ArticleOncogene2012
E2F1-dependent oncogenic addiction of melanoma cells to MDM2.
Article in Oncogene, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- Bispecific Antibodies Progression in Malignant Melanoma.Frontiers in pharmacology · 2022Review
- Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?Cellular & molecular biology letters · 2021Review
- c-Myc-activated USP2-AS1 suppresses senescence and promotes tumor progression via stabilization of E2F1 mRNA.Cell death & disease · 2021Article
- Mining Database for the Clinical Significance and Prognostic Value of ESRP1 in Cutaneous Malignant Melanoma.BioMed research international · 2020Article
- MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21.Science translational medicine · 2019Article
- Article
- E2F1 inhibition mediates cell death of metastatic melanoma.Cell death & disease · 2018Article
- BET and BRAF inhibitors act synergistically against BRAF-mutant melanoma.Cancer medicine · 2016Article
- HEDGEHOG/GLI-E2F1 axis modulates iASPP expression and function and regulates melanoma cell growth.Cell death and differentiation · 2015Article
- Loss of keratinocytic RXRα combined with activated CDK4 or oncogenic NRAS generates UVB-induced melanomas via loss of p53 and PTEN in the tumor microenvironment.Molecular cancer research : MCR · 2015Article
- Transcription addiction: can we garner the Yin and Yang functions of E2F1 for cancer therapy?Cell death & disease · 2014Review
- E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma via promoting ubiquitination-mediated degradation of RARα.Cell cycle (Georgetown, Tex.) · 2014Article
- Senescence and aging: the critical roles of p53.Oncogene · 2013Review
- FK506 binding protein 51 positively regulates melanoma stemness and metastatic potential.Cell death & disease · 2013Article
- The role of miR-18b in MDM2-p53 pathway signaling and melanoma progression.Journal of the National Cancer Institute · 2013Article
- p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis.The Journal of experimental medicine · 2013Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.