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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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Autores principales: Verhaegen, Monique, Checinska, Agnieszka, Riblett, Mary Beth, Wang, Shaomeng, Soengas, María S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3193861/
https://www.ncbi.nlm.nih.gov/pubmed/21743494
http://dx.doi.org/10.1038/onc.2011.277
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author Verhaegen, Monique
Checinska, Agnieszka
Riblett, Mary Beth
Wang, Shaomeng
Soengas, María S.
author_facet Verhaegen, Monique
Checinska, Agnieszka
Riblett, Mary Beth
Wang, Shaomeng
Soengas, María S.
author_sort Verhaegen, Monique
collection PubMed
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 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.
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spelling pubmed-31938612012-08-16 E2F1-Dependent Oncogenic Addiction of Melanoma Cells to MDM2 Verhaegen, Monique Checinska, Agnieszka Riblett, Mary Beth Wang, Shaomeng Soengas, María S. Oncogene Article 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 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. 2011-07-11 2012-02-16 /pmc/articles/PMC3193861/ /pubmed/21743494 http://dx.doi.org/10.1038/onc.2011.277 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Verhaegen, Monique
Checinska, Agnieszka
Riblett, Mary Beth
Wang, Shaomeng
Soengas, María S.
E2F1-Dependent Oncogenic Addiction of Melanoma Cells to MDM2
title 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_short E2F1-Dependent Oncogenic Addiction of Melanoma Cells to MDM2
title_sort e2f1-dependent oncogenic addiction of melanoma cells to mdm2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3193861/
https://www.ncbi.nlm.nih.gov/pubmed/21743494
http://dx.doi.org/10.1038/onc.2011.277
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