ArticleThe Journal of investigative dermatology2020
Regulation of eIF2α by RNF4 Promotes Melanoma Tumorigenesis and Therapy Resistance.
Article in The Journal of investigative dermatology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- Ubiquitin and ubiquitin-like modifications in the endoplasmic reticulum stress response.The FEBS journal · 2026Review
- Article
- ZNF468 stabilization by RNF4 enhances apoptosis resistance and carboplatin resistance in breast cancer via transcription activation of XIAP.Genes & genomics · 2026Article
- Inhibition of EIF2S1 expression regulates the PI3K/AKT pathway to mediate apoptosis in glioma cells: an in vitro study.Neurogenetics · 2026Article
- Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to cancer cell apoptosis and renders synergism to overcome paclitaxel resistance in breast cancer cells.Cancer cell international · 2024Article
- The ubiquitin codes in cellular stress responses.Protein & cell · 2024Review
- miR-184 represses β-catenin and behaves as a skin tumor suppressor.Cell death & disease · 2024Article
- Identification of a mBMC pulmonary medicine · 2023Article
- CSF2RB overexpression promotes the protective effects of mesenchymal stromal cells against ischemic heart injury.Theranostics · 2023Article
- RNF4~RGMb~BMP6 axis required for osteogenic differentiation and cancer cell survival.Cell death & disease · 2022Article
- Review
- Article
- The E3 Ubiquitin-Protein Ligase RNF4 Promotes TNF-α-Induced Cell Death Triggered by RIPK1.International journal of molecular sciences · 2021Article
- SUMO-Targeted Ubiquitin Ligases and Their Functions in Maintaining Genome Stability.International journal of molecular sciences · 2021Review
- An Update on the Role of Ubiquitination in Melanoma Development and Therapies.Journal of clinical medicine · 2021Review
- SPANX Control of Lamin A/C Modulates Nuclear Architecture and Promotes Melanoma Growth.Molecular cancer research : MCR · 2020Article
Corrections and comments
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Authors and funding
16 authors at 7 institutions in 3 countries.
Funding
Abstract
Among the hallmarks of melanoma are impaired proteostasis and rapid development of resistance to targeted therapy that represent a major clinical challenge. However, the molecular machinery that links these processes is unknown. Here we describe that by stabilizing key melanoma oncoproteins, the ubiquitin ligase RNF4 promotes tumorigenesis and confers resistance to targeted therapy in melanoma cells, xenograft mouse models, and patient samples. In patients, RNF4 protein and mRNA levels correlate with poor prognosis and with resistance to MAPK inhibitors. Remarkably, RNF4 tumorigenic properties, including therapy resistance, require the translation initiation factor initiation elongation factor alpha (eIF2α). RNF4 binds, ubiquitinates, and stabilizes the phosphorylated eIF2α (p-eIF2α) but not activating transcription factor 4 or C/EBP homologous protein that mediates the eIF2α-dependent integrated stress response. In accordance, p-eIF2α levels were significantly elevated in high-RNF4 patient-derived melanomas. Thus, RNF4 and p-eIF2α establish a positive feed-forward loop connecting oncogenic translation and ubiquitin-dependent protein stabilization in melanoma.
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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.