relatively low rate of mutations in the p53 gene. However, it is unclear whether p53 is maintained in melanoma cells because it is required for their survival, or because it is functionally disabled. More pressing from a translational perspective, is to define whether there is a tumor cell-selective wiring of p53 that offers a window for therapeutic intervention. Here, we provide genetic and pharmacological evidence demonstrating that p53 represents a liability to melanoma cells, which they thwart by assuming an oncogenic dependency on the E3 ligase murine double minute-2 (MDM2). Specifically, we used a combination of RNA interference and two structurally independent small molecule inhibitors of the p53-MDM2 interaction to assess the relative requirement of both proteins for the viability of normal melanocytes and a broad panel of melanoma cell lines. We demonstrated in vitro and in vivo that MDM2 is selectively required to blunt latent pro-senescence signals in melanoma cells. Notably, the outcome of MDM2 inactivation depends not only on the mutational status of p53, but also on its ability to signal to the transcription factor E2F1. These data support MDM2 as a drug target in melanoma cells, and identify E2F1 as a biomarker to consider when stratifying putative candidates for clinical studies of p53-MDM2 inhibitors.SpringuerNatureNational Institutes of Health (NIH) - USAMinisterio de Ciencia e Innovación (España)Asociación Española Contra el Cáncer20242024-11-0620122012-02-1620122012-02-16research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttps://hdl.handle.net/20.500.12105/25449reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengMinisterio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available SAF2008-01950 ESTRES CELULAR EN LA PROGRESION Y RESISTENCIA A QUIMIOTERAPIA DEL MELANOMAopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/254492026-06-12T12:43:37Z
dc.title.none.fl_str_mv E2F1-dependent oncogenic addiction of melanoma cells to MDM2.
title E2F1-dependent oncogenic addiction of melanoma cells to MDM2.
spellingShingle E2F1-dependent oncogenic addiction of melanoma cells to MDM2.
Verhaegen, M
melanoma
senescence
oncogene dependency
MDM-2 INHIBITORS
title_short E2F1-dependent oncogenic addiction of melanoma cells to MDM2.
title_full E2F1-dependent oncogenic addiction of melanoma cells to MDM2.
title_fullStr E2F1-dependent oncogenic addiction of melanoma cells to MDM2.
title_full_unstemmed E2F1-dependent oncogenic addiction of melanoma cells to MDM2.
title_sort E2F1-dependent oncogenic addiction of melanoma cells to MDM2.
dc.creator.none.fl_str_mv Verhaegen, M
Checinska, A
Riblett, M B
Wang, S
Soengas, MS
author Verhaegen, M
author_facet Verhaegen, M
Checinska, A
Riblett, M B
Wang, S
Soengas, MS
author_role author
author2 Checinska, A
Riblett, M B
Wang, S
Soengas, MS
author2_role author
author
author
author
dc.contributor.none.fl_str_mv National Institutes of Health (NIH) - USA
Ministerio de Ciencia e Innovación (España)
Asociación Española Contra el Cáncer
dc.subject.none.fl_str_mv melanoma
senescence
oncogene dependency
MDM-2 INHIBITORS
topic melanoma
senescence
oncogene dependency
MDM-2 INHIBITORS
description One of the defining features of aggressive melanomas is their complexity. Hundreds of mutations and an ever increasing list of changes in the transcriptome and proteome distinguish normal from malignant melanocytic cells. Yet, despite this altered genetic background, a long-known attribute of melanomas is a relatively low rate of mutations in the p53 gene. However, it is unclear whether p53 is maintained in melanoma cells because it is required for their survival, or because it is functionally disabled. More pressing from a translational perspective, is to define whether there is a tumor cell-selective wiring of p53 that offers a window for therapeutic intervention. Here, we provide genetic and pharmacological evidence demonstrating that p53 represents a liability to melanoma cells, which they thwart by assuming an oncogenic dependency on the E3 ligase murine double minute-2 (MDM2). Specifically, we used a combination of RNA interference and two structurally independent small molecule inhibitors of the p53-MDM2 interaction to assess the relative requirement of both proteins for the viability of normal melanocytes and a broad panel of melanoma cell lines. We demonstrated in vitro and in vivo that MDM2 is selectively required to blunt latent pro-senescence signals in melanoma cells. Notably, the outcome of MDM2 inactivation depends not only on the mutational status of p53, but also on its ability to signal to the transcription factor E2F1. These data support MDM2 as a drug target in melanoma cells, and identify E2F1 as a biomarker to consider when stratifying putative candidates for clinical studies of p53-MDM2 inhibitors.
publishDate 2012
dc.date.none.fl_str_mv 2012
2012-02-16
2012
2012-02-16
2024
2024-11-06
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.12105/25449
url https://hdl.handle.net/20.500.12105/25449
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Ciencia e Innovación http://dx.doi.org/10.13039/501100004837 Not available SAF2008-01950 ESTRES CELULAR EN LA PROGRESION Y RESISTENCIA A QUIMIOTERAPIA DEL MELANOMA
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv SpringuerNature
publisher.none.fl_str_mv SpringuerNature
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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