{"gene":"SIAH1","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":1999,"finding":"SIAH-1 N-terminal RING domain is required for proteolysis of target proteins (DCC), while C-terminal sequences regulate oligomerization and binding to substrates. Point mutations or deletion of the RING domain abolish DCC degradation and stabilize SIAH-1 itself. SIAH-1 undergoes self-degradation via the proteasome, blocked by RING domain mutations.","method":"Mutagenesis, co-immunoprecipitation, proteasome inhibitor assays, antisense knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain mutagenesis combined with functional proteolysis assays and antisense knockdown, multiple orthogonal methods in one study","pmids":["9858595"],"is_preprint":false},{"year":2001,"finding":"SIAH-1 forms an SCF-like E3 ubiquitin ligase complex with SIP (a Sgt1 homolog), Skp1, and the F-box protein Ebi to mediate phosphorylation-independent degradation of beta-catenin; complex assembly is induced by p53 activation, linking genotoxic injury to beta-catenin destruction and reduced TCF/LEF activity.","method":"Co-immunoprecipitation, co-expression degradation assays, yeast two-hybrid","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and functional degradation assays, independently replicated by two concurrent papers (PMID 11389839 and 11389840)","pmids":["11389839","11389840"],"is_preprint":false},{"year":2001,"finding":"SIAH-1 interacts with the C-terminus of APC and promotes GSK3beta-phosphorylation-independent, beta-TrCP-independent degradation of beta-catenin; demonstrated by beta-catenin loss in mammalian cells and hypodorsalization in Xenopus embryos.","method":"Co-immunoprecipitation, overexpression degradation assay, Xenopus embryo microinjection","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mammalian cell degradation, Xenopus in vivo), replicated alongside PMID 11389839","pmids":["11389840"],"is_preprint":false},{"year":2001,"finding":"SIAH-1 directly interacts with and promotes proteasomal degradation of Numb, leading to redistribution of Notch to the cytoplasm/nucleus and augmented Notch-regulated transcription.","method":"Co-immunoprecipitation, pulse-chase degradation assay, reporter assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional reporter assay, single lab, two orthogonal methods","pmids":["11752454"],"is_preprint":false},{"year":2002,"finding":"Crystal/structural analysis revealed that SIAH-1 forms a dimer with a large electronegative concave surface across the dimer interface; site-directed mutagenesis of electronegative residues abolished SIAH-1 binding to SIP both in vitro and in cells.","method":"Structure-based analysis, site-directed mutagenesis, binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural analysis with mutagenesis validation in vitro and in cells, single lab but two orthogonal methods","pmids":["12421809"],"is_preprint":false},{"year":2003,"finding":"SIAH-1 ubiquitinates and promotes proteasomal degradation of synphilin-1 via its RING finger domain; SIAH-1 interacts with the N-terminus of synphilin-1 through its substrate-binding domain; this degradation abrogates synphilin-1's inhibitory effect on dopamine release from PC12 cells. Notably, SIAH-1 does not ubiquitinate or degrade wild-type or mutant alpha-synuclein under these conditions.","method":"Yeast two-hybrid, co-immunoprecipitation from rat brain, confocal microscopy, ubiquitination assay, dopamine release assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro and in vivo ubiquitination assays plus functional readout (dopamine release), multiple orthogonal methods","pmids":["14506261"],"is_preprint":false},{"year":2003,"finding":"PEG10 protein associates with SIAH1 and overexpression of PEG10 decreases SIAH1-mediated cell death, suggesting PEG10 functions as an antagonist of SIAH1 pro-apoptotic activity.","method":"Co-immunoprecipitation, cell death assay with overexpression","journal":"Cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus overexpression phenotype, single lab","pmids":["12810624"],"is_preprint":false},{"year":2004,"finding":"SIAH-1 binds an octapeptide sequence in T-STAR and targets it for proteasome-dependent degradation; a double amino acid substitution in mouse T-STAR that mimics the human SIAH1-binding site brings mouse T-STAR under SIAH1 control. SIAH1-mediated degradation modulates T-STAR-dependent alternative splicing.","method":"Two-hybrid screening, in vivo degradation assay, minigene splicing assay, mutagenesis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis confirming binding site, functional splicing assay, single lab with multiple orthogonal methods","pmids":["15163637"],"is_preprint":false},{"year":2005,"finding":"S-nitrosylation of GAPDH at Cys-150 triggers its binding to SIAH-1; SIAH-1's nuclear localization signal mediates nuclear translocation of GAPDH; nuclear GAPDH stabilizes SIAH-1, facilitating SIAH-1-mediated degradation of nuclear proteins and apoptosis. Activation of macrophages or neurons elicits GAPDH-SIAH-1 binding and nuclear translocation.","method":"Co-immunoprecipitation, S-nitrosylation assay, nuclear fractionation, cell death assays, NO deletion experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple cell types, biochemical S-nitrosylation assays, genetic (NO deletion) confirmation, widely replicated","pmids":["15951807"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of the SIAH-1–SIP complex revealed that SIP engages SIAH-1 via two elements: an N-terminal dimerization domain across the upper surface of the SIAH-1 dimer through a PXAXVXP consensus motif, and a C-terminal Skp1-binding domain protruding from the lower surface. Both elements are required for beta-catenin destruction.","method":"X-ray crystallography, NMR, mutagenesis, cell-based beta-catenin degradation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis and functional validation in cells, multiple orthogonal methods","pmids":["16085652"],"is_preprint":false},{"year":2005,"finding":"SIAH-1 interacts with the scaffold protein POSH to activate the JNK apoptotic pathway; E3 ligase activity of SIAH-1 is required for this proapoptotic effect. Apoptotic stimuli stabilize SIAH-1 protein via a mechanism dependent on JNK pathway activation, POSH interaction, and phosphorylation of SIAH-1 at tyrosines 100 and 126.","method":"Co-immunoprecipitation, siRNA knockdown, phosphorylation mutagenesis, cell death assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RING mutant functional analysis, phosphorylation site mutagenesis, single lab","pmids":["16230351"],"is_preprint":false},{"year":2006,"finding":"SIAH-1 ubiquitinates and promotes proteasomal degradation of FIH (factor inhibiting HIF-1alpha) under hypoxic conditions; SIAH-1 interacts with the JmjC domain of FIH through its substrate-binding domain and uses its RING domain for ubiquitination, thereby regulating HIF-1alpha transcriptional activity.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, proteasome inhibitor experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus siRNA knockdown, single lab, multiple orthogonal methods","pmids":["17188242"],"is_preprint":false},{"year":2006,"finding":"EBV oncoprotein LMP1 upregulates SIAH-1 protein stability, which in turn promotes proteasomal degradation of prolyl hydroxylases PHD1 and PHD3, preventing VHL-HIF-1alpha complex formation and stabilizing HIF-1alpha to activate angiogenic gene expression.","method":"Co-immunoprecipitation, siRNA knockdown, proteasome inhibitor assay, immunoblot","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-immunoprecipitation and siRNA-based functional assays, single lab","pmids":["17047048"],"is_preprint":false},{"year":2007,"finding":"SIAH-1 binds alpha-synuclein and UbcH8 (a brain-enriched E2 enzyme) 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 toxicity. The PD-linked A30P mutation disrupts this ubiquitination; A53T does not.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, aggregation assay, mutagenesis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo ubiquitination assay, mutagenesis of disease-linked substrate residues, functional aggregation readout, single lab with multiple methods","pmids":["18065497"],"is_preprint":false},{"year":2008,"finding":"SIAH-1 colocalizes with and ubiquitinates HIPK2 in unstressed cells, targeting it for proteasomal degradation. DNA damage triggers ATM/ATR-dependent phosphorylation of SIAH-1 at Ser-19, disrupting the HIPK2-SIAH-1 complex and stabilizing HIPK2 to promote apoptosis. Conversely, after sublethal damage, p53-induced SIAH-1 expression drives HIPK2 degradation to promote recovery.","method":"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, site-directed mutagenesis of Ser-19, ATM/ATR inhibitor experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted ubiquitination assay, phospho-site mutagenesis, genetic knockdown with clear phenotypic readout, multiple orthogonal methods","pmids":["18536714"],"is_preprint":false},{"year":2008,"finding":"Structure of S100A6 bound to a SIP fragment (residues 189-219) determined by NMR; SIP(189-219) forms two helices engaging S100A6 in both canonical and novel binding modes. Structure-based mutagenesis confirmed reduced binding; cell-based assay showed S100A6 modulates SCF(TBL1)/SIAH-1 complex activity on beta-catenin.","method":"NMR structure determination, isothermal titration calorimetry, mutagenesis, cell-based functional assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with mutagenesis validation and functional cell assay, single lab with multiple orthogonal methods","pmids":["18803400"],"is_preprint":false},{"year":2008,"finding":"SIAH-1 interacts with, ubiquitinates, and promotes proteasomal degradation of TRB3 (Tribbles 3 homolog); co-expression of SIAH-1 reverses TRB3-mediated upregulation of TGF-beta signaling.","method":"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, overexpression degradation assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP and ubiquitination assay with functional signaling readout, single lab","pmids":["18276110"],"is_preprint":false},{"year":2009,"finding":"SIAH-1 ubiquitinates EB3 (end-binding protein 3) promoting its proteasomal degradation; Aurora-A and Aurora-B phosphorylate EB3 at Ser-176, disrupting the EB3-SIAH-1 complex to stabilize EB3 during mitosis and facilitate cell cycle progression at prometaphase.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, phosphorylation site mutagenesis, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ubiquitination assay with phospho-site mutagenesis and functional cell cycle phenotype, single lab with multiple orthogonal methods","pmids":["19696028"],"is_preprint":false},{"year":2009,"finding":"SIAH-1 is required for high glucose-induced GAPDH nuclear accumulation and cell death in retinal Müller cells; SIAH-1 forms a complex with GAPDH under hyperglycemic conditions and is predominantly nuclear; siRNA knockdown of SIAH-1 blocks GAPDH nuclear translocation and prevents high glucose-induced cell death via inhibiting p53 phosphorylation.","method":"siRNA knockdown, co-immunoprecipitation, nuclear fractionation, cell death assay (annexin V, caspase)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with subcellular fractionation and functional cell death assay, single lab","pmids":["19940145"],"is_preprint":false},{"year":2010,"finding":"SIAH-1 alone is sufficient to polyubiquitinate beta-catenin in vitro; TBL1 competes with SIAH-1 for binding to the same armadillo repeat domain of beta-catenin, protecting beta-catenin from SIAH-1-mediated ubiquitination and proteasomal degradation during Wnt signaling.","method":"In vitro ubiquitination assay with purified components, co-immunoprecipitation, overexpression/knockdown degradation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted ubiquitination assay with purified proteins, confirmed by cell-based competition experiments, single lab","pmids":["20181957"],"is_preprint":false},{"year":2011,"finding":"SIAH-1 (but not SIAH-2) is the E3 ubiquitin ligase for ELL2 polyubiquitination and proteasomal degradation; SIAH-1 cannot access ELL2 when bound in the AFF4 super elongation complex (SEC). At high concentrations, SIAH-1 also degrades AFF4/1 to dismantle SECs. Prostratin and HMBA activate HIV transcription by decreasing SIAH-1 expression and ELL2 ubiquitination.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, HIV transcription reporter assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, siRNA knockdown with functional HIV transcription readout, multiple orthogonal methods","pmids":["22483617"],"is_preprint":false},{"year":2011,"finding":"SIAH-1 interacts with and promotes ubiquitin/proteasome-dependent degradation of the hepatitis B viral X protein (HBx), attenuating HBx-mediated transactivation of GRE, HSE, and CRE promoters; SIAH-1 participates in p53-mediated HBx degradation.","method":"Co-immunoprecipitation, ubiquitination assay, transcriptional reporter assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional reporter assay, single lab","pmids":["21878328"],"is_preprint":false},{"year":2011,"finding":"SIAH-1 interacts with, polyubiquitinates, and promotes proteasomal degradation of PML-RARα via the E2 enzyme UBCH8; TRIAD1 also binds UBCH8 and PML-RARα but, in contrast to SIAH-1/SIAH-2, does not affect PML-RARα turnover.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown degradation assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with side-by-side comparison of SIAH1 vs TRIAD1, single lab","pmids":["22037423"],"is_preprint":false},{"year":2011,"finding":"SIAH-1 interacts with and promotes ubiquitination and proteasomal degradation of HSV ICP0; ICP0 in turn stabilizes SIAH-1 and recruits it into ICP0-containing nuclear bodies. In SIAH-1 knockdown cells, ICP0 levels are higher, less ubiquitinated, and more stable.","method":"Co-immunoprecipitation, ubiquitination assay in vitro and in vivo, siRNA knockdown, half-life assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo ubiquitination assays plus siRNA functional readout, single lab","pmids":["21632771"],"is_preprint":false},{"year":2011,"finding":"SIAH-1 is required for synphilin-1-dependent PINK1-independent mitophagy; synphilin-1 recruits SIAH-1 to mitochondria where SIAH-1 promotes mitochondrial protein ubiquitination and subsequent mitophagy. Catalytically inactive SIAH-1 mutant or SIAH-1 knockdown abrogates this mitophagy pathway.","method":"Co-immunoprecipitation, siRNA knockdown, dominant-negative mutant, LC3/Lamp1 recruitment assay, mitophagy flux assay (Atg5 knockdown)","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus catalytic mutant plus siRNA knockdown with mitophagy phenotype, single lab","pmids":["27334109"],"is_preprint":false},{"year":2012,"finding":"B23/nucleophosmin binds both SIAH-1 and GAPDH in the nucleus; trans-nitrosylation of B23 at Cys-275 by GAPDH enhances B23-SIAH-1 interaction and disrupts the SIAH-1-GAPDH complex; S-nitrosylated B23 abrogates SIAH-1 E3 ligase activity, providing neuroprotection against NMDA-mediated neurotoxicity.","method":"Co-immunoprecipitation, S-nitrosylation assay, mutagenesis (C275S), E3 ligase activity assay, in vivo neurotoxicity model","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution of interaction, mutagenesis, E3 ligase activity assay, in vivo validation, single lab with multiple orthogonal methods","pmids":["23027902"],"is_preprint":false},{"year":2014,"finding":"SIAH-1/2 are transcriptionally induced by ER stress through PERK/ATF4 and IRE1/sXBP1 pathways; SIAH-1/2 attenuate proline hydroxylation of ATF4, stabilizing it and amplifying ER stress-induced cell death. Siah1a+/-::Siah2-/- mice show smaller infarct volume and protection from ischemia-induced death compared to WT.","method":"Genetic mouse model (compound knockout), siRNA knockdown in cultured cells, middle cerebral artery occlusion model, ATF4 hydroxylation assay","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic rescue using compound knockout mice plus cell-based mechanistic assays, multiple orthogonal methods","pmids":["24809345"],"is_preprint":false},{"year":2014,"finding":"SIAH-1/SIP E3 ligase complex mediates glucose starvation-induced proteasomal degradation of cytoplasmic p27(kip1), thereby decreasing cell motility; SIP-/- fibroblasts have elevated cytoplasmic p27 and increased cell migration.","method":"siRNA knockdown, SIP knockout fibroblasts, co-immunoprecipitation, proteasome inhibitor assay, cell migration assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout fibroblasts plus siRNA and co-IP, single lab","pmids":["21734459"],"is_preprint":false},{"year":2014,"finding":"ASK1 (apoptosis signal-regulating kinase 1) interacts with both GAPDH and SIAH-1 and phosphorylates SIAH-1 at Thr-70/74 and Thr-235/239; this phosphorylation triggers GAPDH-SIAH-1 stress signaling and activates p300 acetyltransferase in the nucleus.","method":"Co-immunoprecipitation, in vitro kinase assay, phospho-site mutagenesis, p300 activation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and downstream functional readout, single lab","pmids":["25391652"],"is_preprint":false},{"year":2015,"finding":"High glucose increases SIAH-1 protein levels, induces GAPDH-SIAH-1 complex formation, and causes GAPDH nuclear translocation in human retinal pericytes; blocking the GAPDH-SIAH-1 interaction with directed peptides prevents high glucose-induced pericyte apoptosis.","method":"Co-immunoprecipitation, siRNA knockdown, GAPDH/SIAH-1-blocking peptides, nuclear fractionation, apoptosis assay (annexin V, caspase-3)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus blocking peptide experiments plus siRNA with functional apoptosis readout, single lab","pmids":["26438826"],"is_preprint":false},{"year":2018,"finding":"PARP1 suppresses SIAH-1 at both mRNA level (via NCoR co-repressor complex) and protein level (promoting PARylation-dependent ubiquitination of SIAH-1), thereby elevating ELL2 to form more super elongation complexes and activate HIV-1 transcription.","method":"siRNA knockdown, PARP1 inhibitor, co-immunoprecipitation, ubiquitination assay, HIV transcription assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA plus PARP inhibitor plus Co-IP with functional HIV transcription readout, single lab","pmids":["29949759"],"is_preprint":false},{"year":2019,"finding":"SIAH-1 ubiquitinates Akt3 (but not Akt1 or Akt2) preferentially and promotes its degradation; Akt3 is enriched in axonal shafts where SIAH-1 is prominent. Depletion of SIAH-1 elevates Akt3 levels and causes aberrant axonal branching. The brain-specific Akt3-E17K somatic mutation escapes SIAH-1-mediated degradation, causing dysmorphic neurons.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA/shRNA knockdown, overexpression with mutagenesis, primary neuron imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assay, disease-relevant mutagenesis, and functional neural phenotype, multiple orthogonal methods, single lab","pmids":["31471318"],"is_preprint":false},{"year":2020,"finding":"HCF1 and HCF2 bind and block the substrate-binding domain (SBD) of SIAH-1/2 to prevent SIAH-1 autoubiquitination and trans-ubiquitination of ELL2, thereby stabilizing ELL2 and enhancing super elongation complex formation for HIV-1 transactivation.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, HCF1/2 knockdown, HIV transcription assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with functional HIV transcription readout, single lab","pmids":["32479599"],"is_preprint":false},{"year":2020,"finding":"DBC1 competes with HDAC3 for the same binding sites on ELL1, promoting p300-mediated ELL1 acetylation which stabilizes it against SIAH-1-mediated polyubiquitylation; SIAH-1 ubiquitylates deacetylated ELL1 for proteasomal degradation.","method":"Co-immunoprecipitation, ubiquitination assay, acetylation assay, siRNA knockdown, competition binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay plus acetylation modification assay, single lab, multiple methods","pmids":["32152128"],"is_preprint":false},{"year":2020,"finding":"SIAH-1 binds to and ubiquitinates MyD88, targeting it for proteasomal degradation; SIAH-1 knockdown increases MyD88-dependent TLR7 signaling; dengue virus induces SIAH-1 expression via the unfolded protein response during infection, dampening innate immunity.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, CRISPR MyD88 knockout, TLR7 signaling assay","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, CRISPR knockout functional validation, single lab","pmids":["32117091"],"is_preprint":false},{"year":2022,"finding":"SIAH-1 ubiquitinates YBX-1 at Lys304 via its RING finger domain in the cytoplasm, targeting it for degradation; YBX-1 destabilization leads to instability of its m5C-modified mRNA targets, sensitizing ovarian cancer cells to cisplatin.","method":"Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis (Lys304), siRNA knockdown, in vitro and in vivo tumor assays","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ubiquitination assay with defined ubiquitination site mutagenesis and functional drug sensitivity phenotype in vitro and in vivo, single lab","pmids":["35273154"],"is_preprint":false},{"year":2022,"finding":"SIAH-1 ubiquitinates XIAP, targeting it for proteasomal degradation in nucleus pulposus cells; this promotes NPC senescence and apoptosis in intervertebral disc degeneration; METTL3-mediated m6A methylation of SIAH-1 mRNA enhances its expression.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, m6A RIP, actinomycin D mRNA stability assay","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus m6A RIP with functional phenotype, single lab","pmids":["35580525"],"is_preprint":false},{"year":2022,"finding":"FRK phosphorylates YAP at Tyr391/407/444, which recruits SIAH-1 to catalyze YAP ubiquitination and proteasomal degradation in glioblastoma; SIAH-1 is required for YAP destabilization initiated by FRK.","method":"Co-immunoprecipitation, proximity ligation assay, ubiquitination assay, phosphorylation site mutagenesis, siRNA knockdown, in vivo tumor model","journal":"Neuro-oncology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — Co-IP with mutagenesis, ubiquitination assay, functional in vivo tumor model, single lab with multiple orthogonal methods","pmids":["35723276"],"is_preprint":false},{"year":2000,"finding":"SIAH-1 interacts with alpha-tubulin and promotes proteasomal degradation of the chromokinesin Kid (KIF22) via its RING finger domain during mitosis; overexpression of SIAH-1 but not a deletion mutant lacking the N-terminal domain reduces kinesin levels and disrupts mitosis.","method":"Yeast two-hybrid, co-immunoprecipitation, overexpression degradation assay, dominant-negative mutant","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, functional degradation with dominant-negative mutant, single lab","pmids":["11146551"],"is_preprint":false},{"year":2001,"finding":"SIAH-1 interacts via its C-terminal part with the N-terminus of OBF-1 transcriptional coactivator, leading to OBF-1 protein downregulation via the ubiquitin-proteasome pathway without changing OBF-1 mRNA, and reducing octamer site-dependent transcription; inhibiting the proteasome in B cells elevates OBF-1 protein.","method":"Yeast two-hybrid, co-immunoprecipitation, proteasome inhibitor assay, reporter gene assay, domain mutagenesis","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus proteasome inhibitor plus reporter assay, single lab, multiple methods","pmids":["11483517"],"is_preprint":false},{"year":2003,"finding":"SIAH-1 interacts with CtIP (CtBP-interacting protein) and promotes its proteasomal degradation; however, p21(WAF1) induction by SIAH-1 does not require CtIP degradation, as a RING-deleted SIAH-1 that binds but cannot degrade CtIP still induces p21 transcription to a similar extent.","method":"Yeast two-hybrid, co-immunoprecipitation, ubiquitin-proteasome assay, reporter assay, dominant-negative mutant","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus RING-deletion functional dissection, single lab; negative finding about CtIP-p21 link is mechanistically informative","pmids":["14654780"],"is_preprint":false},{"year":2004,"finding":"SIAH-1 interacts with the cytoplasmic C-terminus of polycystin-1 (PKD1) and promotes its ubiquitination and proteasomal degradation, shortening PKD1-C half-life; overexpression of SIAH-1 promotes degradation of polycystin-1 in membrane-anchored chimeric proteins.","method":"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, pulse-chase half-life assay","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, ubiquitination and half-life assays, single lab","pmids":["15284290"],"is_preprint":false},{"year":2007,"finding":"KSHV ORF45 protein interacts with SIAH-1, and SIAH-1 promotes proteasomal degradation of ORF45 through a RING domain-dependent mechanism in infected cells.","method":"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, half-life assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP and ubiquitination assay with RING domain requirement established, single lab","pmids":["18077711"],"is_preprint":false},{"year":2009,"finding":"SIAH-1 mediates proteasomal degradation of HIPK2; this degradation is blocked by MLK3, EBV LMP-1, or DNA damaging stimuli, revealing multiple pathways that stabilize HIPK2 by escaping SIAH-1-dependent degradation.","method":"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, overexpression/knockdown","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay, consistent with PMID 18536714 but less mechanistically detailed, single lab","pmids":["19250734"],"is_preprint":false},{"year":2011,"finding":"EHMT2 histone methyltransferase suppresses SIAH1 transcription by binding its promoter region (-293 to +51) and methylating H3K9, thereby reducing SIAH1 expression and promoting cancer cell proliferation.","method":"ChIP, promoter reporter assay, siRNA knockdown, western blot","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with promoter reporter assay and functional siRNA knockdown, single lab","pmids":["21847359"],"is_preprint":false},{"year":2011,"finding":"SIAH-1 ubiquitinates and promotes proteasomal degradation of synaptophysin under combined hypoxia and high glucose conditions, mediated by ERK pathway activation; ERK inhibition or SIAH-1 knockdown rescues synaptophysin levels.","method":"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, overexpression, ERK inhibitor","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus siRNA knockdown with functional synaptophysin expression readout, single lab","pmids":["25755825"],"is_preprint":false},{"year":2017,"finding":"SIAH-1/2 promote Th17 cell differentiation by maintaining stability of HIF-1alpha protein, which directly regulates Il17a and Rorgt transcription; in the absence of HIF-1alpha, SIAH1 and SIAH2 have little effect on Th17 differentiation.","method":"cDNA library screen, promoter reporter assay, ex vivo Th17 differentiation, genetic (HIF-1alpha knockout) epistasis","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis using HIF-1alpha KO plus ex vivo differentiation assay, single lab","pmids":["28338984"],"is_preprint":false},{"year":2017,"finding":"HIF-1alpha occupies the SIAH1 promoter in response to nutritional stress and recruits the histone demethylase KDM3A (via p300 crosstalk) to activate SIAH1 transcription through H3K9 demethylation and H3K4 trimethylation/H3 acetylation; HIF-1alpha or KDM3A depletion prevents SIAH1 induction.","method":"ChIP, siRNA knockdown, chetomin inhibitor, promoter reporter assay, histone modification analysis","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with siRNA knockdown and promoter reporter, single lab","pmids":["28843785"],"is_preprint":false},{"year":2019,"finding":"SIAH-1 ubiquitinates ZEB1, targeting it for proteasomal degradation; SIAH-1 overexpression inhibits ZEB1 expression and sensitizes drug-resistant osteosarcoma cells to doxorubicin; upregulation of ZEB1 in resistant cells is due to increased protein half-life associated with reduced SIAH-1 activity.","method":"siRNA/overexpression, proteasome inhibitor, western blot half-life analysis","journal":"Biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression/knockdown without explicit Co-IP or ubiquitination assay, single lab","pmids":["30265649"],"is_preprint":false},{"year":2022,"finding":"SIAH-1 directly interacts with and promotes ubiquitination/degradation of CPSF1; CPSF1 degradation by SIAH-1 reduces generation of the oncogenic AR-v7 splice variant by removing CPSF1 binding to the AR-cryptic exon CE3 polyadenylation signal; m6A methylation of SIAH1 mRNA in PCa represses its expression.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, m6A analysis, minigene/splicing assay","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional splicing assay, single lab","pmids":["35402071"],"is_preprint":false},{"year":2009,"finding":"E2F1 transcription factor directly binds two putative E2F1-binding sites upstream of the SIAH1 transcription start site, activates SIAH1 promoter activity (by luciferase assay and ChIP), and elevates SIAH1 protein levels, thereby suppressing beta-catenin/TCF activity.","method":"Chromatin immunoprecipitation, luciferase reporter assay, shRNA knockdown, western blot","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase reporter plus shRNA knockdown epistasis, single lab","pmids":["20187294"],"is_preprint":false},{"year":2002,"finding":"SIAH-1 promoter has no TATA or CCAAT box; an Sp1 site is responsible for basal promoter activity; p53 upregulates SIAH-1 mRNA but does not directly activate the proximal promoter in reporter assays, suggesting the p53 responsive element lies in a different region.","method":"Promoter deletion/mutation reporter assay, Northern blot, co-transfection","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic promoter deletion with mutagenesis of key Sp1 site, single lab; p53 result is mechanistically informative as a negative result for the proximal promoter","pmids":["11852084"],"is_preprint":false},{"year":2007,"finding":"A novel splice variant of SIAH-1, designated Siah-1S, forms heterodimers with SIAH-1 or homodimers that cannot bind SIP; Siah-1S catalyzes self-ubiquitination and acts as a dominant-negative against SIAH-1 to upregulate beta-catenin/TCF activity and antagonize SIAH-1-mediated apoptosis.","method":"Co-immunoprecipitation, dimerization assay, ubiquitination assay, reporter assay, soft agar colony assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional reporter and colony assay, single lab","pmids":["17420721"],"is_preprint":false},{"year":2022,"finding":"SIAH-1 is essential for sorafenib-induced mitophagy; SIAH-1 silencing markedly represses mitophagy and sensitizes cells to sorafenib-induced death in hepatocellular carcinoma cells.","method":"siRNA knockdown, mitophagy flux assay (mKeima-Red, LC3, PINK1 accumulation), combination treatment in vitro and in vivo","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with mitophagy flux assay and in vivo xenograft, single lab","pmids":["36385558"],"is_preprint":false}],"current_model":"SIAH1 is a RING-domain E3 ubiquitin ligase that functions as a homodimer (or in an SCF-like complex with SIP/CacyBP, Skp1, and Ebi/TBL1) to polyubiquitinate and promote proteasomal degradation of a broad range of substrates—including beta-catenin (phosphorylation-independently), HIPK2, ELL1/ELL2, alpha-synuclein (non-degradative mono/di-ubiquitination promoting aggregation), synphilin-1, DCC, Numb, Kid, EB3, TRB3, FIH, MyD88, YBX-1, CPSF1, Akt3, and YAP—with substrate specificity modulated by complex partners and post-translational modifications; SIAH1 activity is regulated by ATM/ATR-dependent phosphorylation (Ser-19), ASK1-dependent phosphorylation (Thr-70/74, Thr-235/239), S-nitrosylation via GAPDH interaction, and competitor proteins (TBL1, B23, HCF1/2), while its own transcription is induced by p53, HIF-1α/KDM3A, and E2F1, and repressed by EHMT2-mediated H3K9 methylation."},"narrative":{"mechanistic_narrative":"SIAH1 is a RING-domain E3 ubiquitin ligase that controls the abundance of a broad set of signaling, transcriptional, and cytoskeletal proteins by directing them to the proteasome, thereby intersecting Wnt, hypoxia, DNA-damage, and apoptotic pathways [PMID:9858595, PMID:18536714]. Its catalytic activity requires the N-terminal RING domain—mutations there abolish substrate proteolysis and stabilize SIAH1 itself, which otherwise undergoes proteasomal self-degradation—while C-terminal sequences mediate oligomerization and substrate binding [PMID:9858595]. SIAH1 functions as a homodimer presenting an electronegative substrate-engaging surface, and can assemble into an SCF-like complex with the adaptor SIP/CacyBP, Skp1, and the F-box protein Ebi to mediate phosphorylation-independent, beta-TrCP-independent degradation of beta-catenin, linking p53 activation to suppression of TCF/LEF transcription [PMID:11389839, PMID:11389840, PMID:12421809, PMID:16085652, PMID:20181957]. Through this ubiquitin-ligase activity SIAH1 targets numerous substrates including HIPK2, the elongation factors ELL1/ELL2 within the super elongation complex, EB3 and the chromokinesin Kid during mitosis, Numb, Akt3, YAP, MyD88, FIH, TRB3, CPSF1, and YBX-1 [PMID:18536714, PMID:22483617, PMID:19696028, PMID:11146551, PMID:11752454, PMID:31471318, PMID:35723276, PMID:32117091, PMID:17188242, PMID:18276110, PMID:35402071, PMID:35273154]. A distinct non-degradative mode is seen with alpha-synuclein, where SIAH1 together with the E2 UbcH8 catalyzes mono- and di-ubiquitination that promotes aggregation and toxicity rather than turnover, while it degrades the related protein synphilin-1 [PMID:18065497, PMID:14506261]. Substrate selection and ligase output are tuned by post-translational modification of substrates and competitor proteins: phosphorylation of EB3, YAP, and SIAH1 itself (ATM/ATR-dependent Ser-19, ASK1-dependent Thr residues) gate complex formation, and TBL1, HCF1/2, and B23/nucleophosmin block substrate access or catalysis [PMID:18536714, PMID:19696028, PMID:25391652, PMID:20181957, PMID:32479599, PMID:23027902]. A separate, catalysis-dependent role couples SIAH1 to stress signaling and cell death: S-nitrosylated GAPDH binds SIAH1 and is escorted to the nucleus where it stabilizes SIAH1 to drive degradation of nuclear targets and apoptosis, a cascade implicated in hyperglycemic and excitotoxic cell death [PMID:15951807, PMID:23027902, PMID:19940145, PMID:26438826]. SIAH1 also promotes mitophagy when recruited to mitochondria [PMID:27334109, PMID:36385558]. Its own transcription is induced by E2F1 and by HIF-1alpha acting with KDM3A, and repressed by EHMT2-mediated H3K9 methylation [PMID:20187294, PMID:28843785, PMID:21847359].","teleology":[{"year":1999,"claim":"Established that SIAH1 is a self-regulating RING-dependent E3 ligase, defining the catalytic module (N-terminal RING) versus the substrate/oligomerization module (C-terminus) that organizes all later mechanism.","evidence":"Domain mutagenesis, Co-IP, proteasome inhibitor and antisense assays on DCC degradation","pmids":["9858595"],"confidence":"High","gaps":["Did not define the E2 partner","Substrate repertoire beyond DCC unknown at the time"]},{"year":2000,"claim":"Extended SIAH1 substrate control to mitotic machinery, showing it degrades the chromokinesin Kid and associates with alpha-tubulin during mitosis.","evidence":"Yeast two-hybrid, Co-IP, RING-deletion degradation assays","pmids":["11146551"],"confidence":"Medium","gaps":["No in vitro reconstituted ubiquitination","Physiological consequence of Kid turnover only inferred from overexpression"]},{"year":2001,"claim":"Defined a major signaling output—phosphorylation-independent destruction of beta-catenin—through an SCF-like SIAH1/SIP/Skp1/Ebi complex assembled downstream of p53, connecting genotoxic stress to Wnt pathway shutdown.","evidence":"Reciprocal Co-IP, co-expression degradation, yeast two-hybrid, Xenopus microinjection across two concurrent papers","pmids":["11389839","11389840"],"confidence":"High","gaps":["Mechanism of substrate recognition without phospho-degron unresolved","Relative contribution of APC interaction versus SCF complex unclear"]},{"year":2002,"claim":"Provided the structural basis for SIAH1 dimerization and adaptor engagement, showing an electronegative dimer-interface surface required for SIP binding.","evidence":"Structure-based analysis with site-directed mutagenesis and binding assays","pmids":["12421809"],"confidence":"High","gaps":["No structure of a bound degron substrate","Did not resolve how diverse substrates dock the same surface"]},{"year":2003,"claim":"Distinguished SIAH1's substrate selectivity within Parkinson's-relevant proteins, degrading synphilin-1 (relieving its inhibition of dopamine release) but not alpha-synuclein under those conditions.","evidence":"Yeast two-hybrid, brain Co-IP, ubiquitination and dopamine-release assays","pmids":["14506261"],"confidence":"High","gaps":["Conditions permitting alpha-synuclein handling not yet defined","In vivo relevance to neurodegeneration not shown"]},{"year":2005,"claim":"Uncovered a redox-controlled apoptotic axis: S-nitrosylated GAPDH binds SIAH1, which provides the nuclear import signal and is reciprocally stabilized, enabling nuclear substrate degradation and cell death.","evidence":"Reciprocal Co-IP, S-nitrosylation assays, nuclear fractionation, NO-deletion genetics in macrophages and neurons","pmids":["15951807"],"confidence":"High","gaps":["Identity of the critical nuclear substrates driving death incompletely mapped","Quantitative contribution of GAPDH stabilization versus other inputs unclear"]},{"year":2005,"claim":"Resolved how the SIP adaptor bridges SIAH1 to Skp1, defining two structural elements both required for beta-catenin destruction.","evidence":"X-ray crystallography, NMR, mutagenesis, cell-based beta-catenin degradation","pmids":["16085652"],"confidence":"High","gaps":["Did not capture beta-catenin within the complex","F-box/Ebi positioning not structurally resolved"]},{"year":2007,"claim":"Revealed a non-degradative ubiquitination mode in which SIAH1 with UbcH8 mono/di-ubiquitinates alpha-synuclein to promote aggregation rather than turnover, with disease mutations differentially affected.","evidence":"In vivo ubiquitination, aggregation assays, A30P/A53T mutagenesis","pmids":["18065497"],"confidence":"High","gaps":["Structural determinant selecting mono/di- versus poly-ubiquitination unknown","In vivo aggregation consequence not tested in animal models"]},{"year":2008,"claim":"Showed SIAH1 activity is gated by DNA-damage signaling: ATM/ATR phosphorylation of Ser-19 dissociates the HIPK2 complex to stabilize HIPK2 and switch cells between recovery and apoptosis.","evidence":"Co-IP, ubiquitination assay, Ser-19 mutagenesis, ATM/ATR inhibition, siRNA","pmids":["18536714"],"confidence":"High","gaps":["Direct kinase-substrate phosphorylation not reconstituted in vitro","Other phospho-regulated substrate complexes not surveyed"]},{"year":2009,"claim":"Demonstrated phospho-gating of a mitotic substrate, with Aurora-A/B phosphorylation of EB3 disrupting the SIAH1 complex to stabilize EB3 for prometaphase progression.","evidence":"Ubiquitination assay, phospho-site mutagenesis, cell cycle analysis, siRNA","pmids":["19696028"],"confidence":"High","gaps":["Whether SIAH1 acts on EB3 in interphase unclear","Connection to the alpha-tubulin/Kid mitotic roles not integrated"]},{"year":2010,"claim":"Proved SIAH1 alone is a sufficient beta-catenin ligase in vitro and identified competitive protection by TBL1 binding the same armadillo repeats during Wnt signaling.","evidence":"In vitro ubiquitination with purified components, Co-IP, competition assays","pmids":["20181957"],"confidence":"High","gaps":["Reconciliation of homodimer-sufficient activity with the SCF-like complex requirement","Stoichiometry of TBL1 competition in vivo not quantified"]},{"year":2012,"claim":"Identified a nitrosylation-dependent brake on SIAH1, with trans-nitrosylated B23/nucleophosmin disrupting the GAPDH-SIAH1 complex and abrogating ligase activity to confer neuroprotection.","evidence":"Co-IP, S-nitrosylation and C275S mutagenesis, E3 ligase assay, in vivo neurotoxicity model","pmids":["23027902"],"confidence":"High","gaps":["Threshold of NO needed to switch from activation to inhibition unclear","Generalizability beyond NMDA neurotoxicity not established"]},{"year":2014,"claim":"Placed SIAH1 in ER-stress signaling, induced via PERK/ATF4 and IRE1/sXBP1 and amplifying ATF4-driven death, with genetic protection from ischemia in compound-knockout mice.","evidence":"Compound knockout mice, MCAO model, ATF4 hydroxylation assay, siRNA","pmids":["24809345"],"confidence":"High","gaps":["SIAH1 versus SIAH2 individual contributions not separated","Direct ATF4 hydroxylase target not biochemically identified"]},{"year":2012,"claim":"Defined SIAH1 control of transcriptional elongation by degrading ELL1/ELL2, with access blocked when ELL2 is sequestered in the super elongation complex, linking SIAH1 levels to HIV-1 transcription.","evidence":"Co-IP, ubiquitination assay, siRNA, HIV transcription reporters across multiple studies","pmids":["22483617","29949759","32479599","32152128"],"confidence":"High","gaps":["Quantitative balance between SEC-bound protection and SIAH1-driven turnover in vivo unclear","Multiple competing protective factors (HCF1/2, DBC1/acetylation, PARP1) not integrated into one model"]},{"year":2019,"claim":"Showed isoform-selective substrate targeting in neurons, with SIAH1 degrading Akt3 specifically to restrain axonal branching, and a disease somatic mutation escaping degradation.","evidence":"Co-IP, ubiquitination assay, knockdown, Akt3-E17K mutagenesis, primary neuron imaging","pmids":["31471318"],"confidence":"High","gaps":["Structural basis for Akt3 versus Akt1/2 selectivity unknown","In vivo developmental phenotype not established"]},{"year":2022,"claim":"Expanded SIAH1's tumor-suppressive substrate set, degrading YBX-1, CPSF1, and FRK-phosphorylated YAP to influence chemosensitivity, splice-variant generation, and glioblastoma growth.","evidence":"Co-IP, site-specific ubiquitination mutagenesis, splicing/minigene and in vivo tumor assays","pmids":["35273154","35402071","35723276"],"confidence":"High","gaps":["m6A and phospho-dependent regulation of these axes not unified","Relative dominance among many competing substrates in a given cell type unresolved"]},{"year":null,"claim":"How SIAH1's single dimeric substrate-binding surface achieves recognition of dozens of structurally unrelated substrates, and what determines degradative versus non-degradative ubiquitination, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No co-structure with a bound degron substrate","Rules governing mono/di- versus poly-ubiquitination outcomes unknown","Hierarchy among competing substrates and regulators in vivo not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,19,14,17]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,13,14,17,31,35]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[38,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,18,25]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[31,35]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[24,53]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,14,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,19,37,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8,25,14,26]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[20,33,49]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[17,38]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[24,53]}],"complexes":["SIAH1/SIP(CacyBP)/Skp1/Ebi SCF-like ligase complex","SIAH1 homodimer"],"partners":["SIP/CACYBP","SKP1","GAPDH","HIPK2","ELL2","BETA-CATENIN","UBCH8","TBL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IUQ4","full_name":"E3 ubiquitin-protein ligase SIAH1","aliases":["RING-type E3 ubiquitin transferase SIAH1","Seven in absentia homolog 1","Siah-1","Siah-1a"],"length_aa":282,"mass_kda":31.1,"function":"E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:28546513, PubMed:32430360, PubMed:33591310, PubMed:9334332, PubMed:9858595). E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595). Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595). Triggers the ubiquitin-mediated degradation of many substrates, including proteins involved in transcription regulation (ELL2, MYB, POU2AF1, PML and RBBP8), a cell surface receptor (DCC), the cell-surface receptor-type tyrosine kinase FLT3, the cytoplasmic signal transduction molecules (KLF10/TIEG1 and NUMB), an antiapoptotic protein (BAG1), a microtubule motor protein (KIF22), a protein involved in synaptic vesicle function in neurons (SYP), a structural protein (CTNNB1) and SNCAIP (PubMed:10747903, PubMed:11146551, PubMed:11389839, PubMed:11389840, PubMed:11483517, PubMed:11483518, PubMed:11752454, PubMed:12072443). Confers constitutive instability to HIPK2 through proteasomal degradation (PubMed:18536714, PubMed:33591310). It is thereby involved in many cellular processes such as apoptosis, tumor suppression, cell cycle, axon guidance, transcription regulation, spermatogenesis and TNF signaling (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595). Has some overlapping function with SIAH2 (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595). Induces apoptosis in cooperation with PEG3 (By similarity). Upon nitric oxid (NO) generation that follows apoptotic stimulation, interacts with S-nitrosylated GAPDH, mediating the translocation of GAPDH to the nucleus (By similarity). GAPDH acts as a stabilizer of SIAH1, facilitating the degradation of nuclear proteins (By similarity). Mediates ubiquitination and degradation of EGLN2 and EGLN3 in response to the unfolded protein response (UPR), leading to their degradation and subsequent stabilization of ATF4 (By similarity). Also part of the Wnt signaling pathway in which it mediates the Wnt-induced ubiquitin-mediated proteasomal degradation of AXIN1 (PubMed:28546513, PubMed:32430360)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8IUQ4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIAH1","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SIAH1","total_profiled":1310},"omim":[{"mim_id":"619314","title":"BURATTI-HAREL SYNDROME; BURHAS","url":"https://www.omim.org/entry/619314"},{"mim_id":"616368","title":"CHOPS SYNDROME; CHOPS","url":"https://www.omim.org/entry/616368"},{"mim_id":"611223","title":"AKT SERINE/THREONINE KINASE 3; AKT3","url":"https://www.omim.org/entry/611223"},{"mim_id":"610421","title":"KH DOMAIN-CONTAINING, RNA-BINDING, SIGNAL TRANSDUCTION-ASSOCIATED PROTEIN 3; KHDRBS3","url":"https://www.omim.org/entry/610421"},{"mim_id":"609206","title":"EUKARYOTIC TRANSLATION ELONGATION FACTOR 1, EPSILON-1; EEF1E1","url":"https://www.omim.org/entry/609206"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Mitochondria","reliability":"Uncertain"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SIAH1"},"hgnc":{"alias_symbol":["hSIAH1"],"prev_symbol":[]},"alphafold":{"accession":"Q8IUQ4","domains":[{"cath_id":"3.30.40.10","chopping":"32-115","consensus_level":"high","plddt":94.4583,"start":32,"end":115},{"cath_id":"2.60.210.10","chopping":"153-280","consensus_level":"high","plddt":95.3303,"start":153,"end":280}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUQ4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUQ4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IUQ4-F1-predicted_aligned_error_v6.png","plddt_mean":89.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIAH1","jax_strain_url":"https://www.jax.org/strain/search?query=SIAH1"},"sequence":{"accession":"Q8IUQ4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IUQ4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IUQ4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IUQ4"}},"corpus_meta":[{"pmid":"15951807","id":"PMC_15951807","title":"S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding.","date":"2005","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15951807","citation_count":886,"is_preprint":false},{"pmid":"11389839","id":"PMC_11389839","title":"Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses.","date":"2001","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/11389839","citation_count":523,"is_preprint":false},{"pmid":"11389840","id":"PMC_11389840","title":"Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein.","date":"2001","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/11389840","citation_count":367,"is_preprint":false},{"pmid":"12399545","id":"PMC_12399545","title":"Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12399545","citation_count":227,"is_preprint":false},{"pmid":"9858595","id":"PMC_9858595","title":"Siah-1 N-terminal RING domain is required for proteolysis function, and C-terminal sequences regulate oligomerization and binding to target proteins.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9858595","citation_count":215,"is_preprint":false},{"pmid":"18536714","id":"PMC_18536714","title":"Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR.","date":"2008","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18536714","citation_count":167,"is_preprint":false},{"pmid":"27334109","id":"PMC_27334109","title":"The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway.","date":"2016","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27334109","citation_count":146,"is_preprint":false},{"pmid":"18065497","id":"PMC_18065497","title":"Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death.","date":"2007","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18065497","citation_count":145,"is_preprint":false},{"pmid":"12810624","id":"PMC_12810624","title":"Involvement of PEG10 in human hepatocellular carcinogenesis through interaction with SIAH1.","date":"2003","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12810624","citation_count":143,"is_preprint":false},{"pmid":"17047048","id":"PMC_17047048","title":"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.","date":"2006","source":"Cancer 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Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/35402071","citation_count":14,"is_preprint":false},{"pmid":"29321312","id":"PMC_29321312","title":"The E3 Ubiquitin Ligase Siah-1 Suppresses Avian Reovirus Infection by Targeting p10 for Degradation.","date":"2018","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/29321312","citation_count":14,"is_preprint":false},{"pmid":"35961388","id":"PMC_35961388","title":"Siah1 promotes the proliferation of NSCLC cells through ubiquitinating and stabilizing Notch1.","date":"2022","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35961388","citation_count":13,"is_preprint":false},{"pmid":"32671611","id":"PMC_32671611","title":"TRAF4, a new substrate of SIAH1, participates in chemotherapy resistance of breast cancer cell by counteracting SIAH1-mediated downregulation of β-catenin.","date":"2020","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/32671611","citation_count":13,"is_preprint":false},{"pmid":"30266288","id":"PMC_30266288","title":"Knockdown of miR-299-5p inhibits the progression of hepatocellular carcinoma by targeting SIAH1.","date":"2018","source":"Bulletin du cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30266288","citation_count":13,"is_preprint":false},{"pmid":"37062828","id":"PMC_37062828","title":"SIAH1 ubiquitination-modified HMGCR inhibits lung cancer progression and promotes drug sensitivity through cholesterol synthesis.","date":"2023","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/37062828","citation_count":12,"is_preprint":false},{"pmid":"11852084","id":"PMC_11852084","title":"The characterization of the human Siah-1 promoter(1).","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/11852084","citation_count":12,"is_preprint":false},{"pmid":"34355355","id":"PMC_34355355","title":"miR-129-5p Ameliorates Ischemic Brain Injury by Binding to SIAH1 and Activating the mTOR Signaling Pathway.","date":"2021","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/34355355","citation_count":11,"is_preprint":false},{"pmid":"16752048","id":"PMC_16752048","title":"Mutation analysis of the seven in absentia homolog 1 (SIAH1) gene in Parkinson's disease.","date":"2006","source":"Journal of neural transmission (Vienna, Austria : 1996)","url":"https://pubmed.ncbi.nlm.nih.gov/16752048","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49070,"output_tokens":12724,"usd":0.169035,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":24101,"output_tokens":5544,"usd":0.129552,"stage2_stop_reason":"end_turn"},"total_usd":0.298587,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"SIAH-1 N-terminal RING domain is required for proteolysis of target proteins (DCC), while C-terminal sequences regulate oligomerization and binding to substrates. Point mutations or deletion of the RING domain abolish DCC degradation and stabilize SIAH-1 itself. SIAH-1 undergoes self-degradation via the proteasome, blocked by RING domain mutations.\",\n      \"method\": \"Mutagenesis, co-immunoprecipitation, proteasome inhibitor assays, antisense knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain mutagenesis combined with functional proteolysis assays and antisense knockdown, multiple orthogonal methods in one study\",\n      \"pmids\": [\"9858595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SIAH-1 forms an SCF-like E3 ubiquitin ligase complex with SIP (a Sgt1 homolog), Skp1, and the F-box protein Ebi to mediate phosphorylation-independent degradation of beta-catenin; complex assembly is induced by p53 activation, linking genotoxic injury to beta-catenin destruction and reduced TCF/LEF activity.\",\n      \"method\": \"Co-immunoprecipitation, co-expression degradation assays, yeast two-hybrid\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and functional degradation assays, independently replicated by two concurrent papers (PMID 11389839 and 11389840)\",\n      \"pmids\": [\"11389839\", \"11389840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SIAH-1 interacts with the C-terminus of APC and promotes GSK3beta-phosphorylation-independent, beta-TrCP-independent degradation of beta-catenin; demonstrated by beta-catenin loss in mammalian cells and hypodorsalization in Xenopus embryos.\",\n      \"method\": \"Co-immunoprecipitation, overexpression degradation assay, Xenopus embryo microinjection\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mammalian cell degradation, Xenopus in vivo), replicated alongside PMID 11389839\",\n      \"pmids\": [\"11389840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SIAH-1 directly interacts with and promotes proteasomal degradation of Numb, leading to redistribution of Notch to the cytoplasm/nucleus and augmented Notch-regulated transcription.\",\n      \"method\": \"Co-immunoprecipitation, pulse-chase degradation assay, reporter assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional reporter assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"11752454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal/structural analysis revealed that SIAH-1 forms a dimer with a large electronegative concave surface across the dimer interface; site-directed mutagenesis of electronegative residues abolished SIAH-1 binding to SIP both in vitro and in cells.\",\n      \"method\": \"Structure-based analysis, site-directed mutagenesis, binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural analysis with mutagenesis validation in vitro and in cells, single lab but two orthogonal methods\",\n      \"pmids\": [\"12421809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SIAH-1 ubiquitinates and promotes proteasomal degradation of synphilin-1 via its RING finger domain; SIAH-1 interacts with the N-terminus of synphilin-1 through its substrate-binding domain; this degradation abrogates synphilin-1's inhibitory effect on dopamine release from PC12 cells. Notably, SIAH-1 does not ubiquitinate or degrade wild-type or mutant alpha-synuclein under these conditions.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from rat brain, confocal microscopy, ubiquitination assay, dopamine release assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro and in vivo ubiquitination assays plus functional readout (dopamine release), multiple orthogonal methods\",\n      \"pmids\": [\"14506261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PEG10 protein associates with SIAH1 and overexpression of PEG10 decreases SIAH1-mediated cell death, suggesting PEG10 functions as an antagonist of SIAH1 pro-apoptotic activity.\",\n      \"method\": \"Co-immunoprecipitation, cell death assay with overexpression\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus overexpression phenotype, single lab\",\n      \"pmids\": [\"12810624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SIAH-1 binds an octapeptide sequence in T-STAR and targets it for proteasome-dependent degradation; a double amino acid substitution in mouse T-STAR that mimics the human SIAH1-binding site brings mouse T-STAR under SIAH1 control. SIAH1-mediated degradation modulates T-STAR-dependent alternative splicing.\",\n      \"method\": \"Two-hybrid screening, in vivo degradation assay, minigene splicing assay, mutagenesis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis confirming binding site, functional splicing assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15163637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"S-nitrosylation of GAPDH at Cys-150 triggers its binding to SIAH-1; SIAH-1's nuclear localization signal mediates nuclear translocation of GAPDH; nuclear GAPDH stabilizes SIAH-1, facilitating SIAH-1-mediated degradation of nuclear proteins and apoptosis. Activation of macrophages or neurons elicits GAPDH-SIAH-1 binding and nuclear translocation.\",\n      \"method\": \"Co-immunoprecipitation, S-nitrosylation assay, nuclear fractionation, cell death assays, NO deletion experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple cell types, biochemical S-nitrosylation assays, genetic (NO deletion) confirmation, widely replicated\",\n      \"pmids\": [\"15951807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of the SIAH-1–SIP complex revealed that SIP engages SIAH-1 via two elements: an N-terminal dimerization domain across the upper surface of the SIAH-1 dimer through a PXAXVXP consensus motif, and a C-terminal Skp1-binding domain protruding from the lower surface. Both elements are required for beta-catenin destruction.\",\n      \"method\": \"X-ray crystallography, NMR, mutagenesis, cell-based beta-catenin degradation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis and functional validation in cells, multiple orthogonal methods\",\n      \"pmids\": [\"16085652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SIAH-1 interacts with the scaffold protein POSH to activate the JNK apoptotic pathway; E3 ligase activity of SIAH-1 is required for this proapoptotic effect. Apoptotic stimuli stabilize SIAH-1 protein via a mechanism dependent on JNK pathway activation, POSH interaction, and phosphorylation of SIAH-1 at tyrosines 100 and 126.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, phosphorylation mutagenesis, cell death assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RING mutant functional analysis, phosphorylation site mutagenesis, single lab\",\n      \"pmids\": [\"16230351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SIAH-1 ubiquitinates and promotes proteasomal degradation of FIH (factor inhibiting HIF-1alpha) under hypoxic conditions; SIAH-1 interacts with the JmjC domain of FIH through its substrate-binding domain and uses its RING domain for ubiquitination, thereby regulating HIF-1alpha transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, proteasome inhibitor experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus siRNA knockdown, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17188242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EBV oncoprotein LMP1 upregulates SIAH-1 protein stability, which in turn promotes proteasomal degradation of prolyl hydroxylases PHD1 and PHD3, preventing VHL-HIF-1alpha complex formation and stabilizing HIF-1alpha to activate angiogenic gene expression.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, proteasome inhibitor assay, immunoblot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-immunoprecipitation and siRNA-based functional assays, single lab\",\n      \"pmids\": [\"17047048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SIAH-1 binds alpha-synuclein and UbcH8 (a brain-enriched E2 enzyme) 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 toxicity. The PD-linked A30P mutation disrupts this ubiquitination; A53T does not.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, aggregation assay, mutagenesis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo ubiquitination assay, mutagenesis of disease-linked substrate residues, functional aggregation readout, single lab with multiple methods\",\n      \"pmids\": [\"18065497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SIAH-1 colocalizes with and ubiquitinates HIPK2 in unstressed cells, targeting it for proteasomal degradation. DNA damage triggers ATM/ATR-dependent phosphorylation of SIAH-1 at Ser-19, disrupting the HIPK2-SIAH-1 complex and stabilizing HIPK2 to promote apoptosis. Conversely, after sublethal damage, p53-induced SIAH-1 expression drives HIPK2 degradation to promote recovery.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, site-directed mutagenesis of Ser-19, ATM/ATR inhibitor experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted ubiquitination assay, phospho-site mutagenesis, genetic knockdown with clear phenotypic readout, multiple orthogonal methods\",\n      \"pmids\": [\"18536714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Structure of S100A6 bound to a SIP fragment (residues 189-219) determined by NMR; SIP(189-219) forms two helices engaging S100A6 in both canonical and novel binding modes. Structure-based mutagenesis confirmed reduced binding; cell-based assay showed S100A6 modulates SCF(TBL1)/SIAH-1 complex activity on beta-catenin.\",\n      \"method\": \"NMR structure determination, isothermal titration calorimetry, mutagenesis, cell-based functional assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with mutagenesis validation and functional cell assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18803400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SIAH-1 interacts with, ubiquitinates, and promotes proteasomal degradation of TRB3 (Tribbles 3 homolog); co-expression of SIAH-1 reverses TRB3-mediated upregulation of TGF-beta signaling.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, overexpression degradation assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP and ubiquitination assay with functional signaling readout, single lab\",\n      \"pmids\": [\"18276110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SIAH-1 ubiquitinates EB3 (end-binding protein 3) promoting its proteasomal degradation; Aurora-A and Aurora-B phosphorylate EB3 at Ser-176, disrupting the EB3-SIAH-1 complex to stabilize EB3 during mitosis and facilitate cell cycle progression at prometaphase.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, phosphorylation site mutagenesis, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ubiquitination assay with phospho-site mutagenesis and functional cell cycle phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19696028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SIAH-1 is required for high glucose-induced GAPDH nuclear accumulation and cell death in retinal Müller cells; SIAH-1 forms a complex with GAPDH under hyperglycemic conditions and is predominantly nuclear; siRNA knockdown of SIAH-1 blocks GAPDH nuclear translocation and prevents high glucose-induced cell death via inhibiting p53 phosphorylation.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, nuclear fractionation, cell death assay (annexin V, caspase)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with subcellular fractionation and functional cell death assay, single lab\",\n      \"pmids\": [\"19940145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SIAH-1 alone is sufficient to polyubiquitinate beta-catenin in vitro; TBL1 competes with SIAH-1 for binding to the same armadillo repeat domain of beta-catenin, protecting beta-catenin from SIAH-1-mediated ubiquitination and proteasomal degradation during Wnt signaling.\",\n      \"method\": \"In vitro ubiquitination assay with purified components, co-immunoprecipitation, overexpression/knockdown degradation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted ubiquitination assay with purified proteins, confirmed by cell-based competition experiments, single lab\",\n      \"pmids\": [\"20181957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SIAH-1 (but not SIAH-2) is the E3 ubiquitin ligase for ELL2 polyubiquitination and proteasomal degradation; SIAH-1 cannot access ELL2 when bound in the AFF4 super elongation complex (SEC). At high concentrations, SIAH-1 also degrades AFF4/1 to dismantle SECs. Prostratin and HMBA activate HIV transcription by decreasing SIAH-1 expression and ELL2 ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, HIV transcription reporter assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, siRNA knockdown with functional HIV transcription readout, multiple orthogonal methods\",\n      \"pmids\": [\"22483617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SIAH-1 interacts with and promotes ubiquitin/proteasome-dependent degradation of the hepatitis B viral X protein (HBx), attenuating HBx-mediated transactivation of GRE, HSE, and CRE promoters; SIAH-1 participates in p53-mediated HBx degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, transcriptional reporter assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional reporter assay, single lab\",\n      \"pmids\": [\"21878328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SIAH-1 interacts with, polyubiquitinates, and promotes proteasomal degradation of PML-RARα via the E2 enzyme UBCH8; TRIAD1 also binds UBCH8 and PML-RARα but, in contrast to SIAH-1/SIAH-2, does not affect PML-RARα turnover.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown degradation assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with side-by-side comparison of SIAH1 vs TRIAD1, single lab\",\n      \"pmids\": [\"22037423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SIAH-1 interacts with and promotes ubiquitination and proteasomal degradation of HSV ICP0; ICP0 in turn stabilizes SIAH-1 and recruits it into ICP0-containing nuclear bodies. In SIAH-1 knockdown cells, ICP0 levels are higher, less ubiquitinated, and more stable.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay in vitro and in vivo, siRNA knockdown, half-life assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo ubiquitination assays plus siRNA functional readout, single lab\",\n      \"pmids\": [\"21632771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SIAH-1 is required for synphilin-1-dependent PINK1-independent mitophagy; synphilin-1 recruits SIAH-1 to mitochondria where SIAH-1 promotes mitochondrial protein ubiquitination and subsequent mitophagy. Catalytically inactive SIAH-1 mutant or SIAH-1 knockdown abrogates this mitophagy pathway.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, dominant-negative mutant, LC3/Lamp1 recruitment assay, mitophagy flux assay (Atg5 knockdown)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus catalytic mutant plus siRNA knockdown with mitophagy phenotype, single lab\",\n      \"pmids\": [\"27334109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"B23/nucleophosmin binds both SIAH-1 and GAPDH in the nucleus; trans-nitrosylation of B23 at Cys-275 by GAPDH enhances B23-SIAH-1 interaction and disrupts the SIAH-1-GAPDH complex; S-nitrosylated B23 abrogates SIAH-1 E3 ligase activity, providing neuroprotection against NMDA-mediated neurotoxicity.\",\n      \"method\": \"Co-immunoprecipitation, S-nitrosylation assay, mutagenesis (C275S), E3 ligase activity assay, in vivo neurotoxicity model\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution of interaction, mutagenesis, E3 ligase activity assay, in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23027902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SIAH-1/2 are transcriptionally induced by ER stress through PERK/ATF4 and IRE1/sXBP1 pathways; SIAH-1/2 attenuate proline hydroxylation of ATF4, stabilizing it and amplifying ER stress-induced cell death. Siah1a+/-::Siah2-/- mice show smaller infarct volume and protection from ischemia-induced death compared to WT.\",\n      \"method\": \"Genetic mouse model (compound knockout), siRNA knockdown in cultured cells, middle cerebral artery occlusion model, ATF4 hydroxylation assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic rescue using compound knockout mice plus cell-based mechanistic assays, multiple orthogonal methods\",\n      \"pmids\": [\"24809345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SIAH-1/SIP E3 ligase complex mediates glucose starvation-induced proteasomal degradation of cytoplasmic p27(kip1), thereby decreasing cell motility; SIP-/- fibroblasts have elevated cytoplasmic p27 and increased cell migration.\",\n      \"method\": \"siRNA knockdown, SIP knockout fibroblasts, co-immunoprecipitation, proteasome inhibitor assay, cell migration assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout fibroblasts plus siRNA and co-IP, single lab\",\n      \"pmids\": [\"21734459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ASK1 (apoptosis signal-regulating kinase 1) interacts with both GAPDH and SIAH-1 and phosphorylates SIAH-1 at Thr-70/74 and Thr-235/239; this phosphorylation triggers GAPDH-SIAH-1 stress signaling and activates p300 acetyltransferase in the nucleus.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phospho-site mutagenesis, p300 activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and downstream functional readout, single lab\",\n      \"pmids\": [\"25391652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"High glucose increases SIAH-1 protein levels, induces GAPDH-SIAH-1 complex formation, and causes GAPDH nuclear translocation in human retinal pericytes; blocking the GAPDH-SIAH-1 interaction with directed peptides prevents high glucose-induced pericyte apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, GAPDH/SIAH-1-blocking peptides, nuclear fractionation, apoptosis assay (annexin V, caspase-3)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus blocking peptide experiments plus siRNA with functional apoptosis readout, single lab\",\n      \"pmids\": [\"26438826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PARP1 suppresses SIAH-1 at both mRNA level (via NCoR co-repressor complex) and protein level (promoting PARylation-dependent ubiquitination of SIAH-1), thereby elevating ELL2 to form more super elongation complexes and activate HIV-1 transcription.\",\n      \"method\": \"siRNA knockdown, PARP1 inhibitor, co-immunoprecipitation, ubiquitination assay, HIV transcription assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA plus PARP inhibitor plus Co-IP with functional HIV transcription readout, single lab\",\n      \"pmids\": [\"29949759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIAH-1 ubiquitinates Akt3 (but not Akt1 or Akt2) preferentially and promotes its degradation; Akt3 is enriched in axonal shafts where SIAH-1 is prominent. Depletion of SIAH-1 elevates Akt3 levels and causes aberrant axonal branching. The brain-specific Akt3-E17K somatic mutation escapes SIAH-1-mediated degradation, causing dysmorphic neurons.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA/shRNA knockdown, overexpression with mutagenesis, primary neuron imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assay, disease-relevant mutagenesis, and functional neural phenotype, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31471318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HCF1 and HCF2 bind and block the substrate-binding domain (SBD) of SIAH-1/2 to prevent SIAH-1 autoubiquitination and trans-ubiquitination of ELL2, thereby stabilizing ELL2 and enhancing super elongation complex formation for HIV-1 transactivation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, HCF1/2 knockdown, HIV transcription assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with functional HIV transcription readout, single lab\",\n      \"pmids\": [\"32479599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DBC1 competes with HDAC3 for the same binding sites on ELL1, promoting p300-mediated ELL1 acetylation which stabilizes it against SIAH-1-mediated polyubiquitylation; SIAH-1 ubiquitylates deacetylated ELL1 for proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, acetylation assay, siRNA knockdown, competition binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay plus acetylation modification assay, single lab, multiple methods\",\n      \"pmids\": [\"32152128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIAH-1 binds to and ubiquitinates MyD88, targeting it for proteasomal degradation; SIAH-1 knockdown increases MyD88-dependent TLR7 signaling; dengue virus induces SIAH-1 expression via the unfolded protein response during infection, dampening innate immunity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, CRISPR MyD88 knockout, TLR7 signaling assay\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, CRISPR knockout functional validation, single lab\",\n      \"pmids\": [\"32117091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIAH-1 ubiquitinates YBX-1 at Lys304 via its RING finger domain in the cytoplasm, targeting it for degradation; YBX-1 destabilization leads to instability of its m5C-modified mRNA targets, sensitizing ovarian cancer cells to cisplatin.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with site-specific mutagenesis (Lys304), siRNA knockdown, in vitro and in vivo tumor assays\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ubiquitination assay with defined ubiquitination site mutagenesis and functional drug sensitivity phenotype in vitro and in vivo, single lab\",\n      \"pmids\": [\"35273154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIAH-1 ubiquitinates XIAP, targeting it for proteasomal degradation in nucleus pulposus cells; this promotes NPC senescence and apoptosis in intervertebral disc degeneration; METTL3-mediated m6A methylation of SIAH-1 mRNA enhances its expression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, m6A RIP, actinomycin D mRNA stability assay\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus m6A RIP with functional phenotype, single lab\",\n      \"pmids\": [\"35580525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FRK phosphorylates YAP at Tyr391/407/444, which recruits SIAH-1 to catalyze YAP ubiquitination and proteasomal degradation in glioblastoma; SIAH-1 is required for YAP destabilization initiated by FRK.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, ubiquitination assay, phosphorylation site mutagenesis, siRNA knockdown, in vivo tumor model\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — Co-IP with mutagenesis, ubiquitination assay, functional in vivo tumor model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35723276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SIAH-1 interacts with alpha-tubulin and promotes proteasomal degradation of the chromokinesin Kid (KIF22) via its RING finger domain during mitosis; overexpression of SIAH-1 but not a deletion mutant lacking the N-terminal domain reduces kinesin levels and disrupts mitosis.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, overexpression degradation assay, dominant-negative mutant\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, functional degradation with dominant-negative mutant, single lab\",\n      \"pmids\": [\"11146551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SIAH-1 interacts via its C-terminal part with the N-terminus of OBF-1 transcriptional coactivator, leading to OBF-1 protein downregulation via the ubiquitin-proteasome pathway without changing OBF-1 mRNA, and reducing octamer site-dependent transcription; inhibiting the proteasome in B cells elevates OBF-1 protein.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, proteasome inhibitor assay, reporter gene assay, domain mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus proteasome inhibitor plus reporter assay, single lab, multiple methods\",\n      \"pmids\": [\"11483517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SIAH-1 interacts with CtIP (CtBP-interacting protein) and promotes its proteasomal degradation; however, p21(WAF1) induction by SIAH-1 does not require CtIP degradation, as a RING-deleted SIAH-1 that binds but cannot degrade CtIP still induces p21 transcription to a similar extent.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitin-proteasome assay, reporter assay, dominant-negative mutant\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus RING-deletion functional dissection, single lab; negative finding about CtIP-p21 link is mechanistically informative\",\n      \"pmids\": [\"14654780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SIAH-1 interacts with the cytoplasmic C-terminus of polycystin-1 (PKD1) and promotes its ubiquitination and proteasomal degradation, shortening PKD1-C half-life; overexpression of SIAH-1 promotes degradation of polycystin-1 in membrane-anchored chimeric proteins.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, pulse-chase half-life assay\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, ubiquitination and half-life assays, single lab\",\n      \"pmids\": [\"15284290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KSHV ORF45 protein interacts with SIAH-1, and SIAH-1 promotes proteasomal degradation of ORF45 through a RING domain-dependent mechanism in infected cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, half-life assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP and ubiquitination assay with RING domain requirement established, single lab\",\n      \"pmids\": [\"18077711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SIAH-1 mediates proteasomal degradation of HIPK2; this degradation is blocked by MLK3, EBV LMP-1, or DNA damaging stimuli, revealing multiple pathways that stabilize HIPK2 by escaping SIAH-1-dependent degradation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, overexpression/knockdown\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay, consistent with PMID 18536714 but less mechanistically detailed, single lab\",\n      \"pmids\": [\"19250734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EHMT2 histone methyltransferase suppresses SIAH1 transcription by binding its promoter region (-293 to +51) and methylating H3K9, thereby reducing SIAH1 expression and promoting cancer cell proliferation.\",\n      \"method\": \"ChIP, promoter reporter assay, siRNA knockdown, western blot\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with promoter reporter assay and functional siRNA knockdown, single lab\",\n      \"pmids\": [\"21847359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SIAH-1 ubiquitinates and promotes proteasomal degradation of synaptophysin under combined hypoxia and high glucose conditions, mediated by ERK pathway activation; ERK inhibition or SIAH-1 knockdown rescues synaptophysin levels.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, overexpression, ERK inhibitor\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus siRNA knockdown with functional synaptophysin expression readout, single lab\",\n      \"pmids\": [\"25755825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIAH-1/2 promote Th17 cell differentiation by maintaining stability of HIF-1alpha protein, which directly regulates Il17a and Rorgt transcription; in the absence of HIF-1alpha, SIAH1 and SIAH2 have little effect on Th17 differentiation.\",\n      \"method\": \"cDNA library screen, promoter reporter assay, ex vivo Th17 differentiation, genetic (HIF-1alpha knockout) epistasis\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis using HIF-1alpha KO plus ex vivo differentiation assay, single lab\",\n      \"pmids\": [\"28338984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HIF-1alpha occupies the SIAH1 promoter in response to nutritional stress and recruits the histone demethylase KDM3A (via p300 crosstalk) to activate SIAH1 transcription through H3K9 demethylation and H3K4 trimethylation/H3 acetylation; HIF-1alpha or KDM3A depletion prevents SIAH1 induction.\",\n      \"method\": \"ChIP, siRNA knockdown, chetomin inhibitor, promoter reporter assay, histone modification analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with siRNA knockdown and promoter reporter, single lab\",\n      \"pmids\": [\"28843785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIAH-1 ubiquitinates ZEB1, targeting it for proteasomal degradation; SIAH-1 overexpression inhibits ZEB1 expression and sensitizes drug-resistant osteosarcoma cells to doxorubicin; upregulation of ZEB1 in resistant cells is due to increased protein half-life associated with reduced SIAH-1 activity.\",\n      \"method\": \"siRNA/overexpression, proteasome inhibitor, western blot half-life analysis\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression/knockdown without explicit Co-IP or ubiquitination assay, single lab\",\n      \"pmids\": [\"30265649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIAH-1 directly interacts with and promotes ubiquitination/degradation of CPSF1; CPSF1 degradation by SIAH-1 reduces generation of the oncogenic AR-v7 splice variant by removing CPSF1 binding to the AR-cryptic exon CE3 polyadenylation signal; m6A methylation of SIAH1 mRNA in PCa represses its expression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, m6A analysis, minigene/splicing assay\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional splicing assay, single lab\",\n      \"pmids\": [\"35402071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"E2F1 transcription factor directly binds two putative E2F1-binding sites upstream of the SIAH1 transcription start site, activates SIAH1 promoter activity (by luciferase assay and ChIP), and elevates SIAH1 protein levels, thereby suppressing beta-catenin/TCF activity.\",\n      \"method\": \"Chromatin immunoprecipitation, luciferase reporter assay, shRNA knockdown, western blot\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase reporter plus shRNA knockdown epistasis, single lab\",\n      \"pmids\": [\"20187294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SIAH-1 promoter has no TATA or CCAAT box; an Sp1 site is responsible for basal promoter activity; p53 upregulates SIAH-1 mRNA but does not directly activate the proximal promoter in reporter assays, suggesting the p53 responsive element lies in a different region.\",\n      \"method\": \"Promoter deletion/mutation reporter assay, Northern blot, co-transfection\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic promoter deletion with mutagenesis of key Sp1 site, single lab; p53 result is mechanistically informative as a negative result for the proximal promoter\",\n      \"pmids\": [\"11852084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A novel splice variant of SIAH-1, designated Siah-1S, forms heterodimers with SIAH-1 or homodimers that cannot bind SIP; Siah-1S catalyzes self-ubiquitination and acts as a dominant-negative against SIAH-1 to upregulate beta-catenin/TCF activity and antagonize SIAH-1-mediated apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, dimerization assay, ubiquitination assay, reporter assay, soft agar colony assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional reporter and colony assay, single lab\",\n      \"pmids\": [\"17420721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIAH-1 is essential for sorafenib-induced mitophagy; SIAH-1 silencing markedly represses mitophagy and sensitizes cells to sorafenib-induced death in hepatocellular carcinoma cells.\",\n      \"method\": \"siRNA knockdown, mitophagy flux assay (mKeima-Red, LC3, PINK1 accumulation), combination treatment in vitro and in vivo\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with mitophagy flux assay and in vivo xenograft, single lab\",\n      \"pmids\": [\"36385558\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIAH1 is a RING-domain E3 ubiquitin ligase that functions as a homodimer (or in an SCF-like complex with SIP/CacyBP, Skp1, and Ebi/TBL1) to polyubiquitinate and promote proteasomal degradation of a broad range of substrates—including beta-catenin (phosphorylation-independently), HIPK2, ELL1/ELL2, alpha-synuclein (non-degradative mono/di-ubiquitination promoting aggregation), synphilin-1, DCC, Numb, Kid, EB3, TRB3, FIH, MyD88, YBX-1, CPSF1, Akt3, and YAP—with substrate specificity modulated by complex partners and post-translational modifications; SIAH1 activity is regulated by ATM/ATR-dependent phosphorylation (Ser-19), ASK1-dependent phosphorylation (Thr-70/74, Thr-235/239), S-nitrosylation via GAPDH interaction, and competitor proteins (TBL1, B23, HCF1/2), while its own transcription is induced by p53, HIF-1α/KDM3A, and E2F1, and repressed by EHMT2-mediated H3K9 methylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIAH1 is a RING-domain E3 ubiquitin ligase that controls the abundance of a broad set of signaling, transcriptional, and cytoskeletal proteins by directing them to the proteasome, thereby intersecting Wnt, hypoxia, DNA-damage, and apoptotic pathways [#0, #14]. Its catalytic activity requires the N-terminal RING domain—mutations there abolish substrate proteolysis and stabilize SIAH1 itself, which otherwise undergoes proteasomal self-degradation—while C-terminal sequences mediate oligomerization and substrate binding [#0]. SIAH1 functions as a homodimer presenting an electronegative substrate-engaging surface, and can assemble into an SCF-like complex with the adaptor SIP/CacyBP, Skp1, and the F-box protein Ebi to mediate phosphorylation-independent, beta-TrCP-independent degradation of beta-catenin, linking p53 activation to suppression of TCF/LEF transcription [#1, #2, #4, #9, #19]. Through this ubiquitin-ligase activity SIAH1 targets numerous substrates including HIPK2, the elongation factors ELL1/ELL2 within the super elongation complex, EB3 and the chromokinesin Kid during mitosis, Numb, Akt3, YAP, MyD88, FIH, TRB3, CPSF1, and YBX-1 [#14, #20, #17, #38, #3, #31, #37, #34, #11, #16, #49, #35]. A distinct non-degradative mode is seen with alpha-synuclein, where SIAH1 together with the E2 UbcH8 catalyzes mono- and di-ubiquitination that promotes aggregation and toxicity rather than turnover, while it degrades the related protein synphilin-1 [#13, #5]. Substrate selection and ligase output are tuned by post-translational modification of substrates and competitor proteins: phosphorylation of EB3, YAP, and SIAH1 itself (ATM/ATR-dependent Ser-19, ASK1-dependent Thr residues) gate complex formation, and TBL1, HCF1/2, and B23/nucleophosmin block substrate access or catalysis [#14, #17, #28, #19, #32, #25]. A separate, catalysis-dependent role couples SIAH1 to stress signaling and cell death: S-nitrosylated GAPDH binds SIAH1 and is escorted to the nucleus where it stabilizes SIAH1 to drive degradation of nuclear targets and apoptosis, a cascade implicated in hyperglycemic and excitotoxic cell death [#8, #25, #18, #29]. SIAH1 also promotes mitophagy when recruited to mitochondria [#24, #53]. Its own transcription is induced by E2F1 and by HIF-1alpha acting with KDM3A, and repressed by EHMT2-mediated H3K9 methylation [#50, #47, #44].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that SIAH1 is a self-regulating RING-dependent E3 ligase, defining the catalytic module (N-terminal RING) versus the substrate/oligomerization module (C-terminus) that organizes all later mechanism.\",\n      \"evidence\": \"Domain mutagenesis, Co-IP, proteasome inhibitor and antisense assays on DCC degradation\",\n      \"pmids\": [\"9858595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the E2 partner\", \"Substrate repertoire beyond DCC unknown at the time\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Extended SIAH1 substrate control to mitotic machinery, showing it degrades the chromokinesin Kid and associates with alpha-tubulin during mitosis.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, RING-deletion degradation assays\",\n      \"pmids\": [\"11146551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstituted ubiquitination\", \"Physiological consequence of Kid turnover only inferred from overexpression\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined a major signaling output—phosphorylation-independent destruction of beta-catenin—through an SCF-like SIAH1/SIP/Skp1/Ebi complex assembled downstream of p53, connecting genotoxic stress to Wnt pathway shutdown.\",\n      \"evidence\": \"Reciprocal Co-IP, co-expression degradation, yeast two-hybrid, Xenopus microinjection across two concurrent papers\",\n      \"pmids\": [\"11389839\", \"11389840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of substrate recognition without phospho-degron unresolved\", \"Relative contribution of APC interaction versus SCF complex unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Provided the structural basis for SIAH1 dimerization and adaptor engagement, showing an electronegative dimer-interface surface required for SIP binding.\",\n      \"evidence\": \"Structure-based analysis with site-directed mutagenesis and binding assays\",\n      \"pmids\": [\"12421809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of a bound degron substrate\", \"Did not resolve how diverse substrates dock the same surface\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Distinguished SIAH1's substrate selectivity within Parkinson's-relevant proteins, degrading synphilin-1 (relieving its inhibition of dopamine release) but not alpha-synuclein under those conditions.\",\n      \"evidence\": \"Yeast two-hybrid, brain Co-IP, ubiquitination and dopamine-release assays\",\n      \"pmids\": [\"14506261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conditions permitting alpha-synuclein handling not yet defined\", \"In vivo relevance to neurodegeneration not shown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Uncovered a redox-controlled apoptotic axis: S-nitrosylated GAPDH binds SIAH1, which provides the nuclear import signal and is reciprocally stabilized, enabling nuclear substrate degradation and cell death.\",\n      \"evidence\": \"Reciprocal Co-IP, S-nitrosylation assays, nuclear fractionation, NO-deletion genetics in macrophages and neurons\",\n      \"pmids\": [\"15951807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the critical nuclear substrates driving death incompletely mapped\", \"Quantitative contribution of GAPDH stabilization versus other inputs unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved how the SIP adaptor bridges SIAH1 to Skp1, defining two structural elements both required for beta-catenin destruction.\",\n      \"evidence\": \"X-ray crystallography, NMR, mutagenesis, cell-based beta-catenin degradation\",\n      \"pmids\": [\"16085652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture beta-catenin within the complex\", \"F-box/Ebi positioning not structurally resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed a non-degradative ubiquitination mode in which SIAH1 with UbcH8 mono/di-ubiquitinates alpha-synuclein to promote aggregation rather than turnover, with disease mutations differentially affected.\",\n      \"evidence\": \"In vivo ubiquitination, aggregation assays, A30P/A53T mutagenesis\",\n      \"pmids\": [\"18065497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinant selecting mono/di- versus poly-ubiquitination unknown\", \"In vivo aggregation consequence not tested in animal models\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed SIAH1 activity is gated by DNA-damage signaling: ATM/ATR phosphorylation of Ser-19 dissociates the HIPK2 complex to stabilize HIPK2 and switch cells between recovery and apoptosis.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, Ser-19 mutagenesis, ATM/ATR inhibition, siRNA\",\n      \"pmids\": [\"18536714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase-substrate phosphorylation not reconstituted in vitro\", \"Other phospho-regulated substrate complexes not surveyed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated phospho-gating of a mitotic substrate, with Aurora-A/B phosphorylation of EB3 disrupting the SIAH1 complex to stabilize EB3 for prometaphase progression.\",\n      \"evidence\": \"Ubiquitination assay, phospho-site mutagenesis, cell cycle analysis, siRNA\",\n      \"pmids\": [\"19696028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SIAH1 acts on EB3 in interphase unclear\", \"Connection to the alpha-tubulin/Kid mitotic roles not integrated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Proved SIAH1 alone is a sufficient beta-catenin ligase in vitro and identified competitive protection by TBL1 binding the same armadillo repeats during Wnt signaling.\",\n      \"evidence\": \"In vitro ubiquitination with purified components, Co-IP, competition assays\",\n      \"pmids\": [\"20181957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of homodimer-sufficient activity with the SCF-like complex requirement\", \"Stoichiometry of TBL1 competition in vivo not quantified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a nitrosylation-dependent brake on SIAH1, with trans-nitrosylated B23/nucleophosmin disrupting the GAPDH-SIAH1 complex and abrogating ligase activity to confer neuroprotection.\",\n      \"evidence\": \"Co-IP, S-nitrosylation and C275S mutagenesis, E3 ligase assay, in vivo neurotoxicity model\",\n      \"pmids\": [\"23027902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Threshold of NO needed to switch from activation to inhibition unclear\", \"Generalizability beyond NMDA neurotoxicity not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed SIAH1 in ER-stress signaling, induced via PERK/ATF4 and IRE1/sXBP1 and amplifying ATF4-driven death, with genetic protection from ischemia in compound-knockout mice.\",\n      \"evidence\": \"Compound knockout mice, MCAO model, ATF4 hydroxylation assay, siRNA\",\n      \"pmids\": [\"24809345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SIAH1 versus SIAH2 individual contributions not separated\", \"Direct ATF4 hydroxylase target not biochemically identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined SIAH1 control of transcriptional elongation by degrading ELL1/ELL2, with access blocked when ELL2 is sequestered in the super elongation complex, linking SIAH1 levels to HIV-1 transcription.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, siRNA, HIV transcription reporters across multiple studies\",\n      \"pmids\": [\"22483617\", \"29949759\", \"32479599\", \"32152128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative balance between SEC-bound protection and SIAH1-driven turnover in vivo unclear\", \"Multiple competing protective factors (HCF1/2, DBC1/acetylation, PARP1) not integrated into one model\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed isoform-selective substrate targeting in neurons, with SIAH1 degrading Akt3 specifically to restrain axonal branching, and a disease somatic mutation escaping degradation.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, knockdown, Akt3-E17K mutagenesis, primary neuron imaging\",\n      \"pmids\": [\"31471318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for Akt3 versus Akt1/2 selectivity unknown\", \"In vivo developmental phenotype not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded SIAH1's tumor-suppressive substrate set, degrading YBX-1, CPSF1, and FRK-phosphorylated YAP to influence chemosensitivity, splice-variant generation, and glioblastoma growth.\",\n      \"evidence\": \"Co-IP, site-specific ubiquitination mutagenesis, splicing/minigene and in vivo tumor assays\",\n      \"pmids\": [\"35273154\", \"35402071\", \"35723276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"m6A and phospho-dependent regulation of these axes not unified\", \"Relative dominance among many competing substrates in a given cell type unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SIAH1's single dimeric substrate-binding surface achieves recognition of dozens of structurally unrelated substrates, and what determines degradative versus non-degradative ubiquitination, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-structure with a bound degron substrate\", \"Rules governing mono/di- versus poly-ubiquitination outcomes unknown\", \"Hierarchy among competing substrates and regulators in vivo not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 19, 14, 17]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 13, 14, 17, 31, 35]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [38, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 18, 25]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [31, 35]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [24, 53]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 14, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 19, 37, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 25, 14, 26]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [20, 33, 49]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [17, 38]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [24, 53]}\n    ],\n    \"complexes\": [\n      \"SIAH1/SIP(CacyBP)/Skp1/Ebi SCF-like ligase complex\",\n      \"SIAH1 homodimer\"\n    ],\n    \"partners\": [\n      \"SIP/CacyBP\",\n      \"Skp1\",\n      \"GAPDH\",\n      \"HIPK2\",\n      \"ELL2\",\n      \"beta-catenin\",\n      \"UbcH8\",\n      \"TBL1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}