ArticleProceedings of the National Academy of Sciences of the United States of America2014
E3 ubiquitin ligase Cullin-5 modulates multiple molecular and cellular responses to heat shock protein 90 inhibition in human cancer cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers, 1 of them a synthesis that pooled it.
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Who cites it
38 citing papers in PubMed, 1 synthesis or guideline pooled it, 53 citations in OpenAlex.
- Functional variants in DCAF4 associated with lung cancer risk in European populations.Carcinogenesis · 2017Pooled it
- HSP90 shields ROC1/RBX1 from proteasomal degradation by CHIP E3 ubiquitin ligase to promote lung adenocarcinoma.Signal transduction and targeted therapy · 2026Article
- Hsp90: A means to an end.Cell stress & chaperones · 2026Review
- CUL5-mediated ubiquitination in cancer cell therapy: context-dependent roles, molecular networks, and emerging therapeutic avenues.Frontiers in medicine · 2026Review
- The FBXW7-RPAP2 Axis Controls the Growth of Hepatocellular Carcinoma Cells and Determines the Fate of Liver Cell Differentiation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication.Signal transduction and targeted therapy · 2024Article
- CUL-6/cullin ubiquitin ligase-mediated degradation of HSP-90 by intestinal lysosomes promotes thermotolerance.Cell reports · 2024Article
- Molecular glue degrader for tumor treatment.Frontiers in oncology · 2024Review
- Native Size-Exclusion Chromatography-Based Mass Spectrometry Reveals New Components of the Early Heat Shock Protein 90 Inhibition Response Among Limited Global Changes.Molecular & cellular proteomics : MCP · 2023Article
- Correlation between Ubiquitin E3 Ligases (Iranian journal of public health · 2022Article
- Cullin-5 (CUL5) as a potential prognostic marker in a pan-cancer analysis of human tumors.Bioengineered · 2021Article
- CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation.Cancers · 2021Article
- Regulation of ClC-2 Chloride Channel Proteostasis by Molecular Chaperones: Correction of Leukodystrophy-Associated Defect.International journal of molecular sciences · 2021Article
- Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- The functions and properties of cullin-5, a potential therapeutic target for cancers.American journal of translational research · 2020Review
- Genome-wide CRISPR screening reveals genetic modifiers of mutant EGFR dependence in human NSCLC.eLife · 2019Article
- Gold nanoparticles loaded with cullin-5 DNA increase sensitivity to 17-AAG in cullin-5 deficient breast cancer cells.International journal of pharmaceutics · 2019Article
- New insights into intranuclear inclusions in thyroid carcinoma: Association with autophagy and with BRAFV600E mutation.PloS one · 2019Article
- Ganetespib targets multiple levels of the receptor tyrosine kinase signaling cascade and preferentially inhibits ErbB2-overexpressing breast cancer cells.Scientific reports · 2018Article
- Ubiquitin ligases in oncogenic transformation and cancer therapy.Nature reviews. Cancer · 2018Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The molecular chaperone heat shock protein 90 (HSP90) is required for the activity and stability of its client proteins. Pharmacologic inhibition of HSP90 leads to the ubiquitin-mediated degradation of clients, particularly activated or mutant oncogenic protein kinases. Client ubiquitination occurs via the action of one or more E3 ubiquitin ligases. We sought to identify the role of Cullin-RING family E3 ubiquitin ligases in the cellular response to HSP90 inhibition. Through a focused siRNA screen of 28 Cullin-RING ligase family members, we found that CUL5 and RBX2 were required for degradation of several HSP90 clients upon treatment of human cancer cells with the clinical HSP90 inhibitor 17-AAG. Surprisingly, silencing Cullin-5 (CUL5) also delayed the earlier loss of HSP90 client protein activity at the same time as delaying cochaperone dissociation from inhibited HSP90-client complexes. Expression of a dominant-negative CUL5 showed that NEDD8 conjugation of CUL5 is required for client degradation but not for loss of client activity or recruitment of clients and HSP90 to CUL5. Silencing CUL5 reduced cellular sensitivity to three distinct HSP90 inhibitors, across four cancer types driven by different protein kinases. Our results reveal the importance of CUL5 in multiple aspects of the cellular response to HSP90 inhibition.
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