UBE2Q1

UBE2Q1 is an E2 ubiquitin-conjugating enzyme that controls the abundance of substrate proteins to drive cell proliferation, survival, and tumorigenic signaling (PMID:25987028, PMID:29027712). Through its UBC domain it physically binds p53 and promotes p53 turnover, such that UBE2Q1 overexpression lowers p53 levels while its knockdown raises p53 and sensitizes cells to apoptotic signaling via bax, p21, and caspase-3 (PMID:25987028, PMID:24166684, PMID:37198983). Beyond p53, UBE2Q1 stabilizes β-catenin to activate HIF-1α-driven hypoxic glycolysis (Warburg effect) and engages the β-catenin–EGFR–PI3K–Akt–mTOR axis, thereby promoting proliferation, S-phase entry, migration/invasion through EMT, and in vivo tumorigenicity in hepatocellular and colorectal cancer models (PMID:29027712, PMID:27602158, PMID:35156520). It also interacts with DDX3 and regulates its ubiquitination in CML cells, where pharmacologic depletion of UBE2Q1 triggers mitochondrial apoptosis (PMID:39454411). UBE2Q1 expression is held in check post-transcriptionally by miR-338-3p binding to its 3'-UTR (PMID:35156520, PMID:33770685). Genetically, Ube2q1-knockout female mice display pleiotropic reproductive defects — altered oestrus, impaired embryo implantation, and increased embryonic lethality — establishing a required physiological role in female fertility (PMID:23108111). Direct enzymatic demonstration of substrate ubiquitination by UBE2Q1 has not been reported in the available corpus; substrate degradation is inferred from gain/loss-of-function effects on protein abundance.

1. 2013 High

   Established that UBE2Q1 is genetically required for a physiological process, defining female fertility as an in vivo function rather than only a cancer-cell phenotype.

   Evidence Ube2q1 knockout mouse with multi-parameter reproductive phenotyping and uterine expression analysis

   PMID:23108111

   Open questions at the time

   • The molecular substrate(s) mediating the reproductive defect are not identified
   • Does not connect the fertility phenotype to any specific ubiquitination event
2. 2013 Medium

   Linked UBE2Q1 to p53 abundance in a neuronal context, showing bidirectional control (knockdown raises, overexpression lowers p53) with downstream apoptotic readouts.

   Evidence siRNA knockdown and overexpression in PC12 cells plus immunostaining in rat cortex

   PMID:24166684

   Open questions at the time

   • No direct ubiquitination assay demonstrating UBE2Q1 conjugates ubiquitin to p53
   • Nuclear localization shown but not functionally tied to p53 regulation
3. 2015 Medium

   Provided direct binding evidence that UBE2Q1 physically associates with p53, supporting a substrate relationship underlying p53 destabilization.

   Evidence Co-IP and GST pull-down with overexpression in MDA-MB-468 breast cancer cells

   PMID:25987028

   Open questions at the time

   • Degradation mechanism inferred from protein levels, not shown by a ubiquitination assay
   • Single lab, single tumor type
4. 2016 Medium

   Demonstrated a direct cell-cycle role: UBE2Q1 gain-of-function pushes cells from G0/G1 into S phase and increases proliferation and motility.

   Evidence Stable overexpression in SW1116 colorectal cells with MTT, colony, flow cytometry, and wound-healing assays

   PMID:27602158

   Open questions at the time

   • Does not identify the substrate driving cell-cycle progression
   • Correlative pathway link not established here
5. 2017 Medium

   Connected UBE2Q1 to oncogenic signaling, showing loss-of-function reduces proliferation/invasion and tumorigenicity through the β-catenin–EGFR–PI3K–Akt–mTOR axis.

   Evidence siRNA knockdown with in vitro phenotyping, orthotopic xenografts, and pathway Western blots in HCC lines

   PMID:29027712

   Open questions at the time

   • Mechanism by which UBE2Q1 engages the β-catenin axis not defined
   • GADD45α induction mechanism unresolved
6. 2021 Medium

   Identified the upstream regulatory input controlling UBE2Q1, establishing miR-338-3p as a direct 3'-UTR-targeting repressor with functional consequences for autophagy.

   Evidence Luciferase 3'-UTR reporter, overexpression rescue, and in vivo AR rat model in nasal epithelial cells

   PMID:33770685

   Open questions at the time

   • Does not address ubiquitination substrates downstream of UBE2Q1
   • Effect mediated via AKT/mTOR but proximal target unknown
7. 2022 Medium

   Defined a metabolic output: UBE2Q1 stabilizes β-catenin to activate HIF-1α and hypoxic glycolysis, situating it downstream of miR-338-3p in colorectal cancer.

   Evidence Knockdown/overexpression, glycolysis assays under hypoxia, Western blots, and in vivo tumor model

   PMID:35156520

   Open questions at the time

   • β-catenin stabilization inferred from protein levels without direct ubiquitination assay
   • Whether UBE2Q1 acts directly on β-catenin or via an intermediate is unresolved
8. 2023 Low

   Mapped the structural basis of substrate recognition, localizing B4GALT1 and p53 binding to the UBC domain and identifying hot-spot regions.

   Evidence Co-IP with silver staining plus molecular docking of UBC domain against B4GALT1 and p53

   PMID:37198983

   Open questions at the time

   • Computational docking without functional ubiquitination validation
   • Single cell line; predicted interfaces not experimentally mutated
9. 2024 Medium

   Expanded the substrate repertoire to DDX3 and showed UBE2Q1 is a druggable node, with bortezomib depleting it to trigger mitochondrial apoptosis in resistant CML cells.

   Evidence Co-IP of UBE2Q1–DDX3, ubiquitination and apoptosis readouts, and xenograft model in BCR::ABL T315I cells

   PMID:39454411

   Open questions at the time

   • Whether bortezomib directly targets UBE2Q1 versus indirectly reducing its level is unclear
   • Direct E2 catalytic activity on DDX3 not reconstituted

• Whether UBE2Q1 directly catalyzes ubiquitin transfer to its named partners (p53, β-catenin, DDX3, B4GALT1) and which E3 ligases it pairs with remain unestablished.
• No in vitro reconstituted ubiquitination assay for any proposed substrate
• Cognate E3 ligase partner(s) unidentified
• Substrate degradation throughout is inferred from steady-state protein levels