ArticleGenes & development2013
Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15.
Article in Genes & development, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers, 1 of them a synthesis that pooled it.
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Who cites it
84 citing papers in PubMed, 1 synthesis or guideline pooled it, 135 citations in OpenAlex.
- Clinical and Prognostic Implications ofDisease markers · 2020Pooled it
- Lysine deficiency within a conserved lysine desert is critical for EEL-1/HUWE1 to support ubiquitin proteasome system function.PLoS genetics · 2026Article
- PPIL2 suppression induces cellular senescence and inhibits proliferation in hepatocellular carcinoma via c-myc/p21 axis.The Journal of biological chemistry · 2026Article
- Lysine deficiency within a conserved lysine desert is critical for EEL-1/HUWE1 to support ubiquitin proteasome system function.bioRxiv : the preprint server for biology · 2025Article
- HUWE1 stimulates mTORC1 activity by enhancing Rheb interaction with mTORC1 and supports de novo pyrimidine synthesis.Cell reports · 2025Article
- PIN1 serves as a prognostic and therapeutic biomarker in lung adenocarcinoma.Functional & integrative genomics · 2025Article
- Sox2 interacts with Atoh1 and Huwe1 loci to regulate Atoh1 transcription and stability during hair cell differentiation.PLoS genetics · 2025Article
- Excessive MYC-topoisome activity triggers acute DNA damage, MYC degradation, and replacement by a p53-topoisome.Molecular cell · 2024Article
- Review
- Induced degradation of lineage-specific oncoproteins drives the therapeutic vulnerability of small cell lung cancer to PARP inhibitors.Science advances · 2024Article
- HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways.Cell reports · 2023Article
- MYC: a complex problem.Trends in cell biology · 2023Review
- Regulation of apoptosis by ubiquitination in liver cancer.American journal of cancer research · 2023Review
- The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress glioblastoma progression.Cancer communications (London, England) · 2022Article
- Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition.Oncogene · 2022Article
- No Time to Die: How Kidney Cancer Evades Cell Death.International journal of molecular sciences · 2022Review
- p53 Ubiquitination Comediated by HUWE1 and TRAF6 Contributes to White Spot Syndrome Virus Infection in Crustacean.Journal of virology · 2022Article
- The role of Ubiquitination in Apoptosis and Necroptosis.Cell death and differentiation · 2022Review
- The giant E3 ligase HUWE1 is linked to tumorigenesis, spermatogenesis, intellectual disability, and inflammatory diseases.Frontiers in cellular and infection microbiology · 2022Review
- Review
24 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
24 authors at 4 institutions in 3 countries.
Funding
Abstract
Tumorigenesis results from dysregulation of oncogenes and tumor suppressors that influence cellular proliferation, differentiation, apoptosis, and/or senescence. Many gene products involved in these processes are substrates of the E3 ubiquitin ligase Mule/Huwe1/Arf-BP1 (Mule), but whether Mule acts as an oncogene or tumor suppressor in vivo remains controversial. We generated K14Cre;Mule(flox/flox(y)) (Mule kKO) mice and subjected them to DMBA/PMA-induced skin carcinogenesis, which depends on oncogenic Ras signaling. Mule deficiency resulted in increased penetrance, number, and severity of skin tumors, which could be reversed by concomitant genetic knockout of c-Myc but not by knockout of p53 or p19Arf. Notably, in the absence of Mule, c-Myc/Miz1 transcriptional complexes accumulated, and levels of p21CDKN1A (p21) and p15INK4B (p15) were down-regulated. In vitro, Mule-deficient primary keratinocytes exhibited increased proliferation that could be reversed by Miz1 knockdown. Transfer of Mule-deficient transformed cells to nude mice resulted in enhanced tumor growth that again could be abrogated by Miz1 knockdown. Our data demonstrate in vivo that Mule suppresses Ras-mediated tumorigenesis by preventing an accumulation of c-Myc/Miz1 complexes that mediates p21 and p15 down-regulation.
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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.