ArticleCellular and molecular gastroenterology and hepatology2022
UBCH5 Family Members Differentially Impact Stabilization of Mutant p53 via RNF128 Iso1 During Barrett's Progression to Esophageal Adenocarcinoma.
Article in Cellular and molecular gastroenterology and hepatology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 11 citations in OpenAlex.
- Ubiquitin-conjugating Enzymes in Cancer.International journal of biological sciences · 2026Review
- Targeting the Ubiquitin-conjugating Enzyme for Oral Squamous Cell Carcinoma Therapy: Discovering Natural Inhibitors.Current computer-aided drug design · 2026Article
- Gastric Proton Pumpopathy Associated with Protein Sorting Machinery: A Narrative Review.Clinical and experimental gastroenterology · 2026Review
- IFN-γ-driven UBE2D3 upregulation impairs antigen presentation pathways and anti-tumor immunity in pancreatic cancer.Nature communications · 2025Article
- Downregulation of RNF128 Inhibits the Proliferation, Migration, Invasion and EMT of Colorectal Cancer Cells.Biochemical genetics · 2025Article
- Differences in Gender and Overall Survival for Temperature-Sensitive TP53 Mutations in Gastroesophageal Cancer.Medicina (Kaunas, Lithuania) · 2024Article
- GRAIL1 Stabilizes Misfolded Mutant p53 through a Ubiquitin Ligase-Independent, Chaperone Regulatory Function.Molecular cancer research : MCR · 2024Article
- ISG15/GRAIL1/CD3 axis influences survival of patients with esophageal adenocarcinoma.JCI insight · 2024Article
- Isoform alterations in the ubiquitination machinery impacting gastrointestinal malignancies.Cell death & disease · 2024Review
- IGF2BP2-modified UBE2D1 interacts with Smad2/3 to promote the progression of breast cancer.American journal of cancer research · 2023Article
- High UBE2D1 expression is associated with poor prognosis and immunotherapy resistance in head and neck cancer.Journal of oral biology and craniofacial researchArticle
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsTP53 mutations underlie Barrett's esophagus (BE) progression to dysplasia and cancer. During BE progression, the ubiquitin ligase (E3) RNF128/GRAIL switches expression from isoform 2 (Iso2) to Iso1, stabilizing mutant p53. However, the ubiquitin-conjugating enzyme (E2) that partners with Iso1 to stabilize mutant p53 is unknown.
methodsSingle-cell RNA sequencing of paired normal esophagus and BE tissues identified candidate E2s, further investigated in expression data from BE to esophageal adenocarcinoma (EAC) progression samples. Biochemical and cellular studies helped clarify the role of RNF128-E2 on mutant p53 stability.
resultsThe UBE2D family member 2D3 (UBCH5C) is the most abundant E2 in normal esophagus. However, during BE to EAC progression, loss of UBE2D3 copy number and reduced expression of RNF128 Iso2 were noted, 2 known p53 degraders. In contrast, expression of UBE2D1 (UBCH5A) and RNF128 Iso1 in dysplastic BE and EAC forms an inactive E2-E3 complex, stabilizing mutant p53. To destabilize mutant p53, we targeted RNF128 Iso1 either by mutating asparagine (N48, 59, and 101) residues to block glycosylation to facilitate β-TrCP1-mediated degradation or by mutating proline (P54 and 105) residues to restore p53 polyubiquitinating ability. In addition, either loss of UBCH5A catalytic activity, or disruption of the Iso1-UBCH5A interaction promoted Iso1 loss. Consequently, overexpression of either catalytically dead or Iso1-binding-deficient UBCH5A mutants destabilized Iso1 to degrade mutant p53, thus compromising the clonogenic survival of mutant p53-dependent BE cells.
conclusionsLoss of RNF128 Iso2-UBCH5C and persistence of the Iso1-UBCH5A complex favors mutant p53 stability to promote BE cell survival. Therefore, targeting of Iso1-UBCH5A may provide a novel therapeutic strategy to prevent BE progression.
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