Affinage

SIAH1

E3 ubiquitin-protein ligase SIAH1 · UniProt Q8IUQ4

Length
282 aa
Mass
31.1 kDa
Annotated
2026-04-28
100 papers in source corpus 46 papers cited in narrative 46 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIAH1 is a RING-finger E3 ubiquitin ligase that functions as a central effector linking stress-response signaling to targeted protein degradation across diverse cellular pathways including Wnt/β-catenin regulation, apoptosis, mitophagy, and the DNA damage response. Its N-terminal RING domain catalyzes ubiquitination and auto-ubiquitination, while its C-terminal substrate-binding domain dimerizes and, often scaffolded by SIP/CacyBP and Skp1, recruits a broad substrate repertoire—including β-catenin, HIPK2, α-synuclein, synphilin-1, Numb, ELL1/2, Akt3, YAP, and others—for proteasomal degradation or non-degradative ubiquitination (PMID:9858595, PMID:11389839, PMID:16085652, PMID:18065497, PMID:31471318, PMID:35723276). S-nitrosylation of GAPDH triggers formation of a GAPDH–Siah1 complex that translocates to the nucleus via Siah1's NLS, initiating an apoptotic cascade involving nuclear protein degradation, a pathway modulated by B23 trans-nitrosylation and ASK1 phosphorylation of Siah1 (PMID:15951807, PMID:23027902, PMID:25391652). SIAH1 activity is regulated at multiple levels: ATM/ATR phosphorylation at Ser19 disrupts HIPK2 binding to permit apoptotic signaling after DNA damage, Aurora kinase phosphorylation of substrates like EB3 controls cell-cycle-dependent degradation, competing binding partners (TBL1, HCF1/2, EEF1D) block substrate access, and transcriptional control by p53, E2F1, UPR transducers (PERK/ATF4, IRE1/sXBP1), and epigenetic silencing by EHMT2 tunes Siah1 protein levels (PMID:18536714, PMID:19696028, PMID:20181957, PMID:32479599, PMID:24809345, PMID:20187294, PMID:21847359).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 High

    Establishing SIAH1 as a RING-dependent E3 ubiquitin ligase with auto-ubiquitination capacity resolved the fundamental question of how this Drosophila Sina homolog controls substrate proteolysis in mammalian cells.

    Evidence Mutagenesis of RING domain and C-terminal substrate-binding domain, proteasome inhibitor assays, DCC degradation assay

    PMID:9858595

    Open questions at the time
    • No E2 partner identified at this stage
    • Crystal structure of full-length SIAH1 not available
    • Mechanism of auto-ubiquitination versus substrate ubiquitination not distinguished
  2. 2001 High

    Discovery that SIAH1 assembles an SCF-like complex (with SIP, Skp1, Ebi, and APC) to degrade β-catenin independently of GSK3β phosphorylation established a p53-induced alternative route for Wnt pathway antagonism.

    Evidence Co-IP, protein interaction mapping, β-catenin degradation assays, p53 induction, Xenopus embryo dorsalization assay

    PMID:11389839 PMID:11389840

    Open questions at the time
    • Relative contribution of Siah1 vs. GSK3β-dependent degradation in physiological contexts unclear
    • Whether APC and Ebi are simultaneously required in all tissues not resolved
  3. 2001 High

    Identification of Numb and OBF-1 as SIAH1 substrates demonstrated that SIAH1-mediated degradation extends to Notch signaling and B-cell transcription, broadening the ligase's functional scope beyond Wnt.

    Evidence Co-IP, degradation assays, Notch signaling reporter, octamer-dependent transcription reporter, proteasome inhibitor

    PMID:11483517 PMID:11752454

    Open questions at the time
    • In vivo Notch phenotype in Siah1 knockout not shown
    • OBF-1 finding from single lab
  4. 2002 High

    Structural determination of the SIAH1 dimer revealed a large electronegative β-sheet concavity as the SIP-binding surface, providing the first structural framework for understanding substrate recruitment.

    Evidence X-ray crystallography, structure-guided mutagenesis abolishing SIP binding in vitro and in cells

    PMID:12421809

    Open questions at the time
    • RING domain and zinc finger regions not resolved in this structure
    • How dimer interface contributes to substrate selectivity not defined
  5. 2003 High

    Demonstration that SIAH1 ubiquitinates synphilin-1 for proteasomal degradation—more efficiently than Parkin—and that the interaction occurs endogenously in brain tissue linked SIAH1 to Parkinson's disease-relevant protein quality control.

    Evidence Yeast two-hybrid, endogenous Co-IP in rat brain, ubiquitination assay, domain mapping, dopamine release assay

    PMID:14506261

    Open questions at the time
    • Whether SIAH1 loss phenocopies Parkin loss in vivo not tested
    • Lewy body localization of SIAH1 not examined
  6. 2005 High

    The discovery that S-nitrosylation of GAPDH triggers GAPDH–Siah1 complex formation and nuclear translocation to initiate apoptosis established a novel nitric oxide–dependent cell death pathway mediated by SIAH1's NLS.

    Evidence Co-IP, S-nitrosylation assays, nuclear fractionation, NO deletion experiments in macrophages and neurons

    PMID:15951807

    Open questions at the time
    • Nuclear substrates degraded by the GAPDH–Siah1 complex not identified
    • Whether this pathway operates in non-neuronal tissues in vivo unclear
  7. 2005 High

    Crystal structure of the SIP–Siah1 complex showed how SIP's PXAXVXP motif legs straddle the Siah1 dimer surface while projecting a Skp1-binding domain, explaining the SCF-like E3 assembly geometry.

    Evidence Crystal structure, site-directed mutagenesis, cell-based functional assay

    PMID:16085652

    Open questions at the time
    • Full quaternary architecture including Skp1 and substrate not structurally resolved
    • How different substrates engage the same scaffold not determined
  8. 2007 High

    Showing that SIAH1 mono- and di-ubiquitinates α-synuclein in a non-degradative manner that promotes aggregation and toxicity—disrupted by the PD-linked A30P mutation—revealed a pathogenic ubiquitination mode distinct from proteasomal targeting.

    Evidence Co-IP, in vivo ubiquitination with E2 UbcH8 identification, PD mutant analysis, aggregation and viability assays

    PMID:18065497

    Open questions at the time
    • Ubiquitin chain linkage type on α-synuclein not determined
    • Whether this modification occurs in patient brains not verified
  9. 2008 High

    Discovery that ATM/ATR phosphorylation of SIAH1 at Ser19 disrupts HIPK2 binding and stabilizes HIPK2 for apoptotic signaling revealed how the DNA damage response directly modulates SIAH1 substrate access.

    Evidence Co-IP, ubiquitination assay, kinase assay, phospho-site mutagenesis, Siah1 knockdown

    PMID:18536714

    Open questions at the time
    • Whether Ser19 phosphorylation affects other SIAH1 substrates not tested
    • Structural basis of phosphorylation-induced complex disruption unknown
  10. 2009 High

    Identification of Aurora kinase-mediated EB3 phosphorylation as a signal to release EB3 from SIAH1 during mitosis demonstrated cell-cycle-dependent regulation of SIAH1 substrate targeting.

    Evidence Co-IP, ubiquitination assay, kinase assay, phospho-site mutagenesis (Ser176), SIAH1 knockdown

    PMID:19696028

    Open questions at the time
    • Other mitotic substrates regulated similarly not surveyed
    • Mitotic phenotype of Siah1 depletion incompletely characterized
  11. 2010 High

    Reconstitution of SIAH1-mediated polyubiquitination of non-phosphorylated β-catenin with purified proteins, and discovery that TBL1 competitively protects β-catenin during Wnt signaling, clarified the molecular logic of Wnt-dependent substrate shielding.

    Evidence In vitro ubiquitination with purified components, Co-IP, proteasomal degradation assay in cells

    PMID:20181957

    Open questions at the time
    • Whether TBL1 competition operates in all Wnt-responsive tissues not shown
    • Structural basis of TBL1–β-catenin competition with SIAH1 unknown
  12. 2011 High

    Identification of ELL1/ELL2 as SIAH1 substrates regulated by acetylation/deacetylation crosstalk (p300/HDAC3), with AFF4-bound ELL2 in the Super Elongation Complex being protected from SIAH1, linked SIAH1 to transcriptional elongation control and HIV-1 latency reversal.

    Evidence Co-IP, ubiquitination assay, acetylation assay, SEC assembly analysis, HIV-1 transcription assays

    PMID:22483617 PMID:32152128

    Open questions at the time
    • Whether SIAH1 targets other SEC components not assessed
    • In vivo relevance for HIV latency reversal not tested in animal models
  13. 2012 High

    Discovery that nuclear B23/nucleophosmin is trans-S-nitrosylated by GAPDH, enhancing B23–SIAH1 binding and disrupting the GAPDH–SIAH1 complex to suppress SIAH1 ligase activity, revealed a negative feedback loop providing neuroprotection.

    Evidence Co-IP, S-nitrosylation assay, C275S mutagenesis, NMDA neurotoxicity model in vivo

    PMID:23027902

    Open questions at the time
    • Whether other nuclear proteins undergo similar trans-nitrosylation-dependent regulation of SIAH1 unknown
    • Quantitative contribution of B23 pathway versus other SIAH1 regulators not determined
  14. 2014 High

    Demonstration that UPR transducers PERK/ATF4 and IRE1/sXBP1 induce SIAH1 transcription, and that SIAH1 stabilizes ATF4 by attenuating its proline hydroxylation, established a positive feedback loop amplifying ER stress-induced cell death, validated by reduced ischemic infarct in Siah-deficient mice.

    Evidence UPR pathway epistasis, siRNA knockdown, Siah1a+/−::Siah2−/− knockout mice, neuronal ischemia model

    PMID:24809345

    Open questions at the time
    • Whether ATF4 is a direct SIAH1 ubiquitination substrate or indirectly stabilized not fully resolved
    • Contribution of Siah1 vs. Siah2 in the ischemic phenotype not separated
  15. 2016 High

    Discovery that synphilin-1 recruits SIAH1 to mitochondria in a PINK1-dependent manner to drive parkin-independent mitophagy established SIAH1 as an alternative mitophagy E3 ligase.

    Evidence Co-IP, LC3/Lamp1 recruitment, Atg5 knockdown epistasis, catalytically dead SIAH1 mutant, PINK1 disease mutant analysis

    PMID:27334109

    Open questions at the time
    • Mitochondrial substrates ubiquitinated by SIAH1 during mitophagy not identified
    • Physiological significance relative to Parkin-dependent mitophagy not quantified
  16. 2019 High

    Demonstration of isoform-selective Akt3 ubiquitination by SIAH1—with the somatic E17K mutation escaping degradation and causing dysmorphic neurons—linked SIAH1 substrate selectivity to a specific neurodevelopmental pathology.

    Evidence Co-IP, ubiquitination assay, Akt isoform selectivity analysis, Akt3-E17K mutant, neural morphology assay

    PMID:31471318

    Open questions at the time
    • Structural basis for Akt3 selectivity over Akt1/2 not determined
    • Whether other brain somatic mutations escape SIAH1 degradation not explored
  17. 2020 Medium

    Identification of HCF1/HCF2 as SIAH1 substrate-binding domain blockers that prevent both auto-ubiquitination and ELL2 degradation refined the model of competitive inhibition regulating SIAH1 ligase output.

    Evidence Co-IP, ubiquitination assay, ELL2 stability assay, SEC assembly, HIV-1 transactivation assay

    PMID:32479599

    Open questions at the time
    • Whether HCF1/2 protect all SIAH1 substrates or only ELL2 not tested
    • Single-lab finding
  18. 2022 Medium

    Expansion of SIAH1 substrate repertoire to include YBX-1 (at mapped Lys304), TRF2, XIAP, and phospho-YAP connected SIAH1-mediated ubiquitination to RNA modification, telomere maintenance, anti-apoptotic signaling, and Hippo pathway tumor suppression.

    Evidence Co-IP, ubiquitination assays with specific lysine mapping, phospho-site mutagenesis (YAP), in vivo xenograft (glioblastoma), senescence assays

    PMID:35261172 PMID:35273154 PMID:35580525 PMID:35723276

    Open questions at the time
    • Most findings from individual labs awaiting independent replication
    • Relative physiological importance of these substrates versus canonical SIAH1 targets not ranked
    • Tissue specificity of each substrate relationship not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full structural basis for SIAH1's remarkably broad substrate selectivity, the relative contributions of Siah1 versus Siah2 in overlapping pathways, and whether SIAH1 plays non-catalytic scaffolding roles independent of its E3 ligase activity.
  • No full-length SIAH1 structure with RING domain, zinc fingers, and substrate simultaneously resolved
  • Systematic substrate identification (e.g., ubiquitin remnant profiling in SIAH1-null cells) not performed
  • In vivo phenotype of Siah1-specific knockout (separated from Siah2) in adult tissues poorly characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016874 ligase activity 4
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-392499 Metabolism of proteins 7 R-HSA-162582 Signal Transduction 6 R-HSA-5357801 Programmed Cell Death 5 R-HSA-1640170 Cell Cycle 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-9612973 Autophagy 1
Partners
APCCACYBPCTNNB1ELL2GAPDHHIPK2NPM1SNCAIP
Complex memberships
GAPDH-Siah1 nuclear translocation complexPINK1-synphilin-1-SIAH1 mitophagy complexSiah1-SIP/CacyBP-Skp1-Ebi SCF-like complex

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 S-nitrosylation of GAPDH at Cys-150 triggers its binding to Siah1; Siah1's nuclear localization signal mediates nuclear translocation of the GAPDH-Siah1 complex, where Siah1 stabilizes GAPDH and facilitates degradation of nuclear proteins, initiating apoptotic cell death. Co-IP, S-nitrosylation assay, nuclear fractionation, NO deletion experiments in macrophages and neurons Nature cell biology High 15951807
2001 Siah-1 forms a multiprotein SCF-like E3 ligase complex with SIP (a Sgt1 homolog that binds Skp1) and the F-box protein Ebi to degrade beta-catenin independently of GSK3beta-mediated phosphorylation; Siah-1 expression is induced by p53, linking genotoxic stress to beta-catenin destruction. Co-IP, protein interaction mapping, beta-catenin degradation assay, p53 induction assay Molecular cell High 11389839 11389840
2001 Siah-1 interacts with the C-terminus of APC and promotes phosphorylation-independent, beta-TrCP-independent degradation of beta-catenin; demonstrated functionally by hypodorsalization of Xenopus embryos. Co-IP, beta-catenin degradation assay, Xenopus embryo functional assay Molecular cell High 11389840
1999 Siah-1 N-terminal RING finger domain is required for proteolysis of target proteins (e.g., DCC); C-terminal domain mediates oligomerization with itself and other Sina/Siah proteins and binding to substrates. RING domain mutations stabilize Siah-1 itself, indicating auto-ubiquitination. A dominant-negative C-terminal mutant stabilizes DCC endogenously. Mutagenesis, proteasome inhibitor assays, DCC degradation assay, antisense approach Molecular and cellular biology High 9858595
2008 Siah-1 directly interacts with and polyubiquitinates HIPK2, targeting it for proteasomal degradation in unstressed cells. DNA damage triggers ATM/ATR-dependent phosphorylation of Siah-1 at Ser19, disrupting the HIPK2-Siah-1 complex and stabilizing HIPK2 for apoptotic signaling. Co-IP, ubiquitination assay, Siah-1 knockdown, kinase assay, phospho-site mutagenesis Nature cell biology High 18536714
2016 PINK1, synphilin-1, and SIAH-1 form a complex constituting a parkin-independent mitophagy pathway: synphilin-1 recruits SIAH-1 to mitochondria where it promotes mitochondrial protein ubiquitination and mitophagy; catalytically inactive SIAH-1 mutant abrogates this pathway. Co-IP, LC3/Lamp1 recruitment assay, Atg5 knockdown, catalytic-dead mutant, PINK1 disease mutant analysis Human molecular genetics High 27334109
2007 Siah-1 binds alpha-synuclein, recruits E2 enzyme UbcH8, and catalyzes mono- and di-ubiquitination of alpha-synuclein in vivo; this ubiquitination does not target alpha-synuclein for proteasomal degradation but promotes its aggregation and cytotoxicity. The PD-linked A30P mutation disrupts Siah-1-mediated ubiquitination. Co-IP, in vivo ubiquitination assay, PD mutant analysis, aggregation assay, cell viability assay Human molecular genetics High 18065497
2003 Siah-1 interacts with synphilin-1 via its substrate-binding domain (C-terminus of Siah-1 binds N-terminus of synphilin-1) and ubiquitinates synphilin-1 via its RING finger domain, promoting synphilin-1 degradation via the ubiquitin-proteasome pathway more efficiently than Parkin; Siah-1 abrogates synphilin-1's inhibitory effect on dopamine release. Yeast two-hybrid, Co-IP in rat brain, ubiquitination assay, domain mapping, dopamine release assay The Journal of biological chemistry High 14506261
2010 Siah-1 alone can directly polyubiquitinate non-phosphorylated beta-catenin in vitro; TBL1 competes with Siah-1 for the same armadillo repeat domain of beta-catenin, protecting it from Siah-1-mediated ubiquitination and proteasomal degradation during Wnt signaling. In vitro ubiquitination assay with purified proteins, Co-IP, proteasomal degradation assay The Journal of biological chemistry High 20181957
2005 SIP engages Siah1 via two elements: an N-terminal dimerization domain that sits across the saddle-shaped upper surface of Siah1 with PXAXVXP motif legs, and a C-terminal Skp1-binding domain that protrudes from the lower surface of Siah1, forming the scaffold for bringing substrate and E2 into apposition. Crystal structure, site-directed mutagenesis, functional cell-based assay The Journal of biological chemistry High 16085652
2002 Structural analysis of Siah1 dimer reveals a large electronegative beta-sheet concavity across the dimer interface that mediates interaction with SIP; site-directed mutagenesis of these electronegative residues abolishes Siah1-SIP binding in vitro and in cells. Structure-based approach, site-directed mutagenesis, in vitro and cell binding assays The Journal of biological chemistry High 12421809
2001 Siah-1 directly interacts with and promotes proteasomal degradation of the cell fate regulator Numb; Siah-1-mediated Numb degradation causes redistribution of Notch from cell surface to cytoplasm/nucleus and augments Notch-regulated transcriptional activity. Co-IP, pulldown, degradation assay, Notch signaling reporter assay Proceedings of the National Academy of Sciences of the United States of America High 11752454
2001 Siah-1 interacts with the transcriptional coactivator OBF-1 via its C-terminal domain; this interaction leads to proteasomal degradation of OBF-1 protein and reduction in octamer site-dependent transcription. Inhibition of ubiquitin-proteasome pathway elevates OBF-1 protein in B cells. Co-IP, domain mapping, OBF-1 degradation assay, transcription reporter assay, proteasome inhibitor The EMBO journal High 11483517
2012 Siah1 is the E3 ubiquitin ligase for ELL2 polyubiquitination and proteasomal degradation; Siah1 cannot access ELL2 bound to AFF4 within the Super Elongation Complex (SEC). Prostratin and HMBA activate HIV transcription by decreasing Siah1 expression and ELL2 polyubiquitination. Co-IP, in vivo ubiquitination assay, SEC assembly assay, Siah1 knockdown/overexpression Molecular cell High 22483617
2005 Siah1 is a binding partner of POSH scaffold protein; Siah1 contributes to apoptosis by activating the JNK pathway in a manner requiring its E3 ligase activity. Apoptotic stimuli stabilize Siah1 protein via JNK pathway activation and POSH interaction; SIAH1 stabilization is enhanced by phosphorylation at Tyr100 and Tyr126. Co-IP, JNK pathway assays, siRNA knockdown, phospho-site analysis, cell death assays The Journal of biological chemistry High 16230351
2000 SIAH-1 interacts with alpha-tubulin and degrades the chromokinesin Kid via the ubiquitin-proteasome pathway during mitosis; N-terminal RING domain is required for Kid degradation. SIAH-1 overexpression causes mitotic alterations including multinucleated giant cells. Yeast two-hybrid, ubiquitin-proteasome degradation assay, N-terminal deletion mutant, confocal microscopy Oncogene Medium 11146551
2009 SIAH-1 facilitates EB3 polyubiquitination and proteasomal degradation; Aurora-A and Aurora-B phosphorylate EB3 at Ser-176 during mitosis, triggering disruption of the EB3-SIAH-1 complex and EB3 stabilization during mitosis with subsequent degradation at G1. Co-IP, ubiquitination assay, SIAH-1 knockdown, kinase assay, phospho-site mutagenesis The Journal of biological chemistry High 19696028
2006 Siah-1 interacts with and ubiquitinates FIH (factor inhibiting HIF-1alpha) via its RING finger domain, binding the JmjC domain of FIH through its substrate-binding domain, and promotes FIH degradation via the ubiquitin-proteasome pathway, thereby regulating HIF-1alpha transcriptional activity. Co-IP, ubiquitination assay, domain mapping, Siah-1 siRNA knockdown, proteasome inhibitor Biochemical and biophysical research communications Medium 17188242
2006 EBV LMP1 up-regulates Siah1 E3 ubiquitin ligase by enhancing its stability; elevated Siah1 then promotes proteasomal degradation of prolyl hydroxylases PHD1 and PHD3, preventing VHL/HIF-1alpha complex formation and stabilizing HIF-1alpha to drive angiogenesis. Co-IP, proteasomal degradation assay, Siah1 knockdown/overexpression, VHL co-IP Cancer research Medium 17047048
2003 SIAH1 interacts with and promotes ubiquitin-proteasome-mediated degradation of CtIP (CtBP-interacting protein); SIAH-1 interaction with CtIP leads to p21(Waf1) induction, but this induction does not require CtIP degradation (a RING-deleted mutant also induces p21). Yeast two-hybrid, Co-IP, ubiquitination/degradation assay, RING deletion mutant, luciferase reporter Oncogene Medium 14654780
2004 SIAH1 binds an octapeptide sequence in T-STAR and targets it for proteasome-dependent degradation; rodent T-STAR orthologs are not degraded unless humanized at the SIAH1-binding site. SIAH1-mediated T-STAR degradation modulates alternative splicing activity. Yeast two-hybrid, domain/peptide mapping, degradation assay, alternative splicing minigene assay Human molecular genetics High 15163637
2008 SIAH1 interacts with and ubiquitinates TRB3 (Tribbles 3 homolog), targeting it for proteasome-dependent degradation; SIAH1-induced degradation of TRB3 counteracts TRB3-mediated upregulation of TGF-beta signaling. Yeast two-hybrid, Co-IP, ubiquitination assay, TGF-beta signaling reporter Cellular signalling Medium 18276110
2011 Siah-1 polyubiquitinates and promotes proteasomal degradation of ELL (ELL1), regulated by site-specific acetylation (p300-mediated) and deacetylation (HDAC3-mediated) of ELL; acetylated ELL is more stable because deacetylation by HDAC3 enables Siah1-mediated polyubiquitination. DBC1 competes with HDAC3 for ELL binding, stabilizing ELL. Co-IP, ubiquitination assay, acetylation assay, siRNA knockdown, domain competition assay Proceedings of the National Academy of Sciences of the United States of America High 32152128
2011 Siah-1 polyubiquitinates PML-RARα for proteasomal degradation together with E2 enzyme UBCH8; this is distinct from TRIAD1, which binds but does not degrade PML-RARα. Co-IP, ubiquitination assay, comparison with TRIAD1 The international journal of biochemistry & cell biology Medium 22037423
2011 SIAH-1 interacts with and promotes proteasomal degradation of HBx (hepatitis B viral X protein) via polyubiquitylation, thereby attenuating HBx-dependent transactivation of GRE, HSE, and CRE signal pathways; SIAH-1 participates in p53-mediated HBx degradation. Co-IP, ubiquitination assay, transcriptional reporter assay, p53 pathway analysis FEBS letters Medium 21878328
2004 Siah-1 interacts with the intracellular C-terminal domain of polycystin-1 and promotes its ubiquitination and proteasomal degradation, shortening its half-life. Yeast two-hybrid, Co-IP, ubiquitination assay, half-life assay Journal of the American Society of Nephrology Medium 15284290
2011 SIAH-1 interacts with and promotes ubiquitylation and proteasomal degradation of HSV ICP0; the virus-host interaction stabilizes SIAH-1 and recruits it into ICP0-containing nuclear bodies. Knockdown of SIAH-1 increases ICP0 levels and stability. Co-IP, in vitro and in vivo ubiquitination assay, SIAH-1 knockdown, nuclear body imaging Journal of virology Medium 21632771
2009 Siah1, interacting with Siah-interacting protein (SIP/CacyBP), promotes proteasome-dependent degradation of cytoplasmic p27 under glucose starvation, thereby regulating cell motility. SIP-/- fibroblasts have increased cytoplasmic p27 and enhanced cell motility. Ubiquitination assay, SIP-/- MEFs, glucose starvation, cell motility assay Cell cycle Medium 21734459
2014 High levels of ER stress induce Siah1/2 transcription via PERK/ATF4 and IRE1/sXBP1 UPR transducers; Siah1/2 in turn attenuates proline hydroxylation of ATF4, stabilizing it and augmenting ER stress-induced cell death. Siah1a+/-::Siah2-/- mice show reduced infarct volume after neuronal ischemia. UPR pathway analysis, siRNA knockdown, Siah1a/2 knockout mice, ischemia model PLoS genetics High 24809345
2009 siah-1 is required for high glucose-induced GAPDH nuclear accumulation and cell death in Müller cells; under hyperglycemic conditions, siah-1 forms a complex with GAPDH and localizes predominantly in the nucleus. Siah-1 knockdown prevents GAPDH nuclear accumulation and inhibits p53 phosphorylation and cell death. siRNA knockdown, Co-IP, nuclear fractionation, apoptosis assay, p53 phosphorylation assay The Journal of biological chemistry High 19940145
2012 B23/nucleophosmin binds both SIAH1 and GAPDH in the nucleus; S-nitrosylation of B23 at Cys275 (by trans-nitrosylation from GAPDH) enhances B23-SIAH1 binding, disrupts SIAH1-GAPDH complex, and abrogates SIAH1 E3 ligase activity, providing neuroprotection. Co-IP, S-nitrosylation assay, site-directed mutagenesis (C275S), in vivo NMDA neurotoxicity model The Journal of cell biology High 23027902
2014 ASK1 (apoptosis signal-regulating kinase 1) interacts with both GAPDH and Siah1; ASK1 phosphorylates Siah1 at Thr70/Thr74 and Thr235/Thr239, triggering GAPDH-Siah1 stress signaling and activating nuclear p300 acetyltransferase. Co-IP, in vitro kinase assay, phospho-site mutagenesis, p300 activation assay The Journal of biological chemistry Medium 25391652
2008 S100A6 interacts with the SIP C-terminal domain (residues 189-219) in a bimodal fashion determined by NMR structure; the first helix binds S100A6 canonically while the second helix contacts the S100A6 dimer interface in a novel mode. S100A6-SIP interaction modulates SCF-TBL1 E3 ligase activity. NMR structure, isothermal titration calorimetry, structure-based mutagenesis, cell-based functional assay Biochemistry High 18803400
2018 PARP1 suppresses Siah1 expression at both mRNA level (coordinating with co-repressor NCoR) and protein level (promoting PARylation-dependent ubiquitination/proteolysis of Siah1), thereby increasing ELL2 levels and promoting HIV-1 transcription via ELL2-SEC. Siah1 mRNA/protein level assays, NCoR Co-IP, PARylation assay, HIV-1 transcription assay Cell reports Medium 29949759
2020 Host cell factors HCF1 and HCF2 bind and block the substrate-binding domain (SBD) of Siah1/2 to prevent auto-ubiquitination and trans-ubiquitination of ELL2, stabilizing ELL2 and enhancing ELL2-SEC formation for HIV-1 transactivation. Co-IP, ubiquitination assay, ELL2 stability assay, SEC assembly assay, HIV-1 transactivation assay Nucleic acids research Medium 32479599
2020 SIAH1 binds to and ubiquitinates MyD88, targeting it for proteasomal degradation; SIAH1 knockdown increases MyD88-dependent TLR7 signaling and reduces DENV2 replication. SIAH1 is induced during dengue infection via UPR activation. Co-IP, ubiquitination assay, CRISPR MyD88 knockout, siRNA knockdown, viral replication assay Frontiers in microbiology Medium 32117091
2011 EHMT2 (G9a) suppresses SIAH1 transcription by binding to the SIAH1 promoter region (-293 to +51) and methylating histone H3 lysine 9 (H3K9), thus reducing SIAH1 expression in cancer cells. ChIP, promoter binding assay, siRNA knockdown, H3K9 methylation assay Neoplasia Medium 21847359
2009 E2F1 directly binds to two putative E2F1-binding sites in the Siah1 promoter (as demonstrated by ChIP) and activates Siah1 transcription, thereby suppressing beta-catenin/TCF activity. Siah1 mediates E2F1's repression of Wnt/beta-catenin signaling. ChIP, luciferase reporter assay, E2F1 knockdown (shRNA), Siah1 shRNA epistasis Journal of cellular and molecular medicine Medium 20187294
2007 A novel splice variant of Siah-1, Siah-1S, acts as a dominant negative by forming heterodimers with Siah-1 that cannot bind SIP, thereby counteracting Siah-1-mediated beta-catenin downregulation and antagonizing Siah-1-potentiated apoptosis. Alternative splicing characterization, Co-IP, beta-catenin assay, apoptosis assay, soft agar assay Oncogene Medium 17420721
2011 Eukaryotic translation elongation factor 1 delta (EEF1D) interacts with the Cys-rich domain of SIAH-1 and inhibits SIAH-1 auto-ubiquitination and degradation, as well as inhibiting SIAH-1-mediated degradation of substrate HPH2, thereby negatively regulating SIAH-1 ubiquitin ligase activity. Co-IP, in vitro and in vivo interaction assay, ubiquitination assay, substrate degradation assay Molecular and cellular biochemistry Medium 21633900
2019 SIAH1 ubiquitin ligase preferentially interacts with Akt3 (not Akt1 or Akt2) and facilitates Akt3 ubiquitination and proteasomal degradation; the somatic brain mutation Akt3-E17K escapes Siah1-mediated degradation, causing abnormal neural development with dysmorphic neurons. Co-IP, ubiquitination assay, isoform selectivity analysis, Akt3-E17K mutant, neural morphology assay The Journal of biological chemistry High 31471318
2022 SIAH1 interacts with and ubiquitinates YBX-1 at Lys304 via its RING finger domain in the cytoplasm, targeting it for proteasomal degradation; YBX-1 ubiquitination by SIAH1 leads to instability of YBX-1 target m5C-modified mRNAs, sensitizing ovarian cancer cells to cisplatin. Co-IP, ubiquitination assay with specific lysine mapping, m5C mRNA stability assay, drug sensitivity assay Oncogenesis Medium 35273154
2022 SIAH1 interacts with and ubiquitinates TRF2, promoting its degradation in the cytoplasm; ROS-induced SIAH1 upregulation reduces TRF2, leading to telomere abnormalities and granulosa cell senescence in premature ovarian failure. Co-IP, ubiquitination assay, SIAH1 knockdown, colocalization assay, telomere dysfunction assay Journal of cellular and molecular medicine Medium 35261172
2022 SIAH1 interacts with and ubiquitinates XIAP, targeting it for proteasomal degradation; METTL3-mediated m6A methylation of SIAH1 mRNA regulates SIAH1 expression, and SIAH1-mediated XIAP degradation promotes senescence and apoptosis in nucleus pulposus cells. Co-IP, ubiquitination assay, m6A RIP, actinomycin D RNA stability assay, SA-β-gal senescence assay Tissue & cell Medium 35580525
2022 FRK tyrosine kinase phosphorylates YAP at Tyr391/407/444, which recruits SIAH1 to catalyze YAP ubiquitination and degradation; Siah1 is required for FRK-initiated YAP destabilization and tumor suppression in glioblastoma. Co-IP, ubiquitination assay, kinase assay, phospho-site mutagenesis, Siah1 knockdown epistasis, in vivo xenograft Neuro-oncology High 35723276
2014 Siah1 promotes proteasome-dependent degradation of cytoplasmic p27 in glioma cells via its interaction facilitated by CacyBP/SIP scaffold; CacyBP/SIP overexpression promotes p27-Siah1 interaction and p27 ubiquitination, reducing glioma cell migration. Co-IP, ubiquitination assay, Siah1 knockdown, cell migration assay Cell biology international Medium 29024247

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nature cell biology 884 15951807
2001 Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. Molecular cell 521 11389839
2001 Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Molecular cell 367 11389840
2002 Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1. Proceedings of the National Academy of Sciences of the United States of America 226 12399545
1999 Siah-1 N-terminal RING domain is required for proteolysis function, and C-terminal sequences regulate oligomerization and binding to target proteins. Molecular and cellular biology 215 9858595
2008 Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nature cell biology 166 18536714
2016 The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway. Human molecular genetics 144 27334109
2007 Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Human molecular genetics 144 18065497
2003 Involvement of PEG10 in human hepatocellular carcinogenesis through interaction with SIAH1. Cancer research 143 12810624
2006 EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1alpha through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells. Cancer research 118 17047048
1999 SIAH-1 promotes apoptosis and tumor suppression through a network involving the regulation of protein folding, unfolding, and trafficking: identification of common effectors with p53 and p21(Waf1). Proceedings of the National Academy of Sciences of the United States of America 104 10393949
2011 Enhanced expression of EHMT2 is involved in the proliferation of cancer cells through negative regulation of SIAH1. Neoplasia (New York, N.Y.) 101 21847359
2003 Siah-1 facilitates ubiquitination and degradation of synphilin-1. The Journal of biological chemistry 93 14506261
2017 LncRNA SNHG1 promotes α-synuclein aggregation and toxicity by targeting miR-15b-5p to activate SIAH1 in human neuroblastoma SH-SY5Y cells. Neurotoxicology 90 29217406
2010 Direct ubiquitination of beta-catenin by Siah-1 and regulation by the exchange factor TBL1. The Journal of biological chemistry 88 20181957
2005 Structural analysis of Siah1-Siah-interacting protein interactions and insights into the assembly of an E3 ligase multiprotein complex. The Journal of biological chemistry 86 16085652
2001 Siah-1 binds and regulates the function of Numb. Proceedings of the National Academy of Sciences of the United States of America 82 11752454
2000 SIAH-1 interacts with alpha-tubulin and degrades the kinesin Kid by the proteasome pathway during mitosis. Oncogene 75 11146551
2001 The RING finger protein Siah-1 regulates the level of the transcriptional coactivator OBF-1. The EMBO journal 69 11483517
2012 The ubiquitin ligase Siah1 controls ELL2 stability and formation of super elongation complexes to modulate gene transcription. Molecular cell 57 22483617
2005 Siah1 interacts with the scaffold protein POSH to promote JNK activation and apoptosis. The Journal of biological chemistry 56 16230351
2008 Structure of the S100A6 complex with a fragment from the C-terminal domain of Siah-1 interacting protein: a novel mode for S100 protein target recognition. Biochemistry 55 18803400
2014 miR-135a leads to cervical cancer cell transformation through regulation of β-catenin via a SIAH1-dependent ubiquitin proteosomal pathway. Carcinogenesis 52 24503442
2009 Mitotic regulation of the stability of microtubule plus-end tracking protein EB3 by ubiquitin ligase SIAH-1 and Aurora mitotic kinases. The Journal of biological chemistry 48 19696028
2009 siah-1 Protein is necessary for high glucose-induced glyceraldehyde-3-phosphate dehydrogenase nuclear accumulation and cell death in Muller cells. The Journal of biological chemistry 48 19940145
2022 SIAH1 reverses chemoresistance in epithelial ovarian cancer via ubiquitination of YBX-1. Oncogenesis 45 35273154
2007 SIAH1 causes growth arrest and apoptosis in hepatoma cells through beta-catenin degradation-dependent and -independent mechanisms. Oncology reports 45 17273732
2011 E3 ubiquitin ligase Siah-1 facilitates poly-ubiquitylation and proteasomal degradation of the hepatitis B viral X protein. FEBS letters 44 21878328
2004 SIAH1 targets the alternative splicing factor T-STAR for degradation by the proteasome. Human molecular genetics 44 15163637
2010 S100A6 binding protein and Siah-1 interacting protein (CacyBP/SIP): spotlight on properties and cellular function. Amino acids 43 20182755
2018 PHF19 promotes the proliferation, migration, and chemosensitivity of glioblastoma to doxorubicin through modulation of the SIAH1/β-catenin axis. Cell death & disease 41 30323224
2011 Nuclear expression of the ubiquitin ligase seven in absentia homolog (SIAH)-1 induces proliferation and migration of liver cancer cells. Journal of hepatology 41 21356256
2003 SIAH1 inactivation correlates with tumor progression in hepatocellular carcinomas. Genes, chromosomes & cancer 41 12557228
1999 SIAH-1 inhibits cell growth by altering the mitotic process. Oncogene 41 10597311
2019 The SIAH1-HIPK2-p53ser46 Damage Response Pathway is Involved in Temozolomide-Induced Glioblastoma Cell Death. Molecular cancer research : MCR 40 30796178
2002 Structural analysis of Siah1 and its interactions with Siah-interacting protein (SIP). The Journal of biological chemistry 40 12421809
2016 Up-regulation of Siah1 by ethanol triggers apoptosis in neural crest cells through p38 MAPK-mediated activation of p53 signaling pathway. Archives of toxicology 39 27270636
2012 S-nitrosylation of B23/nucleophosmin by GAPDH protects cells from the SIAH1-GAPDH death cascade. The Journal of cell biology 39 23027902
2016 Suppression of cell migration is promoted by miR-944 through targeting of SIAH1 and PTP4A1 in breast cancer cells. BMC cancer 38 27377268
2008 E3 ubiquitin ligase SIAH1 mediates ubiquitination and degradation of TRB3. Cellular signalling 38 18276110
2004 Inactivating mutations of the Siah-1 gene in gastric cancer. Oncogene 37 15467739
2003 SIAH-1 interacts with CtIP and promotes its degradation by the proteasome pathway. Oncogene 37 14654780
2018 The PARP1-Siah1 Axis Controls HIV-1 Transcription and Expression of Siah1 Substrates. Cell reports 33 29949759
2014 Fine tuning of the UPR by the ubiquitin ligases Siah1/2. PLoS genetics 33 24809345
2011 Siah1/SIP regulates p27(kip1) stability and cell migration under metabolic stress. Cell cycle (Georgetown, Tex.) 33 21734459
2008 Abundance of aspargynyl-hydroxylase FIH is regulated by Siah-1 under normoxic conditions. Neuroscience letters 33 18280659
2012 Calcyclin binding protein and Siah-1 interacting protein in Alzheimer's disease pathology: neuronal localization and possible function. Neurobiology of aging 32 23260124
2004 Siah-1 interacts with the intracellular region of polycystin-1 and affects its stability via the ubiquitin-proteasome pathway. Journal of the American Society of Nephrology : JASN 31 15284290
2022 Simultaneous treatment with sorafenib and glucose restriction inhibits hepatocellular carcinoma in vitro and in vivo by impairing SIAH1-mediated mitophagy. Experimental & molecular medicine 30 36385558
2015 High Glucose-induced Retinal Pericyte Apoptosis Depends on Association of GAPDH and Siah1. The Journal of biological chemistry 29 26438826
2010 The expression of SIAH1 is downregulated and associated with Bim and apoptosis in human breast cancer tissues and cells. Molecular carcinogenesis 29 20082325
2009 Stabilization of HIPK2 by escape from proteasomal degradation mediated by the E3 ubiquitin ligase Siah1. Cancer letters 28 19250734
2017 HIF-1α coordinates epigenetic activation of SIAH1 in hepatocytes in response to nutritional stress. Biochimica et biophysica acta. Gene regulatory mechanisms 27 28843785
2015 MiR-107 down-regulates SIAH1 expression in human breast cancer cells and silencing of miR-107 inhibits tumor growth in a nude mouse model of triple-negative breast cancer. Molecular carcinogenesis 26 25851994
2011 Herpes simplex virus immediate-early protein ICP0 is targeted by SIAH-1 for proteasomal degradation. Journal of virology 26 21632771
2009 SIAH1 induced apoptosis by activation of the JNK pathway and inhibited invasion by inactivation of the ERK pathway in breast cancer cells. Cancer science 26 19775288
2006 Siah-1 facilitates ubiquitination and degradation of factor inhibiting HIF-1alpha (FIH). Biochemical and biophysical research communications 26 17188242
2011 Differential regulation of PML-RARα stability by the ubiquitin ligases SIAH1/SIAH2 and TRIAD1. The international journal of biochemistry & cell biology 24 22037423
2022 Reactive oxygen species-induced SIAH1 promotes granulosa cells' senescence in premature ovarian failure. Journal of cellular and molecular medicine 23 35261172
2014 Ubiquitin ligase Siah1 promotes the migration and invasion of human glioma cells by regulating HIF-1α signaling under hypoxia. Oncology reports 23 25572001
2007 SIAH-1 interacts with the Kaposi's sarcoma-associated herpesvirus-encoded ORF45 protein and promotes its ubiquitylation and proteasomal degradation. Journal of virology 23 18077711
2020 Downregulation of Siah1 promotes colorectal cancer cell proliferation and migration by regulating AKT and YAP ubiquitylation and proteasome degradation. Cancer cell international 22 32082080
2020 The E3 Ubiquitin Ligase SIAH1 Targets MyD88 for Proteasomal Degradation During Dengue Virus Infection. Frontiers in microbiology 22 32117091
2014 The β-catenin E3 ubiquitin ligase SIAH-1 is regulated by CSN5/JAB1 in CRC cells. Cellular signalling 22 24882689
2009 E2F1 represses beta-catenin/TCF activity by direct up-regulation of Siah1. Journal of cellular and molecular medicine 22 20187294
2000 Lack of somatic mutation in the coding sequence of SIAH1 in tumors hemizygous for this candidate tumor suppressor gene. International journal of cancer 21 10956387
2020 DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes. Proceedings of the National Academy of Sciences of the United States of America 20 32152128
2019 Identification and characterization of small molecule inhibitors of the ubiquitin ligases Siah1/2 in melanoma and prostate cancer cells. Cancer letters 20 30771432
2017 Membrane-bound β-catenin degradation is enhanced by ETS2-mediated Siah1 induction in Helicobacter pylori-infected gastric cancer cells. Oncogenesis 20 28481365
2017 Hepatitis B virus X protein activates E3 ubiquitin ligase Siah-1 to control virus propagation via a negative feedback loop. The Journal of general virology 20 28714848
2010 Distinct expression patterns of the E3 ligase SIAH-1 and its partner Kid/KIF22 in normal tissues and in the breast tumoral processes. Journal of experimental & clinical cancer research : CR 20 20144232
2009 Isoreserpine promotes beta-catenin degradation via Siah-1 up-regulation in HCT116 colon cancer cells. Biochemical and biophysical research communications 19 19607803
2019 SIAH1 ubiquitin ligase mediates ubiquitination and degradation of Akt3 in neural development. The Journal of biological chemistry 18 31471318
2017 CacyBP/SIP inhibits the migration and invasion behaviors of glioblastoma cells through activating Siah1 mediated ubiquitination and degradation of cytoplasmic p27. Cell biology international 18 29024247
2016 E3 Ubiquitin Ligase Siah-1 is Down-regulated and Fails to Target Natural HBx Truncates for Degradation in Hepatocellular Carcinoma. Journal of Cancer 17 26918055
2014 Role of apoptosis signal-regulating kinase 1 (ASK1) as an activator of the GAPDH-Siah1 stress-signaling cascade. The Journal of biological chemistry 17 25391652
2020 Host cell factors stimulate HIV-1 transcription by antagonizing substrate-binding function of Siah1 ubiquitin ligase to stabilize transcription elongation factor ELL2. Nucleic acids research 16 32479599
2017 E3 ubiquitin ligases SIAH1/2 regulate hypoxia-inducible factor-1 (HIF-1)-mediated Th17 cell differentiation. International immunology 16 28338984
2015 E3 ubiquitin ligase Siah-1 downregulates synaptophysin expression under high glucose and hypoxia. American journal of translational research 16 25755825
2014 Sec6 regulated cytoplasmic translocation and degradation of p27 via interactions with Jab1 and Siah1. Cellular signalling 16 24949832
2007 Siah-1S, a novel splice variant of Siah-1 (seven in absentia homolog), counteracts Siah-1-mediated downregulation of beta-catenin. Oncogene 16 17420721
2022 Circ-CCNB1 Modulates Trophoblast Proliferation and Invasion in Spontaneous Abortion by Regulating miR-223/SIAH1 axis. Endocrinology 15 35731831
2020 MicroRNA-135a Protects Against Ethanol-Induced Apoptosis in Neural Crest Cells and Craniofacial Defects in Zebrafish by Modulating the Siah1/p38/p53 Pathway. Frontiers in cell and developmental biology 15 33134300
2019 SIAH1/ZEB1/IL-6 axis is involved in doxorubicin (Dox) resistance of osteosarcoma cells. Biological chemistry 15 30265649
2018 Tp53 Mutation Inhibits Ubiquitination and Degradation of WISP1 via Down-Regulation of Siah1 in Pancreatic Carcinogenesis. Frontiers in pharmacology 15 30123132
2018 PUM1 and PUM2 exhibit different modes of regulation for SIAH1 that involve cooperativity with NANOS paralogues. Cellular and molecular life sciences : CMLS 15 30269240
2011 Eukaryotic translation elongation factor 1 delta inhibits the ubiquitin ligase activity of SIAH-1. Molecular and cellular biochemistry 15 21633900
2010 Siah1 proteins enhance radiosensitivity of human breast cancer cells. BMC cancer 15 20682032
2022 SIAH1 promotes senescence and apoptosis of nucleus pulposus cells to exacerbate disc degeneration through ubiquitinating XIAP. Tissue & cell 14 35580525
2022 FRK inhibits glioblastoma progression via phosphorylating YAP and inducing its ubiquitylation and degradation by Siah1. Neuro-oncology 14 35723276
2018 The E3 Ubiquitin Ligase Siah-1 Suppresses Avian Reovirus Infection by Targeting p10 for Degradation. Journal of virology 14 29321312
2016 Jab1 promotes glioma cell proliferation by regulating Siah1/β-catenin pathway. Journal of neuro-oncology 14 27640199
2022 m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1. Molecular therapy. Nucleic acids 13 35402071
2020 TRAF4, a new substrate of SIAH1, participates in chemotherapy resistance of breast cancer cell by counteracting SIAH1-mediated downregulation of β-catenin. Breast cancer research and treatment 13 32671611
2018 Knockdown of miR-299-5p inhibits the progression of hepatocellular carcinoma by targeting SIAH1. Bulletin du cancer 13 30266288
2023 SIAH1 ubiquitination-modified HMGCR inhibits lung cancer progression and promotes drug sensitivity through cholesterol synthesis. Cancer cell international 12 37062828
2022 Siah1 promotes the proliferation of NSCLC cells through ubiquitinating and stabilizing Notch1. Experimental cell research 12 35961388
2002 The characterization of the human Siah-1 promoter(1). FEBS letters 12 11852084
2017 The synthetic cannabinoid WIN55212-2 ameliorates traumatic spinal cord injury via inhibition of GAPDH/Siah1 in a CB2-receptor dependent manner. Brain research 11 28716633
2006 Mutation analysis of the seven in absentia homolog 1 (SIAH1) gene in Parkinson's disease. Journal of neural transmission (Vienna, Austria : 1996) 11 16752048