ArticleScience signaling2013
A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.
Article in Science signaling, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 65 citations in OpenAlex.
- UTERINE FIBROIDS.Physiological reviews · 2025Review
- Selective ubiquitination of drug-like small molecules by the ubiquitin ligase HUWE1.Nature communications · 2025Article
- Potentially actionable molecular alterations in particular related to poor oncologic outcomes in salivary gland carcinomas.BMC cancer · 2025Article
- Emerging opportunities to treat drug-resistant breast cancer: Discovery of novel small-molecule inhibitors against different targets.Frontiers in pharmacology · 2025Review
- The role of KDM4A-mediated histone methylation on temozolomide resistance in glioma cells through the HUWE1/ROCK2 axis.The Kaohsiung journal of medical sciences · 2024Article
- Protein degradation: expanding the toolbox to restrain cancer drug resistance.Journal of hematology & oncology · 2023Review
- The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress glioblastoma progression.Cancer communications (London, England) · 2022Article
- Review
- p53 Ubiquitination Comediated by HUWE1 and TRAF6 Contributes to White Spot Syndrome Virus Infection in Crustacean.Journal of virology · 2022Article
- SGK2, 14-3-3, and HUWE1 Cooperate to Control the Localization, Stability, and Function of the Oncoprotein PTOV1.Molecular cancer research : MCR · 2022Article
- The giant E3 ligase HUWE1 is linked to tumorigenesis, spermatogenesis, intellectual disability, and inflammatory diseases.Frontiers in cellular and infection microbiology · 2022Review
- Parthenolide and arsenic trioxide co-trigger autophagy-accompanied apoptosis in hepatocellular carcinoma cells.Frontiers in oncology · 2022Article
- Proteasome interaction with ubiquitinated substrates: from mechanisms to therapies.The FEBS journal · 2021Review
- The roles and regulation of MDM2 and MDMX: it is not just about p53.Genes & development · 2021Review
- HDAC2 links ubiquitination to tumor suppression in synovial sarcoma.Molecular & cellular oncology · 2021Article
- CIBERSORT analysis of TCGA and METABRIC identifies subgroups with better outcomes in triple negative breast cancer.Scientific reports · 2021Article
- E3 Ubiquitin Ligase in Anticancer Drugdsla Resistance: Recent Advances and Future Potential.Frontiers in pharmacology · 2021Review
- Direct regulation of Chk1 protein stability by E3 ubiquitin ligase HUWE1.The FEBS journal · 2020Article
- Targeting MDM2 for novel molecular therapy: Beyond oncology.Medicinal research reviews · 2020Review
- Carboxypeptidase E down-regulation regulates transcriptional and epigenetic profiles in pancreatic cancer cell line: A network analysis.Cancer biomarkers : section A of Disease markers · 2020Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
In the intrinsic pathway of apoptosis, cell-damaging signals promote the release of cytochrome c from mitochondria, triggering activation of the Apaf-1 and caspase-9 apoptosome. The ubiquitin E3 ligase MDM2 decreases the stability of the proapoptotic factor p53. We show that it also coordinated apoptotic events in a p53-independent manner by ubiquitylating the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. HUWE1 ubiquitylates the antiapoptotic factor Mcl-1, and we found that HUWE1 also ubiquitylated PP5 (protein phosphatase 5), which indirectly inhibited apoptosome activation. Breast cancers that are positive for the tyrosine receptor kinase HER2 (human epidermal growth factor receptor 2) tend to be highly aggressive. In HER2-positive breast cancer cells treated with the HER2 tyrosine kinase inhibitor lapatinib, MDM2 was degraded and HUWE1 was stabilized. In contrast, in breast cancer cells that acquired resistance to lapatinib, the abundance of MDM2 was not decreased and HUWE1 was degraded, which inhibited apoptosis, regardless of p53 status. MDM2 inhibition overcame lapatinib resistance in cells with either wild-type or mutant p53 and in xenograft models. These findings demonstrate broader, p53-independent roles for MDM2 and HUWE1 in apoptosis and specifically suggest the potential for therapy directed against MDM2 to overcome lapatinib resistance.
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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.