ArticleProceedings of the National Academy of Sciences of the United States of America2019
Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 99 citations in OpenAlex.
- Article
- An immunocompetent model of MCPyV-driven Merkel cell carcinoma reveals tumor evolution under immune selection.bioRxiv : the preprint server for biology · 2026Article
- Targeted degradation of MDM2 overcomes feedback regulation of p53 signaling in Merkel cell carcinoma models.The Journal of clinical investigation · 2026Article
- Differentiation-independent Activation of HPV Genome Replication by the lncRNA DINO.bioRxiv : the preprint server for biology · 2026Article
- Viruses and the host replisome: discovering oncogenic mechanisms of small DNA tumor viruses.Journal of virology · 2026Review
- MCPyV small T antigen enhances HPV16 oncogene expression, promotes Ca Ski cell proliferation, and reduces 5-fluorouracil-induced apoptosis in cervical cancer cells.Infectious medicine · 2025Article
- Genomic Signatures of Poor Prognosis in Merkel Cell Carcinoma: A Single-Institution Prospective Study.Molecular cancer research : MCR · 2025Article
- Dependence on Mdm2 for Mdm4 inhibition of p53 activity.Cancer letters · 2025Article
- IMPDH inhibition induces DNA replication stress and ATR sensitivity in Merkel cell carcinoma.iScience · 2025Article
- Epstein-Barr virus nuclear antigen 1 (EBNA1) increases the expression levels of MDM2 and MDM4 genes in HeLa cells: a review on MDM2 and MDM4 roles in cancer.BMC research notes · 2025Article
- Understanding Merkel Cell Carcinoma: Pathogenic Signaling, Extracellular Matrix Dynamics, and Novel Treatment Approaches.Cancers · 2025Review
- Small T Oncoprotein of Merkel Cell Polyomavirus Attenuates Cisplatin-Induced Apoptosis and Enhances E1, E6/E7, MMP-1, and Ki-67 Expression in HeLa Cervical Cancer Cells.Advanced pharmaceutical bulletin · 2025Article
- Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma.The Journal of clinical investigation · 2025Article
- Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma.bioRxiv : the preprint server for biology · 2024Article
- Advancing Treatment Options for Merkel Cell Carcinoma: A Review of Tumor-Targeted Therapies.International journal of molecular sciences · 2024Review
- Synthetic lethality of combined ULK1 defection and p53 restoration induce pyroptosis by directly upregulating GSDME transcription and cleavage activation through ROS/NLRP3 signaling.Journal of experimental & clinical cancer research : CR · 2024Article
- Review
- Polyomavirus ALTOs, but not MTs, downregulate viral early gene expression by activating the NF-κB pathway.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The small tumor antigen of Merkel cell polyomavirus accomplishes cellular transformation by uniquely localizing to the nucleus despite the absence of a known nuclear localization signal.Virology journal · 2024Article
- Polyomavirus ALTOs, but not MTs, downregulate viral early gene expression by activating the NF-κB pathway.bioRxiv : the preprint server for biology · 2024Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 5 institutions in 4 countries.
Funding
Abstract
Merkel cell polyomavirus (MCV) contributes to approximately 80% of all Merkel cell carcinomas (MCCs), a highly aggressive neuroendocrine carcinoma of the skin. MCV-positive MCC expresses small T antigen (ST) and a truncated form of large T antigen (LT) and usually contains wild-type p53 (TP53) and RB (RB1). In contrast, virus-negative MCC contains inactivating mutations in TP53 and RB1. While the MCV-truncated LT can bind and inhibit RB, it does not bind p53. We report here that MCV LT binds to RB, leading to increased levels of ARF, an inhibitor of MDM2, and activation of p53. However, coexpression of ST reduced p53 activation. MCV ST recruits the MYC homologue MYCL (L-Myc) to the EP400 chromatin remodeler complex and transactivates specific target genes. We observed that depletion of EP400 in MCV-positive MCC cell lines led to increased p53 target gene expression. We suspected that the MCV ST-MYCL-EP400 complex could functionally inactivate p53, but the underlying mechanism was not known. Integrated ChIP and RNA-sequencing analysis following EP400 depletion identified MDM2 as well as CK1α, an activator of MDM4, as target genes of the ST-MYCL-EP400 complex. In addition, MCV-positive MCC cells expressed high levels of MDM4. Combining MDM2 inhibitors with lenalidomide targeting CK1α or an MDM4 inhibitor caused synergistic activation of p53, leading to an apoptotic response in MCV-positive MCC cells and MCC-derived xenografts in mice. These results support dual targeting of MDM2 and MDM4 in virus-positive MCC and other p53 wild-type tumors.
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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.