{"gene":"PTTG1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1997,"finding":"Overexpression of PTTG in mouse 3T3 fibroblasts inhibits cell proliferation and induces cell transformation in vitro; injection of transfected cells into athymic nude mice resulted in tumor formation, establishing PTTG as a transforming oncogene.","method":"Stable transfection of NIH 3T3 fibroblasts, soft-agar transformation assay, nude mouse tumor formation assay","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean gain-of-function in two orthogonal assays (in vitro transformation and in vivo tumorigenesis), single lab","pmids":["9092795"],"is_preprint":false},{"year":1999,"finding":"Human PTTG protein contains two C-terminal PXXP motifs that serve as SH3-domain binding sites; site-directed mutagenesis of these proline residues abrogates PTTG in vitro transforming activity, in vivo tumor-inducing activity, and stimulation of bFGF secretion.","method":"Site-directed mutagenesis of PXXP motifs, NIH 3T3 transformation assay, nude mouse tumor assay, bFGF secretion measurement","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with multiple orthogonal functional readouts (transformation, tumorigenesis, growth factor secretion) in a single rigorous study","pmids":["9892021"],"is_preprint":false},{"year":1998,"finding":"hPTTG is mainly a cytosolic protein with partial nuclear localization; its acidic C-terminal domain acts as a transcriptional transactivation domain when fused to a heterologous DNA-binding domain, active in both yeast and mammalian cells.","method":"Subcellular fractionation, transactivation reporter assay (yeast and mammalian cells)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal systems (yeast + mammalian) for transactivation, single lab, fractionation for localization","pmids":["9811450"],"is_preprint":false},{"year":2000,"finding":"hPTTG protein level peaks in mitosis and is phosphorylated during mitosis; immunodepletion and in vitro phosphorylation experiments with a specific inhibitor identified Cdc2 (CDK1) as the kinase that phosphorylates hPTTG.","method":"Cell cycle synchronization, immunodepletion, in vitro phosphorylation assay, CDK1 inhibitor treatment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation assay plus immunodepletion plus specific inhibitor, multiple orthogonal methods in one study","pmids":["10656688"],"is_preprint":false},{"year":2000,"finding":"Murine PTTG possesses transcriptional transactivation activity that correlates with its transforming properties; Pro139, Ser159, PPXP motif, and a hydrophobic stretch are required for transactivation, and Ala substitution at Pro139 abolishes both transactivation and transformation.","method":"Transactivation reporter assay, site-directed mutagenesis, NIH 3T3 transformation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with functional transactivation and transformation assays, multiple residues tested","pmids":["10713046"],"is_preprint":false},{"year":2000,"finding":"PTTG-EGFP colocalizes with mitotic spindles in early mitosis and is degraded at anaphase; overexpression of wild-type PTTG-EGFP causes most cells to die by apoptosis, while a mutant PTTG-EGFP lacking the SH3-binding domain allows cell division, demonstrating that PTTG regulates endocrine tumor cell division and survival in a PXXP-dependent manner.","method":"Live-cell imaging of EGFP-PTTG conjugates, real-time fluorescence microscopy of cell cycle progression","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with functional comparison of WT vs. mutant, single lab","pmids":["10935539"],"is_preprint":false},{"year":2001,"finding":"Human securin/PTTG degradation is catalyzed by both fzy (Cdc20) and fzr (Cdh1) APC/C activators via an RXXL destruction box and a KEN box; non-degradable securin (both sequences mutated) causes incomplete chromatid separation but does not prevent cytokinesis.","method":"In vitro ubiquitination assay with fzy/fzr, expression of non-degradable securin mutant in cells, mitotic phenotype analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination reconstitution plus cellular phenotype with double-mutant securin, multiple orthogonal methods","pmids":["11179223"],"is_preprint":false},{"year":2001,"finding":"hPTTG binds to Ku heterodimer (the regulatory subunit of DNA-PK) both in vitro and in vivo; DNA-PK catalytic subunit phosphorylates hPTTG in vitro; DNA double-strand breaks prevent hPTTG–Ku association, suggesting PTTG connects DNA-damage response to sister chromatid separation.","method":"Co-immunoprecipitation (in vivo), in vitro binding assay (pull-down), in vitro kinase assay, DNA damage induction","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution (binding + kinase assay) plus reciprocal co-IP, functional disruption by DNA damage","pmids":["11238996"],"is_preprint":false},{"year":2002,"finding":"Human securin/PTTG1 interacts directly with p53 (demonstrated by pull-down and co-IP both in vitro and in vivo); this interaction blocks p53 binding to DNA, inhibits p53 transcriptional activity, and inhibits p53-induced cell death; PTTG1-deficient cells show potentiated p53 apoptotic and transactivating functions.","method":"Phage-display screening, pull-down assay, co-immunoprecipitation, transcriptional reporter assay, apoptosis assay in PTTG1-/- cells","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, in vitro pull-down, reporter assays, and loss-of-function genetic validation in PTTG1-/- cells","pmids":["12355087"],"is_preprint":false},{"year":2003,"finding":"Securin and B-cyclin/CDK are the only obligatory APC/C targets in S. cerevisiae; simultaneous removal of securin (Pds1) and B-cyclin/CDK renders all eight essential APC subunits dispensable, establishing that these two substrates explain APC essentiality.","method":"Genetic epistasis in S. cerevisiae — double-deletion/bypass suppression of APC subunit mutations by simultaneous removal of Pds1 (securin) and Clb/CDK","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic genetic epistasis across all essential APC subunits, replicated across multiple alleles in one rigorous study","pmids":["14634663"],"is_preprint":false},{"year":2003,"finding":"PTTG/securin represses prolactin (PRL) promoter activity and mRNA/protein expression via its intact C-terminal PPSP motif; mutation of the PXXP motif abolishes this repression; estrogen partially rescues PRL expression in PTTG C-terminus transfectants.","method":"Stable transfection in GH3 cells, PRL promoter luciferase assay, Northern/Western blot, site-directed mutagenesis of PXXP motif","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus reporter assay plus hormone measurement, single lab","pmids":["12554778"],"is_preprint":false},{"year":2003,"finding":"Sp1 and NF-Y transcription factors bind within nucleotides –540 to –500 of the PTTG promoter in vivo; mutation of the Sp1 consensus reduces PTTG promoter activity by ~70%, and combined Sp1+NF-Y mutation causes ~90% loss, identifying Sp1 as the primary transcriptional regulator of PTTG.","method":"5' RACE, deletion analysis, EMSA, chromatin immunoprecipitation (ChIP), site-directed mutagenesis, luciferase reporter assay","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo ChIP plus EMSA plus mutagenesis plus reporter assay, multiple orthogonal methods in one study","pmids":["14644503"],"is_preprint":false},{"year":2005,"finding":"Human full-length Securin is a natively unfolded/intrinsically disordered protein lacking tertiary and secondary structure under physiological conditions, with only a small poly-(L-proline) type II helix; analytical ultracentrifugation and fluorescence anisotropy detected no direct interaction between unmodified recombinant Securin and p53 in vitro.","method":"NMR, circular dichroism, size-exclusion chromatography, analytical ultracentrifugation, fluorescence anisotropy","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple biophysical methods in one study; the negative p53 interaction finding is explicitly confirmed by two independent in vitro methods","pmids":["15929994"],"is_preprint":false},{"year":2005,"finding":"Pttg silencing in AtT20 corticotrophs markedly induces p21 mRNA/protein, decreases Rb phosphorylation, and reduces S-phase cells by 24%; Pttg-null mice have pituitary hypoplasia and Rb+/-Pttg-/- double-knockout mice show dramatically reduced pituitary tumor incidence (30% vs. 86%), placing PTTG upstream of p21/Rb in the pituitary cell cycle pathway.","method":"shRNA knockdown in AtT20 cells, p21/Rb Western blot, BrdU S-phase measurement, Pttg-/- × Rb+/- genetic cross, tumor incidence analysis","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (double knockout) plus in vitro RNAi with molecular readouts, replicated across in vitro and in vivo systems","pmids":["15919720"],"is_preprint":false},{"year":2005,"finding":"PTTG overexpression induces genetic instability in thyroid follicular cells (FTC133) in a dose-dependent manner; PTTG expression correlates with genomic instability index in thyroid cancers in vivo, establishing PTTG as a direct inducer of chromosomal instability.","method":"FISSR-PCR genomic instability assay, PTTG transfection into FTC133 cells at different doses, correlation analysis in cancer tissue","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro dose-response transfection with genomic readout plus in vivo correlation, single lab","pmids":["15897900"],"is_preprint":false},{"year":2005,"finding":"Ectopic PTTG1 expression in human HEK293 cells promotes tumorigenesis through increased secretion/expression of bFGF, VEGF, and IL-8; mutation of C-terminal proline-rich (PXXP) motifs abolishes oncogenic properties and growth factor induction.","method":"Stable transfection of HEK293 cells, soft-agar colony formation, nude mouse tumor assay, ELISA/RT-PCR for growth factors, PXXP site-directed mutagenesis","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays plus mutagenesis, single lab, first demonstration in human cells","pmids":["15649325"],"is_preprint":false},{"year":2004,"finding":"PTTG C-terminal PXXP motif phosphorylation status independently controls cell proliferation (phosphorylation inhibits transformation; phosphomimetic mutants reduce proliferation) and transactivation of FGF-2 requires intact PXXP but not phosphorylation; live-cell imaging shows PTTG mitotic regulation is independent of phosphorylation.","method":"Live-cell imaging of EGFP-PTTG, colony-formation assay, [3H]thymidine incorporation, FGF-2 transactivation in primary thyroid and PTTG-null cells, site-directed mutagenesis","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with phosphorylation-mimicking mutants, single lab","pmids":["15591026"],"is_preprint":false},{"year":2007,"finding":"PTTG and its binding factor PBF repress sodium iodide symporter (NIS) mRNA expression and iodide uptake; repression is mediated through the NIS upstream enhancer element (hNUE) via a PAX8-USF1 response element, with PTTG repression specifically dependent on the USF1 site; FGF-2 mediates this process at least in part.","method":"NIS promoter luciferase assay (deletion/mutation analysis), iodide uptake assay in FRTL-5 cells, primary human thyroid cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis plus functional iodide uptake assay in two cell systems, single lab","pmids":["17297475"],"is_preprint":false},{"year":2008,"finding":"UV radiation induces securin degradation via the SCF(βTrCP) E3 ubiquitin ligase; GSK-3β inhibitors prevent UV-induced securin degradation; βTrCP recognizes a conserved unconventional motif (DDAYPE) in securin; βTrCP knockdown causes securin accumulation even in non-irradiated cells.","method":"In vivo ubiquitination assay, CUL1/βTrCP co-expression/knockdown, GSK-3β inhibitor treatment, UV irradiation, identification of βTrCP recognition motif","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo ubiquitination reconstitution, motif identification, pharmacological and genetic (siRNA) validation, multiple orthogonal methods","pmids":["18460583"],"is_preprint":false},{"year":2009,"finding":"E2F1 directly binds the hPTTG1 promoter and transactivates PTTG1 expression; Rb inactivation by siRNA concordantly elevates E2F1 and PTTG1; endogenous p53/p21 constrains E2F1-induced PTTG1 transactivation; E2F1 and PTTG1 are concordantly overexpressed in Rb+/- murine and human pituitary tumors.","method":"ChIP, biotin-streptavidin pull-down assay, luciferase reporter assay, E2F1/DP1 co-transfection, siRNA knockdown of Rb/p53/p21","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct promoter binding confirmed by two independent methods (ChIP + pull-down), functional reporter assay, multiple genetic loss-of-function validations","pmids":["19837943"],"is_preprint":false},{"year":2009,"finding":"PTTG overexpression induces Dlk1 expression by promoting stability/accumulation of Dlk1 mRNA (posttranscriptional regulation); PTTG overexpression inhibits adipogenesis in 3T3-L1 cells and this is accomplished through Dlk1.","method":"Inducible PTTG expression cell lines, differential display, Dlk1 mRNA stability assay, adipogenesis assay in 3T3-L1 cells","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible expression system, mRNA stability assay, functional differentiation readout, single lab","pmids":["19477929"],"is_preprint":false},{"year":2009,"finding":"HBx protein promotes accumulation of PTTG1 protein (without affecting mRNA) by inhibiting PTTG1 ubiquitination and disrupting its interaction with the SCF ubiquitin ligase complex; HBx co-localizes with PTTG1 and Cul1 by confocal microscopy.","method":"In vitro ubiquitination assay, GST pull-down, co-immunoprecipitation, confocal microscopy, HBx transgenic mouse liver and patient biopsies","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination assay plus GST pull-down plus co-IP plus colocalization, multiple orthogonal methods in one study","pmids":["20198633"],"is_preprint":false},{"year":2009,"finding":"Histone acetyltransferase p300 upregulates hPTTG expression at the level of promoter activity, mRNA, and protein; p300 HAT activity is required; p300 overexpression elevates histone H3 acetylation at the hPTTG promoter (by ChIP); NF-Y sites at the promoter synergize with p300; HDAC3 decreases and the HDAC inhibitor TSA increases hPTTG promoter activity.","method":"Luciferase reporter assay, ChIP for histone H3 acetylation, HDAC3 overexpression, TSA treatment, Western/RT-PCR","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus HAT-dead mutant, single lab","pmids":["19539243"],"is_preprint":false},{"year":2009,"finding":"PTTG deletion in mice causes beta-cell apoptosis and senescence (SA-β-gal activity) associated with progressive p21 upregulation and DNA damage; p21 deletion partially rescues PTTG-/- mice from diabetes, placing PTTG upstream of p21-dependent senescence in pancreatic beta cells.","method":"PTTG-/- mouse model, p21-/- × PTTG-/- genetic cross, SA-β-gal staining, apoptosis assay, p21 Western blot, DNA damage gene array","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (double knockout rescue) plus multiple cellular phenotype readouts (apoptosis, senescence, proliferation), in vivo","pmids":["19213844"],"is_preprint":false},{"year":2011,"finding":"A portion of cytoplasmic PTTG1 associates with the cis face of the Golgi apparatus in a phosphorylation-dependent manner; PTTG1 forms a complex with microtubule nucleation proteins GM130, AKAP450, and γ-tubulin at the Golgi; RNAi depletion of PTTG1 delays centrosomal and non-centrosomal microtubule nucleation and causes severe defects in cell polarization and directional migration.","method":"Subcellular fractionation, immunofluorescence colocalization, co-immunoprecipitation, RNAi knockdown, wound-healing/migration assay, microtubule regrowth assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus co-localization plus RNAi functional phenotype across multiple cell types, multiple orthogonal methods","pmids":["21937724"],"is_preprint":false},{"year":2011,"finding":"GSK3β phosphorylates securin/PTTG1 to promote its proteolysis via SCF(βTrCP) E3 ubiquitin ligase; GSK3β inactivation correlates with securin accumulation in human breast cancer tissues.","method":"In vitro kinase assay, ubiquitination assay, GSK3β inhibitor treatment, correlation analysis in breast cancer tissue specimens","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus in vitro ubiquitination assay, validated in patient tissue, multiple orthogonal methods","pmids":["21757741"],"is_preprint":false},{"year":2011,"finding":"Securin and separase associate with membranes and their depletion causes trans-Golgi network swelling, appearance of large perinuclear endocytic vesicles, diminished constitutive protein secretion, impaired receptor recycling/degradation, and defective acidification of early endosomes with increased V-ATPase membrane recruitment.","method":"siRNA depletion of securin/separase, fluorescence microscopy, secretion assays, receptor recycling/degradation assays, endosomal pH measurement, V-ATPase localization","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with multiple cellular phenotype readouts (secretion, recycling, acidification), single lab","pmids":["21272169"],"is_preprint":false},{"year":2011,"finding":"PTTG promotes lymph node metastasis in esophageal squamous cell carcinoma by upregulating S100A4 and galectin-1 secretion and downregulating TIMP-2; PTTG activates E-box transcription and induces c-Myc protein, which then binds the galectin-1 promoter (confirmed by ChIP); galectin-1 siRNA constrains PTTG-induced cell motility.","method":"Mass spectrometric analysis of conditioned media, Western blot, RT-PCR, ChIP assay for c-Myc binding to galectin-1 promoter, siRNA knockdown, in vivo lymph node metastasis model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus mass spectrometry plus siRNA epistasis plus in vivo metastasis model, multiple orthogonal methods","pmids":["19351864"],"is_preprint":false},{"year":2012,"finding":"A single point mutation T60A in securin/PTTG1 enhances its oncogenic properties, inducing chromosomal instability (by FACS and FISH) and increased cell invasion.","method":"Site-directed mutagenesis, FACS cell cycle analysis, FISH for aneuploidy, tumor cell migration/invasion assays, gene expression microarray","journal":"European journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with multiple functional readouts, single lab","pmids":["22819078"],"is_preprint":false},{"year":2013,"finding":"STAT3 directly binds the human PTTG promoter and induces PTTG transcriptional activity; STAT3-induced cell growth, colony formation, migration and invasion in colorectal cancer cells require PTTG; STAT3 and PTTG are concordantly expressed in human colorectal tumors.","method":"ChIP assay, luciferase reporter assay, STAT3/STAT3-C/STAT3-DN transfection, PTTG siRNA knockdown, in vivo tumor xenograft, nude mouse metastasis model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus reporter assay plus in vitro and in vivo genetic rescue experiments, multiple orthogonal methods","pmids":["23416975"],"is_preprint":false},{"year":2015,"finding":"FoxM1 directly binds the PTTG1 promoter at the –391 to –385 bp region and transactivates PTTG1 expression; FoxM1-PTTG1 pathway promotes colorectal cancer cell migration, invasion, and liver metastasis in vivo; PTTG1 suppresses DKK1, a WNT pathway inhibitor.","method":"Luciferase reporter assay, EMSA, ChIP assay, Boyden chamber migration/invasion assay, splenic injection liver metastasis model, Illumina microarray","journal":"BMC medical genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter binding confirmed by EMSA and ChIP, functional rescue with invasion and in vivo metastasis, multiple orthogonal methods","pmids":["26264222"],"is_preprint":false},{"year":2011,"finding":"PTTG induces EMT in lung cancer cells through upregulation of integrin αVβ3 and activation of FAK; downstream adhesion complex molecules (paxillin, metavincullin, talin) and Rho GTPases (Rac1, RhoA, Cdc42, DOCK180) are upregulated; blockade of integrin αV by echistatin or siRNA abolishes FAK activation and subsequent actin cytoskeleton disruption.","method":"Adenoviral PTTG overexpression/siRNA knockdown, Western blot, integrin αV antagonist (echistatin), αV-specific siRNA, actin cytoskeleton staining, cell motility assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic + pharmacological blockade of integrin αV with molecular readouts, single lab","pmids":["22081074"],"is_preprint":false},{"year":2006,"finding":"PTTG overexpression induces MMP-2 secretion and expression (at mRNA and protein levels) and enhances MMP-2 promoter activity in HEK293 cells; conditioned medium from PTTG-overexpressing cells increases cell migration, invasion, and HUVEC tubule formation; pre-treatment with MMP-2-specific antibody significantly decreases these effects.","method":"Zymography, RT-PCR, ELISA, MMP-2 promoter luciferase assay, cell migration/invasion assay, HUVEC tubule formation assay, MMP-2 antibody neutralization","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays plus antibody neutralization epistasis, single lab","pmids":["17096843"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structures of human separase in complex with securin and with CDK1-cyclin B1-CKS1 reveal that securin inhibits separase via pseudosubstrate motifs that block substrate binding at the catalytic site and nearby docking sites; securin contains its own pseudosubstrate motifs analogous to C. elegans and yeast securin.","method":"Cryo-electron microscopy structural determination of human separase–securin and separase–CDK1-cyclin B1-CKS1 complexes","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with functional validation, published in Nature","pmids":["34290405"],"is_preprint":false},{"year":2018,"finding":"Structural review: full-length S. cerevisiae and C. elegans separase–securin structures show securin has extensive contacts with separase consistent with a chaperone function and inhibits separase by binding as a pseudo-substrate at the catalytic site.","method":"Review of crystal/cryo-EM structures of yeast and C. elegans separase–securin complexes","journal":"Current opinion in structural biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — review synthesizing structural data; primary structures not generated in this paper","pmids":["29452922"],"is_preprint":false},{"year":2020,"finding":"SGO2-MAD2 can functionally replace securin as a separase inhibitor; SGO2 uses a pseudo-substrate sequence to block the active site of separase, similar to securin; APC/C-dependent ubiquitylation and TRIP13-p31comet liberate separase from SGO2-MAD2 in vitro; acute loss of both securin and SGO2 (but not either alone) results in premature cohesin cleavage and cytotoxicity, demonstrating securin-independent separase regulation.","method":"In vitro separase liberation assay, securin-knockout cell characterization, genetic co-depletion of securin and SGO2, biochemical fractionation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution plus genetic double-knockout epistasis, published in Nature","pmids":["32322060"],"is_preprint":false},{"year":2008,"finding":"Dicoumarol represses PTTG1/Securin gene expression through inhibition of Hsp90; established Hsp90 inhibitors (17-AAG and novobiocin) also repress PTTG1 expression; overexpression of Hsp90 in yeast confers hypersensitivity to dicoumarol; PTTG1 repression by dicoumarol is partially attributable to inhibition of the Ras/Raf/ERK pathway.","method":"Hsp90 inhibitor treatment, Hsp90 overexpression in yeast, in vivo heat-shock luciferase recovery assay, Western blot for Hsp90 clients, pathway inhibitor analysis","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic (yeast overexpression) evidence, multiple Hsp90 inhibitors tested, single lab","pmids":["18347135"],"is_preprint":false},{"year":2011,"finding":"PTTG1 attenuates drug-induced cellular senescence by suppressing p21; PTTG1-/- HCT116 cells show ~4-fold more doxorubicin/TSA-induced senescence and ~3-fold higher p21 induction; binding of Sp1, p53, and p300 to the p21 promoter is enhanced in PTTG1-/- cells after treatment; p21 knockdown abrogates the senescent effects, placing PTTG1 upstream of p21 in this pathway.","method":"PTTG1-/- cell line, SA-β-gal senescence assay, BrdU incorporation, ChIP (Sp1/p53/p300 on p21 promoter), p21 siRNA epistasis, in vivo xenograft with doxorubicin treatment","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus genetic epistasis (p21 siRNA rescue) plus in vivo validation, multiple orthogonal methods","pmids":["21858218"],"is_preprint":false},{"year":2019,"finding":"ECT2 regulates PTTG1 expression by stabilizing the E2F1 transcription factor through the deubiquitinating enzyme PSMD14; ECT2 upregulates PSMD14, which prevents E2F1 ubiquitination/degradation, allowing E2F1 to drive PTTG1 transcription and glioma cell proliferation.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, Western blot, siRNA knockdown, in vivo xenograft experiments","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo ubiquitination assay plus siRNA genetic epistasis, single lab","pmids":["30590814"],"is_preprint":false},{"year":2005,"finding":"Beta-catenin/TCF pathway activates PTTG transcription in esophageal squamous cell carcinoma; a TCF4-binding element (TBE) was identified in the PTTG promoter; S37A β-catenin activates PTTG promoter activity dependent on the intact TBE; TCF-4 protein binds the TBE by biotin-streptavidin pull-down; dominant-negative TCF suppresses activation.","method":"PTTG promoter luciferase assay with deletion/mutation analysis, biotin-streptavidin pull-down for TCF-4 binding, S37Aβ-catenin and dominant-negative TCF transfection","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis plus physical pull-down evidence, single lab","pmids":["15514942"],"is_preprint":false},{"year":2014,"finding":"PTTG1 promotes prostate cancer cell proliferation by inhibiting SMAD3 (a TGFβ signaling effector); PTTG1 overexpression significantly decreases SMAD3 levels; re-expression of SMAD3 rescues the PTTG1-induced proliferation; SMAD3 siRNA knockdown rescues proliferation inhibited by PTTG1 shRNA.","method":"PTTG1 transgene and shRNA in PC3 cells, Western blot for SMAD3, SMAD3 re-expression rescue, SMAD3 siRNA epistasis, in vitro and in vivo proliferation assays","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic epistasis (gain and loss of function of both PTTG1 and SMAD3), single lab","pmids":["24627133"],"is_preprint":false},{"year":2023,"finding":"PTTG1 promotes asparagine synthetase (ASNS) transcription by directly binding to its promoter, increasing asparagine (Asn) levels, which subsequently activate the mTOR pathway to facilitate HCC progression; HBx promotes ASNS and Asn metabolism by upregulating PTTG1; asparaginase treatment reverses PTTG1 overexpression-induced proliferation.","method":"PTTG1-deficient DEN-induced and HBx-induced HCC mouse models, ChIP/promoter binding assay, amino acid metabolomics, mTOR pathway Western blot, asparaginase rescue experiment","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models plus promoter binding plus metabolic rescue, single lab","pmids":["37159932"],"is_preprint":false},{"year":2023,"finding":"PTTG1 is a bona fide β-catenin binding protein that inhibits destruction complex assembly, promoting β-catenin stabilization and nuclear localization; PTTG1 subcellular distribution is regulated by PP2A-mediated dephosphorylation at Ser165/171 (preventing nuclear translocation), reversible by PP2A inhibitor okadaic acid; PTTG1 competitively binds PP2A with GSK3β, decreasing GSK3β Ser9-phosphorylation-inactivation and indirectly stabilizing cytoplasmic β-catenin.","method":"Co-immunoprecipitation (PTTG1–β-catenin), phosphorylation mutant analysis, PP2A inhibitor treatment (okadaic acid), subcellular fractionation, Western blot, luciferase reporter for Wnt activity","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus phosphorylation mutants plus pharmacological PP2A inhibition, multiple mechanistic layers, single lab","pmids":["37400529"],"is_preprint":false},{"year":2021,"finding":"Nuclear localization of PTTG1 correlates with aggressive phenotype in seminoma cells and promotes invasiveness through activation of MMP-2; PTTG1 modulation (overexpression/knockdown) confirms causality; MMP-2 levels are significantly higher in seminomas where PTTG1 is nuclear.","method":"Immunofluorescence for PTTG1 nuclear vs. cytoplasmic localization, wound-healing assay, Matrigel invasion, zymography for MMP-2, RNAi and overexpression in seminoma cell lines","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization tied to functional invasion phenotype with bidirectional genetic manipulation, single lab","pmids":["33430117"],"is_preprint":false}],"current_model":"PTTG1 (securin) is a natively disordered protein that inhibits separase by acting as a pseudo-substrate until APC/C-Cdc20/Cdh1-mediated ubiquitination targets it for proteasomal degradation via RXXL and KEN box motifs (or via SCF-βTrCP after UV damage), allowing separase-mediated cohesin cleavage and anaphase onset; its C-terminal PXXP motifs mediate SH3-domain interactions required for oncogenic transformation, transactivation of target genes (bFGF, FGF-2, MMP-2, galectin-1, ASNS), and repression of NIS/prolactin; CDK1 phosphorylates PTTG1 in mitosis while GSK-3β phosphorylation targets it for interphase degradation; PTTG1 binds p53 (inhibiting its transcriptional and pro-apoptotic activity), interacts with the Ku/DNA-PK complex linking it to DNA-damage responses, associates with Golgi-resident microtubule nucleation complexes (GM130/AKAP450/γ-tubulin) to regulate non-centrosomal microtubule nucleation and directional cell migration, and stabilizes β-catenin by competing for PP2A binding; upstream, PTTG1 transcription is driven by E2F1 (released by Rb inactivation), STAT3, FoxM1, Sp1/NF-Y, and p300-mediated histone acetylation, placing PTTG1 at a nexus of cell-cycle control, chromosomal stability, DNA repair, and oncogenic signaling."},"narrative":{"mechanistic_narrative":"PTTG1 (securin) is a natively disordered protein that operates as the principal regulator of sister-chromatid separation while doubling as a transforming oncogene that rewires transcriptional and signaling programs [PMID:9092795, PMID:15929994]. In its canonical mitotic role, PTTG1 inhibits separase by binding as a pseudo-substrate that occludes the catalytic and docking sites, as resolved by cryo-EM of the human separase–securin complex [PMID:34290405]; timely anaphase requires its destruction, which is achieved by APC/C-Cdc20 and APC/C-Cdh1 acting through an RXXL destruction box and a KEN box, with non-degradable securin causing incomplete chromatid separation [PMID:11179223]. Genetic epistasis in yeast establishes securin (with B-cyclin/CDK) as one of the two obligate APC/C substrates that explain APC essentiality [PMID:14634663], and an alternative SGO2-MAD2 pseudo-substrate inhibitor can functionally replace securin, revealing redundant control of separase [PMID:32322060]. PTTG1 protein peaks in mitosis and is phosphorylated by CDK1 [PMID:10656688], while GSK-3β phosphorylation routes it for SCF(βTrCP)-mediated degradation during interphase and after UV damage via a DDAYPE motif [PMID:18460583, PMID:21757741]; consistent with a damage-surveillance link, PTTG1 binds the Ku/DNA-PK complex and is phosphorylated by DNA-PK, an association disrupted by DNA double-strand breaks [PMID:11238996]. Dysregulated PTTG1 is directly oncogenic and a driver of chromosomal instability [PMID:9092795, PMID:15897900], activities that depend on C-terminal PXXP/SH3-binding motifs and a C-terminal transactivation domain required for transformation, tumorigenesis, and induction of secreted factors including bFGF, VEGF, IL-8, MMP-2, and galectin-1 [PMID:9892021, PMID:10713046, PMID:15649325, PMID:19351864, PMID:17096843]. PTTG1 suppresses tumor-suppressive programs by binding p53 to block its DNA binding and pro-apoptotic transcription [PMID:12355087] and by restraining p21-dependent senescence upstream of the p21/Rb axis [PMID:15919720, PMID:21858218]. Beyond mitosis, PTTG1 associates with Golgi-resident microtubule nucleation machinery (GM130, AKAP450, γ-tubulin) to control microtubule nucleation, cell polarity, and directional migration [PMID:21937724], and stabilizes β-catenin by competing with GSK3β for PP2A binding to sustain Wnt signaling [PMID:37400529]. Its expression is driven by a convergent transcriptional network including E2F1 (downstream of Rb inactivation), STAT3, FoxM1, Sp1/NF-Y, and p300-mediated histone acetylation [PMID:14644503, PMID:19837943, PMID:19539243, PMID:23416975, PMID:26264222].","teleology":[{"year":1997,"claim":"Established that PTTG is a transforming oncogene rather than a passive cell-cycle component, motivating mechanistic dissection of its oncogenic activity.","evidence":"Stable transfection of NIH 3T3 fibroblasts with soft-agar transformation and nude-mouse tumor assays","pmids":["9092795"],"confidence":"Medium","gaps":["Did not define the molecular domain or partner responsible for transformation","Single lab, single cell background"]},{"year":1999,"claim":"Mapped oncogenic activity to C-terminal PXXP SH3-binding motifs, defining a structural determinant of transformation and growth-factor induction.","evidence":"Site-directed mutagenesis of PXXP prolines with transformation, tumorigenesis, and bFGF secretion readouts","pmids":["9892021"],"confidence":"High","gaps":["SH3-domain partner protein not identified","Mechanistic link between PXXP motifs and growth-factor secretion unresolved"]},{"year":2000,"claim":"Defined PTTG as a transactivator whose acidic/proline-rich C-terminus drives transcription in a manner tied to its transforming capacity, and identified CDK1 as the mitotic kinase phosphorylating it.","evidence":"Transactivation reporter assays in yeast and mammalian cells, mutagenesis, immunodepletion plus in vitro phosphorylation with CDK1 inhibitor","pmids":["9811450","10713046","10656688"],"confidence":"High","gaps":["Direct transcriptional target genes not identified at this stage","Functional consequence of CDK1 phosphorylation site unmapped"]},{"year":2001,"claim":"Established the canonical mitotic mechanism: APC/C-Cdc20/Cdh1 degrades securin via RXXL and KEN box motifs to permit chromatid separation, and connected PTTG to DNA-damage sensing through Ku/DNA-PK.","evidence":"In vitro ubiquitination reconstitution with fzy/fzr, non-degradable securin phenotype, plus reciprocal Co-IP and in vitro kinase assay with DNA-PK","pmids":["11179223","11238996"],"confidence":"High","gaps":["The separase-inhibitory mechanism was not yet structurally defined","Physiological role of DNA-PK phosphorylation of PTTG unresolved"]},{"year":2002,"claim":"Identified p53 as a direct PTTG1 partner, providing a route by which oncogenic PTTG1 suppresses apoptosis and transcription.","evidence":"Phage display, reciprocal pull-down/Co-IP, reporter and apoptosis assays in PTTG1-/- cells","pmids":["12355087"],"confidence":"High","gaps":["Biophysical study later found no interaction between unmodified recombinant securin and p53, implying a modification- or cofactor-dependent interaction not yet defined"]},{"year":2003,"claim":"Generalized securin as one of only two obligate APC/C substrates, explaining why the APC is essential, and extended PTTG transcriptional control to endocrine genes.","evidence":"Systematic genetic epistasis across essential APC subunits in S. cerevisiae; GH3 prolactin promoter reporter with PXXP mutagenesis","pmids":["14634663","12554778"],"confidence":"High","gaps":["Yeast bypass does not address metazoan-specific APC functions","Mechanism of PRL promoter repression by the PXXP motif unresolved"]},{"year":2005,"claim":"Resolved that securin is intrinsically disordered and placed PTTG genetically upstream of the p21/Rb cell-cycle and chromosomal-instability axis.","evidence":"Multi-method biophysics (NMR, CD, AUC); shRNA in corticotrophs with Pttg-/-×Rb+/- crosses; FISSR-PCR genomic instability assay","pmids":["15929994","15919720","15897900"],"confidence":"High","gaps":["Disordered state complicates structural rationalization of partner binding","Causal chain from PTTG to genomic instability mechanistically incomplete"]},{"year":2008,"claim":"Defined an interphase, separase-independent degradation route in which GSK-3β-primed SCF(βTrCP) targets securin via a DDAYPE motif, especially after UV damage.","evidence":"In vivo ubiquitination, βTrCP/CUL1 co-expression and knockdown, GSK-3β inhibitors, motif identification","pmids":["18460583"],"confidence":"High","gaps":["Physiological signals coupling GSK-3β to securin outside UV stress not fully defined"]},{"year":2009,"claim":"Built the upstream transcriptional and post-translational regulatory network of PTTG (E2F1/Rb, p300/HAT, viral HBx stabilization) and extended its functions to senescence and differentiation control.","evidence":"ChIP and pull-down for E2F1; ChIP for H3 acetylation by p300; in vitro ubiquitination/Co-IP for HBx; Pttg-/-×p21-/- crosses; Dlk1 mRNA-stability and adipogenesis assays","pmids":["19837943","19539243","20198633","19213844"],"confidence":"High","gaps":["Hierarchy among the multiple transcriptional inputs unresolved","Mechanism of HBx-mediated SCF disruption not structurally defined"]},{"year":2011,"claim":"Expanded PTTG1 into non-mitotic territory: Golgi-associated microtubule nucleation and migration, membrane-traffic/endosomal control with separase, and GSK3β-driven SCF(βTrCP) turnover linked to breast cancer.","evidence":"Co-IP/colocalization and RNAi migration assays for GM130/AKAP450/γ-tubulin; siRNA secretion/recycling/acidification assays; in vitro kinase and ubiquitination assays with tissue correlation","pmids":["21937724","21272169","21757741"],"confidence":"High","gaps":["How a securin pool is partitioned to the Golgi versus the spindle is unclear","Direct enzymatic versus scaffolding contribution to microtubule nucleation undefined"]},{"year":2013,"claim":"Positioned PTTG1 as a downstream effector of oncogenic transcription factors (STAT3, FoxM1) and metastatic secretory programs (galectin-1/c-Myc, MMP-2, integrin-αV/FAK).","evidence":"ChIP, reporter assays, siRNA epistasis and in vivo metastasis models across colorectal, esophageal, and lung cancer systems","pmids":["23416975","26264222","19351864","17096843","22081074"],"confidence":"High","gaps":["Whether these effects require nuclear PTTG1, the PXXP motif, or partner recruitment is not uniformly resolved"]},{"year":2021,"claim":"Provided the high-resolution structural mechanism of separase inhibition and showed securin is functionally redundant with SGO2-MAD2.","evidence":"Cryo-EM of human separase–securin and separase–CDK1–cyclinB1–CKS1 complexes; in vitro separase liberation and securin/SGO2 co-depletion epistasis","pmids":["34290405","32322060"],"confidence":"High","gaps":["Structural basis of PTTG1's non-mitotic interactions (p53, β-catenin, Golgi complex) not addressed"]},{"year":2023,"claim":"Defined new oncogenic mechanisms: β-catenin stabilization through PP2A competition with GSK3β, and metabolic reprogramming via ASNS-driven asparagine/mTOR signaling.","evidence":"Co-IP, phospho-mutant and PP2A-inhibitor analysis; in vivo HCC models with ChIP, metabolomics, and asparaginase rescue","pmids":["37400529","37159932"],"confidence":"Medium","gaps":["Single-lab findings without independent replication","Integration of metabolic, Wnt, and mitotic roles within one cell undefined"]},{"year":null,"claim":"How PTTG1's intrinsically disordered structure encodes its diverse, mutually exclusive interactions and how its subcellular partitioning (spindle, Golgi, nucleus) is governed remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model for non-separase partners","Determinants directing PTTG1 between mitotic, migratory, and transcriptional pools unknown","Reconciliation of in-cell p53 binding with negative in vitro biophysics outstanding"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,4,41]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[33,6,35]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[33,34]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[24,42]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,24]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,43]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5,24]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[24,26]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,6,9,33]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,14,29,30]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[42,39]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,18,25]}],"complexes":["separase-securin complex","Golgi microtubule nucleation complex (GM130/AKAP450/γ-tubulin)"],"partners":["ESPL1","TP53","XRCC6","PRKDC","GM130","CTNNB1","PPP2CA","GSK3B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95997","full_name":"Securin","aliases":["Esp1-associated protein","Pituitary tumor-transforming gene 1 protein","Tumor-transforming protein 1","hPTTG"],"length_aa":202,"mass_kda":22.0,"function":"Regulatory protein, which plays a central role in chromosome stability, in the p53/TP53 pathway, and DNA repair. Probably acts by blocking the action of key proteins. During the mitosis, it blocks Separase/ESPL1 function, preventing the proteolysis of the cohesin complex and the subsequent segregation of the chromosomes. At the onset of anaphase, it is ubiquitinated, conducting to its destruction and to the liberation of ESPL1. Its function is however not limited to a blocking activity, since it is required to activate ESPL1. Negatively regulates the transcriptional activity and related apoptosis activity of TP53. The negative regulation of TP53 may explain the strong transforming capability of the protein when it is overexpressed. May also play a role in DNA repair via its interaction with Ku, possibly by connecting DNA damage-response pathways with sister chromatid separation","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O95997/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PTTG1","classification":"Common Essential","n_dependent_lines":439,"n_total_lines":1208,"dependency_fraction":0.36341059602649006},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTTG1","total_profiled":1310},"omim":[{"mim_id":"621165","title":"AARF DOMAIN-CONTAINING KINASE 5; ADCK5","url":"https://www.omim.org/entry/621165"},{"mim_id":"614534","title":"ANAPHASE-PROMOTING COMPLEX SUBUNIT 11; ANAPC11","url":"https://www.omim.org/entry/614534"},{"mim_id":"614184","title":"DIS3-LIKE 3-PRIME-5-PRIME EXORIBONUCLEASE 2; DIS3L2","url":"https://www.omim.org/entry/614184"},{"mim_id":"613992","title":"PROTEIN PHOSPHATASE 2, REGULATORY SUBUNIT B, DELTA; PPP2R2D","url":"https://www.omim.org/entry/613992"},{"mim_id":"613745","title":"ANAPHASE-PROMOTING COMPLEX, SUBUNIT 10; ANAPC10","url":"https://www.omim.org/entry/613745"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":150.9},{"tissue":"lymphoid tissue","ntpm":135.4},{"tissue":"testis","ntpm":163.9}],"url":"https://www.proteinatlas.org/search/PTTG1"},"hgnc":{"alias_symbol":["PTTG","HPTTG","EAP1","securin","ECRAR"],"prev_symbol":["TUTR1"]},"alphafold":{"accession":"O95997","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95997","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95997-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95997-F1-predicted_aligned_error_v6.png","plddt_mean":63.16},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTTG1","jax_strain_url":"https://www.jax.org/strain/search?query=PTTG1"},"sequence":{"accession":"O95997","fasta_url":"https://rest.uniprot.org/uniprotkb/O95997.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95997/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95997"}},"corpus_meta":[{"pmid":"9092795","id":"PMC_9092795","title":"Isolation and characterization of a pituitary tumor-transforming gene (PTTG).","date":"1997","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/9092795","citation_count":467,"is_preprint":false},{"pmid":"10022450","id":"PMC_10022450","title":"Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas.","date":"1999","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/10022450","citation_count":333,"is_preprint":false},{"pmid":"9892021","id":"PMC_9892021","title":"Structure, expression, and function of human pituitary tumor-transforming gene (PTTG).","date":"1999","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/9892021","citation_count":282,"is_preprint":false},{"pmid":"11179223","id":"PMC_11179223","title":"Securin degradation is mediated by fzy and fzr, and is required for complete chromatid separation but not for cytokinesis.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11179223","citation_count":197,"is_preprint":false},{"pmid":"12355087","id":"PMC_12355087","title":"Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis.","date":"2002","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12355087","citation_count":164,"is_preprint":false},{"pmid":"9811450","id":"PMC_9811450","title":"hpttg, a human homologue of rat pttg, is overexpressed in hematopoietic neoplasms. 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athymic nude mice resulted in tumor formation, establishing PTTG as a transforming oncogene.\",\n      \"method\": \"Stable transfection of NIH 3T3 fibroblasts, soft-agar transformation assay, nude mouse tumor formation assay\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain-of-function in two orthogonal assays (in vitro transformation and in vivo tumorigenesis), single lab\",\n      \"pmids\": [\"9092795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human PTTG protein contains two C-terminal PXXP motifs that serve as SH3-domain binding sites; site-directed mutagenesis of these proline residues abrogates PTTG in vitro transforming activity, in vivo tumor-inducing activity, and stimulation of bFGF secretion.\",\n      \"method\": \"Site-directed mutagenesis of PXXP motifs, NIH 3T3 transformation assay, nude mouse tumor assay, bFGF secretion measurement\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with multiple orthogonal functional readouts (transformation, tumorigenesis, growth factor secretion) in a single rigorous study\",\n      \"pmids\": [\"9892021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"hPTTG is mainly a cytosolic protein with partial nuclear localization; its acidic C-terminal domain acts as a transcriptional transactivation domain when fused to a heterologous DNA-binding domain, active in both yeast and mammalian cells.\",\n      \"method\": \"Subcellular fractionation, transactivation reporter assay (yeast and mammalian cells)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal systems (yeast + mammalian) for transactivation, single lab, fractionation for localization\",\n      \"pmids\": [\"9811450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"hPTTG protein level peaks in mitosis and is phosphorylated during mitosis; immunodepletion and in vitro phosphorylation experiments with a specific inhibitor identified Cdc2 (CDK1) as the kinase that phosphorylates hPTTG.\",\n      \"method\": \"Cell cycle synchronization, immunodepletion, in vitro phosphorylation assay, CDK1 inhibitor treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation assay plus immunodepletion plus specific inhibitor, multiple orthogonal methods in one study\",\n      \"pmids\": [\"10656688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Murine PTTG possesses transcriptional transactivation activity that correlates with its transforming properties; Pro139, Ser159, PPXP motif, and a hydrophobic stretch are required for transactivation, and Ala substitution at Pro139 abolishes both transactivation and transformation.\",\n      \"method\": \"Transactivation reporter assay, site-directed mutagenesis, NIH 3T3 transformation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with functional transactivation and transformation assays, multiple residues tested\",\n      \"pmids\": [\"10713046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PTTG-EGFP colocalizes with mitotic spindles in early mitosis and is degraded at anaphase; overexpression of wild-type PTTG-EGFP causes most cells to die by apoptosis, while a mutant PTTG-EGFP lacking the SH3-binding domain allows cell division, demonstrating that PTTG regulates endocrine tumor cell division and survival in a PXXP-dependent manner.\",\n      \"method\": \"Live-cell imaging of EGFP-PTTG conjugates, real-time fluorescence microscopy of cell cycle progression\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with functional comparison of WT vs. mutant, single lab\",\n      \"pmids\": [\"10935539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human securin/PTTG degradation is catalyzed by both fzy (Cdc20) and fzr (Cdh1) APC/C activators via an RXXL destruction box and a KEN box; non-degradable securin (both sequences mutated) causes incomplete chromatid separation but does not prevent cytokinesis.\",\n      \"method\": \"In vitro ubiquitination assay with fzy/fzr, expression of non-degradable securin mutant in cells, mitotic phenotype analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination reconstitution plus cellular phenotype with double-mutant securin, multiple orthogonal methods\",\n      \"pmids\": [\"11179223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"hPTTG binds to Ku heterodimer (the regulatory subunit of DNA-PK) both in vitro and in vivo; DNA-PK catalytic subunit phosphorylates hPTTG in vitro; DNA double-strand breaks prevent hPTTG–Ku association, suggesting PTTG connects DNA-damage response to sister chromatid separation.\",\n      \"method\": \"Co-immunoprecipitation (in vivo), in vitro binding assay (pull-down), in vitro kinase assay, DNA damage induction\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution (binding + kinase assay) plus reciprocal co-IP, functional disruption by DNA damage\",\n      \"pmids\": [\"11238996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Human securin/PTTG1 interacts directly with p53 (demonstrated by pull-down and co-IP both in vitro and in vivo); this interaction blocks p53 binding to DNA, inhibits p53 transcriptional activity, and inhibits p53-induced cell death; PTTG1-deficient cells show potentiated p53 apoptotic and transactivating functions.\",\n      \"method\": \"Phage-display screening, pull-down assay, co-immunoprecipitation, transcriptional reporter assay, apoptosis assay in PTTG1-/- cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, in vitro pull-down, reporter assays, and loss-of-function genetic validation in PTTG1-/- cells\",\n      \"pmids\": [\"12355087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Securin and B-cyclin/CDK are the only obligatory APC/C targets in S. cerevisiae; simultaneous removal of securin (Pds1) and B-cyclin/CDK renders all eight essential APC subunits dispensable, establishing that these two substrates explain APC essentiality.\",\n      \"method\": \"Genetic epistasis in S. cerevisiae — double-deletion/bypass suppression of APC subunit mutations by simultaneous removal of Pds1 (securin) and Clb/CDK\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic genetic epistasis across all essential APC subunits, replicated across multiple alleles in one rigorous study\",\n      \"pmids\": [\"14634663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PTTG/securin represses prolactin (PRL) promoter activity and mRNA/protein expression via its intact C-terminal PPSP motif; mutation of the PXXP motif abolishes this repression; estrogen partially rescues PRL expression in PTTG C-terminus transfectants.\",\n      \"method\": \"Stable transfection in GH3 cells, PRL promoter luciferase assay, Northern/Western blot, site-directed mutagenesis of PXXP motif\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus reporter assay plus hormone measurement, single lab\",\n      \"pmids\": [\"12554778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Sp1 and NF-Y transcription factors bind within nucleotides –540 to –500 of the PTTG promoter in vivo; mutation of the Sp1 consensus reduces PTTG promoter activity by ~70%, and combined Sp1+NF-Y mutation causes ~90% loss, identifying Sp1 as the primary transcriptional regulator of PTTG.\",\n      \"method\": \"5' RACE, deletion analysis, EMSA, chromatin immunoprecipitation (ChIP), site-directed mutagenesis, luciferase reporter assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo ChIP plus EMSA plus mutagenesis plus reporter assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"14644503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human full-length Securin is a natively unfolded/intrinsically disordered protein lacking tertiary and secondary structure under physiological conditions, with only a small poly-(L-proline) type II helix; analytical ultracentrifugation and fluorescence anisotropy detected no direct interaction between unmodified recombinant Securin and p53 in vitro.\",\n      \"method\": \"NMR, circular dichroism, size-exclusion chromatography, analytical ultracentrifugation, fluorescence anisotropy\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple biophysical methods in one study; the negative p53 interaction finding is explicitly confirmed by two independent in vitro methods\",\n      \"pmids\": [\"15929994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Pttg silencing in AtT20 corticotrophs markedly induces p21 mRNA/protein, decreases Rb phosphorylation, and reduces S-phase cells by 24%; Pttg-null mice have pituitary hypoplasia and Rb+/-Pttg-/- double-knockout mice show dramatically reduced pituitary tumor incidence (30% vs. 86%), placing PTTG upstream of p21/Rb in the pituitary cell cycle pathway.\",\n      \"method\": \"shRNA knockdown in AtT20 cells, p21/Rb Western blot, BrdU S-phase measurement, Pttg-/- × Rb+/- genetic cross, tumor incidence analysis\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (double knockout) plus in vitro RNAi with molecular readouts, replicated across in vitro and in vivo systems\",\n      \"pmids\": [\"15919720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PTTG overexpression induces genetic instability in thyroid follicular cells (FTC133) in a dose-dependent manner; PTTG expression correlates with genomic instability index in thyroid cancers in vivo, establishing PTTG as a direct inducer of chromosomal instability.\",\n      \"method\": \"FISSR-PCR genomic instability assay, PTTG transfection into FTC133 cells at different doses, correlation analysis in cancer tissue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro dose-response transfection with genomic readout plus in vivo correlation, single lab\",\n      \"pmids\": [\"15897900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ectopic PTTG1 expression in human HEK293 cells promotes tumorigenesis through increased secretion/expression of bFGF, VEGF, and IL-8; mutation of C-terminal proline-rich (PXXP) motifs abolishes oncogenic properties and growth factor induction.\",\n      \"method\": \"Stable transfection of HEK293 cells, soft-agar colony formation, nude mouse tumor assay, ELISA/RT-PCR for growth factors, PXXP site-directed mutagenesis\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays plus mutagenesis, single lab, first demonstration in human cells\",\n      \"pmids\": [\"15649325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PTTG C-terminal PXXP motif phosphorylation status independently controls cell proliferation (phosphorylation inhibits transformation; phosphomimetic mutants reduce proliferation) and transactivation of FGF-2 requires intact PXXP but not phosphorylation; live-cell imaging shows PTTG mitotic regulation is independent of phosphorylation.\",\n      \"method\": \"Live-cell imaging of EGFP-PTTG, colony-formation assay, [3H]thymidine incorporation, FGF-2 transactivation in primary thyroid and PTTG-null cells, site-directed mutagenesis\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with phosphorylation-mimicking mutants, single lab\",\n      \"pmids\": [\"15591026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTTG and its binding factor PBF repress sodium iodide symporter (NIS) mRNA expression and iodide uptake; repression is mediated through the NIS upstream enhancer element (hNUE) via a PAX8-USF1 response element, with PTTG repression specifically dependent on the USF1 site; FGF-2 mediates this process at least in part.\",\n      \"method\": \"NIS promoter luciferase assay (deletion/mutation analysis), iodide uptake assay in FRTL-5 cells, primary human thyroid cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis plus functional iodide uptake assay in two cell systems, single lab\",\n      \"pmids\": [\"17297475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"UV radiation induces securin degradation via the SCF(βTrCP) E3 ubiquitin ligase; GSK-3β inhibitors prevent UV-induced securin degradation; βTrCP recognizes a conserved unconventional motif (DDAYPE) in securin; βTrCP knockdown causes securin accumulation even in non-irradiated cells.\",\n      \"method\": \"In vivo ubiquitination assay, CUL1/βTrCP co-expression/knockdown, GSK-3β inhibitor treatment, UV irradiation, identification of βTrCP recognition motif\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo ubiquitination reconstitution, motif identification, pharmacological and genetic (siRNA) validation, multiple orthogonal methods\",\n      \"pmids\": [\"18460583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"E2F1 directly binds the hPTTG1 promoter and transactivates PTTG1 expression; Rb inactivation by siRNA concordantly elevates E2F1 and PTTG1; endogenous p53/p21 constrains E2F1-induced PTTG1 transactivation; E2F1 and PTTG1 are concordantly overexpressed in Rb+/- murine and human pituitary tumors.\",\n      \"method\": \"ChIP, biotin-streptavidin pull-down assay, luciferase reporter assay, E2F1/DP1 co-transfection, siRNA knockdown of Rb/p53/p21\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct promoter binding confirmed by two independent methods (ChIP + pull-down), functional reporter assay, multiple genetic loss-of-function validations\",\n      \"pmids\": [\"19837943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PTTG overexpression induces Dlk1 expression by promoting stability/accumulation of Dlk1 mRNA (posttranscriptional regulation); PTTG overexpression inhibits adipogenesis in 3T3-L1 cells and this is accomplished through Dlk1.\",\n      \"method\": \"Inducible PTTG expression cell lines, differential display, Dlk1 mRNA stability assay, adipogenesis assay in 3T3-L1 cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible expression system, mRNA stability assay, functional differentiation readout, single lab\",\n      \"pmids\": [\"19477929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HBx protein promotes accumulation of PTTG1 protein (without affecting mRNA) by inhibiting PTTG1 ubiquitination and disrupting its interaction with the SCF ubiquitin ligase complex; HBx co-localizes with PTTG1 and Cul1 by confocal microscopy.\",\n      \"method\": \"In vitro ubiquitination assay, GST pull-down, co-immunoprecipitation, confocal microscopy, HBx transgenic mouse liver and patient biopsies\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination assay plus GST pull-down plus co-IP plus colocalization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20198633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Histone acetyltransferase p300 upregulates hPTTG expression at the level of promoter activity, mRNA, and protein; p300 HAT activity is required; p300 overexpression elevates histone H3 acetylation at the hPTTG promoter (by ChIP); NF-Y sites at the promoter synergize with p300; HDAC3 decreases and the HDAC inhibitor TSA increases hPTTG promoter activity.\",\n      \"method\": \"Luciferase reporter assay, ChIP for histone H3 acetylation, HDAC3 overexpression, TSA treatment, Western/RT-PCR\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus HAT-dead mutant, single lab\",\n      \"pmids\": [\"19539243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PTTG deletion in mice causes beta-cell apoptosis and senescence (SA-β-gal activity) associated with progressive p21 upregulation and DNA damage; p21 deletion partially rescues PTTG-/- mice from diabetes, placing PTTG upstream of p21-dependent senescence in pancreatic beta cells.\",\n      \"method\": \"PTTG-/- mouse model, p21-/- × PTTG-/- genetic cross, SA-β-gal staining, apoptosis assay, p21 Western blot, DNA damage gene array\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (double knockout rescue) plus multiple cellular phenotype readouts (apoptosis, senescence, proliferation), in vivo\",\n      \"pmids\": [\"19213844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A portion of cytoplasmic PTTG1 associates with the cis face of the Golgi apparatus in a phosphorylation-dependent manner; PTTG1 forms a complex with microtubule nucleation proteins GM130, AKAP450, and γ-tubulin at the Golgi; RNAi depletion of PTTG1 delays centrosomal and non-centrosomal microtubule nucleation and causes severe defects in cell polarization and directional migration.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence colocalization, co-immunoprecipitation, RNAi knockdown, wound-healing/migration assay, microtubule regrowth assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus co-localization plus RNAi functional phenotype across multiple cell types, multiple orthogonal methods\",\n      \"pmids\": [\"21937724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GSK3β phosphorylates securin/PTTG1 to promote its proteolysis via SCF(βTrCP) E3 ubiquitin ligase; GSK3β inactivation correlates with securin accumulation in human breast cancer tissues.\",\n      \"method\": \"In vitro kinase assay, ubiquitination assay, GSK3β inhibitor treatment, correlation analysis in breast cancer tissue specimens\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus in vitro ubiquitination assay, validated in patient tissue, multiple orthogonal methods\",\n      \"pmids\": [\"21757741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Securin and separase associate with membranes and their depletion causes trans-Golgi network swelling, appearance of large perinuclear endocytic vesicles, diminished constitutive protein secretion, impaired receptor recycling/degradation, and defective acidification of early endosomes with increased V-ATPase membrane recruitment.\",\n      \"method\": \"siRNA depletion of securin/separase, fluorescence microscopy, secretion assays, receptor recycling/degradation assays, endosomal pH measurement, V-ATPase localization\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with multiple cellular phenotype readouts (secretion, recycling, acidification), single lab\",\n      \"pmids\": [\"21272169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTTG promotes lymph node metastasis in esophageal squamous cell carcinoma by upregulating S100A4 and galectin-1 secretion and downregulating TIMP-2; PTTG activates E-box transcription and induces c-Myc protein, which then binds the galectin-1 promoter (confirmed by ChIP); galectin-1 siRNA constrains PTTG-induced cell motility.\",\n      \"method\": \"Mass spectrometric analysis of conditioned media, Western blot, RT-PCR, ChIP assay for c-Myc binding to galectin-1 promoter, siRNA knockdown, in vivo lymph node metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus mass spectrometry plus siRNA epistasis plus in vivo metastasis model, multiple orthogonal methods\",\n      \"pmids\": [\"19351864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A single point mutation T60A in securin/PTTG1 enhances its oncogenic properties, inducing chromosomal instability (by FACS and FISH) and increased cell invasion.\",\n      \"method\": \"Site-directed mutagenesis, FACS cell cycle analysis, FISH for aneuploidy, tumor cell migration/invasion assays, gene expression microarray\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with multiple functional readouts, single lab\",\n      \"pmids\": [\"22819078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"STAT3 directly binds the human PTTG promoter and induces PTTG transcriptional activity; STAT3-induced cell growth, colony formation, migration and invasion in colorectal cancer cells require PTTG; STAT3 and PTTG are concordantly expressed in human colorectal tumors.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, STAT3/STAT3-C/STAT3-DN transfection, PTTG siRNA knockdown, in vivo tumor xenograft, nude mouse metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus reporter assay plus in vitro and in vivo genetic rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"23416975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FoxM1 directly binds the PTTG1 promoter at the –391 to –385 bp region and transactivates PTTG1 expression; FoxM1-PTTG1 pathway promotes colorectal cancer cell migration, invasion, and liver metastasis in vivo; PTTG1 suppresses DKK1, a WNT pathway inhibitor.\",\n      \"method\": \"Luciferase reporter assay, EMSA, ChIP assay, Boyden chamber migration/invasion assay, splenic injection liver metastasis model, Illumina microarray\",\n      \"journal\": \"BMC medical genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter binding confirmed by EMSA and ChIP, functional rescue with invasion and in vivo metastasis, multiple orthogonal methods\",\n      \"pmids\": [\"26264222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTTG induces EMT in lung cancer cells through upregulation of integrin αVβ3 and activation of FAK; downstream adhesion complex molecules (paxillin, metavincullin, talin) and Rho GTPases (Rac1, RhoA, Cdc42, DOCK180) are upregulated; blockade of integrin αV by echistatin or siRNA abolishes FAK activation and subsequent actin cytoskeleton disruption.\",\n      \"method\": \"Adenoviral PTTG overexpression/siRNA knockdown, Western blot, integrin αV antagonist (echistatin), αV-specific siRNA, actin cytoskeleton staining, cell motility assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic + pharmacological blockade of integrin αV with molecular readouts, single lab\",\n      \"pmids\": [\"22081074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PTTG overexpression induces MMP-2 secretion and expression (at mRNA and protein levels) and enhances MMP-2 promoter activity in HEK293 cells; conditioned medium from PTTG-overexpressing cells increases cell migration, invasion, and HUVEC tubule formation; pre-treatment with MMP-2-specific antibody significantly decreases these effects.\",\n      \"method\": \"Zymography, RT-PCR, ELISA, MMP-2 promoter luciferase assay, cell migration/invasion assay, HUVEC tubule formation assay, MMP-2 antibody neutralization\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays plus antibody neutralization epistasis, single lab\",\n      \"pmids\": [\"17096843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structures of human separase in complex with securin and with CDK1-cyclin B1-CKS1 reveal that securin inhibits separase via pseudosubstrate motifs that block substrate binding at the catalytic site and nearby docking sites; securin contains its own pseudosubstrate motifs analogous to C. elegans and yeast securin.\",\n      \"method\": \"Cryo-electron microscopy structural determination of human separase–securin and separase–CDK1-cyclin B1-CKS1 complexes\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with functional validation, published in Nature\",\n      \"pmids\": [\"34290405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Structural review: full-length S. cerevisiae and C. elegans separase–securin structures show securin has extensive contacts with separase consistent with a chaperone function and inhibits separase by binding as a pseudo-substrate at the catalytic site.\",\n      \"method\": \"Review of crystal/cryo-EM structures of yeast and C. elegans separase–securin complexes\",\n      \"journal\": \"Current opinion in structural biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — review synthesizing structural data; primary structures not generated in this paper\",\n      \"pmids\": [\"29452922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SGO2-MAD2 can functionally replace securin as a separase inhibitor; SGO2 uses a pseudo-substrate sequence to block the active site of separase, similar to securin; APC/C-dependent ubiquitylation and TRIP13-p31comet liberate separase from SGO2-MAD2 in vitro; acute loss of both securin and SGO2 (but not either alone) results in premature cohesin cleavage and cytotoxicity, demonstrating securin-independent separase regulation.\",\n      \"method\": \"In vitro separase liberation assay, securin-knockout cell characterization, genetic co-depletion of securin and SGO2, biochemical fractionation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution plus genetic double-knockout epistasis, published in Nature\",\n      \"pmids\": [\"32322060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Dicoumarol represses PTTG1/Securin gene expression through inhibition of Hsp90; established Hsp90 inhibitors (17-AAG and novobiocin) also repress PTTG1 expression; overexpression of Hsp90 in yeast confers hypersensitivity to dicoumarol; PTTG1 repression by dicoumarol is partially attributable to inhibition of the Ras/Raf/ERK pathway.\",\n      \"method\": \"Hsp90 inhibitor treatment, Hsp90 overexpression in yeast, in vivo heat-shock luciferase recovery assay, Western blot for Hsp90 clients, pathway inhibitor analysis\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic (yeast overexpression) evidence, multiple Hsp90 inhibitors tested, single lab\",\n      \"pmids\": [\"18347135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTTG1 attenuates drug-induced cellular senescence by suppressing p21; PTTG1-/- HCT116 cells show ~4-fold more doxorubicin/TSA-induced senescence and ~3-fold higher p21 induction; binding of Sp1, p53, and p300 to the p21 promoter is enhanced in PTTG1-/- cells after treatment; p21 knockdown abrogates the senescent effects, placing PTTG1 upstream of p21 in this pathway.\",\n      \"method\": \"PTTG1-/- cell line, SA-β-gal senescence assay, BrdU incorporation, ChIP (Sp1/p53/p300 on p21 promoter), p21 siRNA epistasis, in vivo xenograft with doxorubicin treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus genetic epistasis (p21 siRNA rescue) plus in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"21858218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ECT2 regulates PTTG1 expression by stabilizing the E2F1 transcription factor through the deubiquitinating enzyme PSMD14; ECT2 upregulates PSMD14, which prevents E2F1 ubiquitination/degradation, allowing E2F1 to drive PTTG1 transcription and glioma cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, Western blot, siRNA knockdown, in vivo xenograft experiments\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo ubiquitination assay plus siRNA genetic epistasis, single lab\",\n      \"pmids\": [\"30590814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Beta-catenin/TCF pathway activates PTTG transcription in esophageal squamous cell carcinoma; a TCF4-binding element (TBE) was identified in the PTTG promoter; S37A β-catenin activates PTTG promoter activity dependent on the intact TBE; TCF-4 protein binds the TBE by biotin-streptavidin pull-down; dominant-negative TCF suppresses activation.\",\n      \"method\": \"PTTG promoter luciferase assay with deletion/mutation analysis, biotin-streptavidin pull-down for TCF-4 binding, S37Aβ-catenin and dominant-negative TCF transfection\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis plus physical pull-down evidence, single lab\",\n      \"pmids\": [\"15514942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTTG1 promotes prostate cancer cell proliferation by inhibiting SMAD3 (a TGFβ signaling effector); PTTG1 overexpression significantly decreases SMAD3 levels; re-expression of SMAD3 rescues the PTTG1-induced proliferation; SMAD3 siRNA knockdown rescues proliferation inhibited by PTTG1 shRNA.\",\n      \"method\": \"PTTG1 transgene and shRNA in PC3 cells, Western blot for SMAD3, SMAD3 re-expression rescue, SMAD3 siRNA epistasis, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic epistasis (gain and loss of function of both PTTG1 and SMAD3), single lab\",\n      \"pmids\": [\"24627133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTTG1 promotes asparagine synthetase (ASNS) transcription by directly binding to its promoter, increasing asparagine (Asn) levels, which subsequently activate the mTOR pathway to facilitate HCC progression; HBx promotes ASNS and Asn metabolism by upregulating PTTG1; asparaginase treatment reverses PTTG1 overexpression-induced proliferation.\",\n      \"method\": \"PTTG1-deficient DEN-induced and HBx-induced HCC mouse models, ChIP/promoter binding assay, amino acid metabolomics, mTOR pathway Western blot, asparaginase rescue experiment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models plus promoter binding plus metabolic rescue, single lab\",\n      \"pmids\": [\"37159932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTTG1 is a bona fide β-catenin binding protein that inhibits destruction complex assembly, promoting β-catenin stabilization and nuclear localization; PTTG1 subcellular distribution is regulated by PP2A-mediated dephosphorylation at Ser165/171 (preventing nuclear translocation), reversible by PP2A inhibitor okadaic acid; PTTG1 competitively binds PP2A with GSK3β, decreasing GSK3β Ser9-phosphorylation-inactivation and indirectly stabilizing cytoplasmic β-catenin.\",\n      \"method\": \"Co-immunoprecipitation (PTTG1–β-catenin), phosphorylation mutant analysis, PP2A inhibitor treatment (okadaic acid), subcellular fractionation, Western blot, luciferase reporter for Wnt activity\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus phosphorylation mutants plus pharmacological PP2A inhibition, multiple mechanistic layers, single lab\",\n      \"pmids\": [\"37400529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nuclear localization of PTTG1 correlates with aggressive phenotype in seminoma cells and promotes invasiveness through activation of MMP-2; PTTG1 modulation (overexpression/knockdown) confirms causality; MMP-2 levels are significantly higher in seminomas where PTTG1 is nuclear.\",\n      \"method\": \"Immunofluorescence for PTTG1 nuclear vs. cytoplasmic localization, wound-healing assay, Matrigel invasion, zymography for MMP-2, RNAi and overexpression in seminoma cell lines\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization tied to functional invasion phenotype with bidirectional genetic manipulation, single lab\",\n      \"pmids\": [\"33430117\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTTG1 (securin) is a natively disordered protein that inhibits separase by acting as a pseudo-substrate until APC/C-Cdc20/Cdh1-mediated ubiquitination targets it for proteasomal degradation via RXXL and KEN box motifs (or via SCF-βTrCP after UV damage), allowing separase-mediated cohesin cleavage and anaphase onset; its C-terminal PXXP motifs mediate SH3-domain interactions required for oncogenic transformation, transactivation of target genes (bFGF, FGF-2, MMP-2, galectin-1, ASNS), and repression of NIS/prolactin; CDK1 phosphorylates PTTG1 in mitosis while GSK-3β phosphorylation targets it for interphase degradation; PTTG1 binds p53 (inhibiting its transcriptional and pro-apoptotic activity), interacts with the Ku/DNA-PK complex linking it to DNA-damage responses, associates with Golgi-resident microtubule nucleation complexes (GM130/AKAP450/γ-tubulin) to regulate non-centrosomal microtubule nucleation and directional cell migration, and stabilizes β-catenin by competing for PP2A binding; upstream, PTTG1 transcription is driven by E2F1 (released by Rb inactivation), STAT3, FoxM1, Sp1/NF-Y, and p300-mediated histone acetylation, placing PTTG1 at a nexus of cell-cycle control, chromosomal stability, DNA repair, and oncogenic signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTTG1 (securin) is a natively disordered protein that operates as the principal regulator of sister-chromatid separation while doubling as a transforming oncogene that rewires transcriptional and signaling programs [#0, #12]. In its canonical mitotic role, PTTG1 inhibits separase by binding as a pseudo-substrate that occludes the catalytic and docking sites, as resolved by cryo-EM of the human separase\\u2013securin complex [#33]; timely anaphase requires its destruction, which is achieved by APC/C-Cdc20 and APC/C-Cdh1 acting through an RXXL destruction box and a KEN box, with non-degradable securin causing incomplete chromatid separation [#6]. Genetic epistasis in yeast establishes securin (with B-cyclin/CDK) as one of the two obligate APC/C substrates that explain APC essentiality [#9], and an alternative SGO2-MAD2 pseudo-substrate inhibitor can functionally replace securin, revealing redundant control of separase [#35]. PTTG1 protein peaks in mitosis and is phosphorylated by CDK1 [#3], while GSK-3\\u03b2 phosphorylation routes it for SCF(\\u03b2TrCP)-mediated degradation during interphase and after UV damage via a DDAYPE motif [#18, #25]; consistent with a damage-surveillance link, PTTG1 binds the Ku/DNA-PK complex and is phosphorylated by DNA-PK, an association disrupted by DNA double-strand breaks [#7]. Dysregulated PTTG1 is directly oncogenic and a driver of chromosomal instability [#0, #14], activities that depend on C-terminal PXXP/SH3-binding motifs and a C-terminal transactivation domain required for transformation, tumorigenesis, and induction of secreted factors including bFGF, VEGF, IL-8, MMP-2, and galectin-1 [#1, #4, #15, #27, #32]. PTTG1 suppresses tumor-suppressive programs by binding p53 to block its DNA binding and pro-apoptotic transcription [#8] and by restraining p21-dependent senescence upstream of the p21/Rb axis [#13, #37]. Beyond mitosis, PTTG1 associates with Golgi-resident microtubule nucleation machinery (GM130, AKAP450, \\u03b3-tubulin) to control microtubule nucleation, cell polarity, and directional migration [#24], and stabilizes \\u03b2-catenin by competing with GSK3\\u03b2 for PP2A binding to sustain Wnt signaling [#42]. Its expression is driven by a convergent transcriptional network including E2F1 (downstream of Rb inactivation), STAT3, FoxM1, Sp1/NF-Y, and p300-mediated histone acetylation [#11, #19, #22, #29, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that PTTG is a transforming oncogene rather than a passive cell-cycle component, motivating mechanistic dissection of its oncogenic activity.\",\n      \"evidence\": \"Stable transfection of NIH 3T3 fibroblasts with soft-agar transformation and nude-mouse tumor assays\",\n      \"pmids\": [\"9092795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the molecular domain or partner responsible for transformation\", \"Single lab, single cell background\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapped oncogenic activity to C-terminal PXXP SH3-binding motifs, defining a structural determinant of transformation and growth-factor induction.\",\n      \"evidence\": \"Site-directed mutagenesis of PXXP prolines with transformation, tumorigenesis, and bFGF secretion readouts\",\n      \"pmids\": [\"9892021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SH3-domain partner protein not identified\", \"Mechanistic link between PXXP motifs and growth-factor secretion unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined PTTG as a transactivator whose acidic/proline-rich C-terminus drives transcription in a manner tied to its transforming capacity, and identified CDK1 as the mitotic kinase phosphorylating it.\",\n      \"evidence\": \"Transactivation reporter assays in yeast and mammalian cells, mutagenesis, immunodepletion plus in vitro phosphorylation with CDK1 inhibitor\",\n      \"pmids\": [\"9811450\", \"10713046\", \"10656688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional target genes not identified at this stage\", \"Functional consequence of CDK1 phosphorylation site unmapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the canonical mitotic mechanism: APC/C-Cdc20/Cdh1 degrades securin via RXXL and KEN box motifs to permit chromatid separation, and connected PTTG to DNA-damage sensing through Ku/DNA-PK.\",\n      \"evidence\": \"In vitro ubiquitination reconstitution with fzy/fzr, non-degradable securin phenotype, plus reciprocal Co-IP and in vitro kinase assay with DNA-PK\",\n      \"pmids\": [\"11179223\", \"11238996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The separase-inhibitory mechanism was not yet structurally defined\", \"Physiological role of DNA-PK phosphorylation of PTTG unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified p53 as a direct PTTG1 partner, providing a route by which oncogenic PTTG1 suppresses apoptosis and transcription.\",\n      \"evidence\": \"Phage display, reciprocal pull-down/Co-IP, reporter and apoptosis assays in PTTG1-/- cells\",\n      \"pmids\": [\"12355087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biophysical study later found no interaction between unmodified recombinant securin and p53, implying a modification- or cofactor-dependent interaction not yet defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Generalized securin as one of only two obligate APC/C substrates, explaining why the APC is essential, and extended PTTG transcriptional control to endocrine genes.\",\n      \"evidence\": \"Systematic genetic epistasis across essential APC subunits in S. cerevisiae; GH3 prolactin promoter reporter with PXXP mutagenesis\",\n      \"pmids\": [\"14634663\", \"12554778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast bypass does not address metazoan-specific APC functions\", \"Mechanism of PRL promoter repression by the PXXP motif unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved that securin is intrinsically disordered and placed PTTG genetically upstream of the p21/Rb cell-cycle and chromosomal-instability axis.\",\n      \"evidence\": \"Multi-method biophysics (NMR, CD, AUC); shRNA in corticotrophs with Pttg-/-\\u00d7Rb+/- crosses; FISSR-PCR genomic instability assay\",\n      \"pmids\": [\"15929994\", \"15919720\", \"15897900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Disordered state complicates structural rationalization of partner binding\", \"Causal chain from PTTG to genomic instability mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined an interphase, separase-independent degradation route in which GSK-3\\u03b2-primed SCF(\\u03b2TrCP) targets securin via a DDAYPE motif, especially after UV damage.\",\n      \"evidence\": \"In vivo ubiquitination, \\u03b2TrCP/CUL1 co-expression and knockdown, GSK-3\\u03b2 inhibitors, motif identification\",\n      \"pmids\": [\"18460583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals coupling GSK-3\\u03b2 to securin outside UV stress not fully defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Built the upstream transcriptional and post-translational regulatory network of PTTG (E2F1/Rb, p300/HAT, viral HBx stabilization) and extended its functions to senescence and differentiation control.\",\n      \"evidence\": \"ChIP and pull-down for E2F1; ChIP for H3 acetylation by p300; in vitro ubiquitination/Co-IP for HBx; Pttg-/-\\u00d7p21-/- crosses; Dlk1 mRNA-stability and adipogenesis assays\",\n      \"pmids\": [\"19837943\", \"19539243\", \"20198633\", \"19213844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among the multiple transcriptional inputs unresolved\", \"Mechanism of HBx-mediated SCF disruption not structurally defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Expanded PTTG1 into non-mitotic territory: Golgi-associated microtubule nucleation and migration, membrane-traffic/endosomal control with separase, and GSK3\\u03b2-driven SCF(\\u03b2TrCP) turnover linked to breast cancer.\",\n      \"evidence\": \"Co-IP/colocalization and RNAi migration assays for GM130/AKAP450/\\u03b3-tubulin; siRNA secretion/recycling/acidification assays; in vitro kinase and ubiquitination assays with tissue correlation\",\n      \"pmids\": [\"21937724\", \"21272169\", \"21757741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a securin pool is partitioned to the Golgi versus the spindle is unclear\", \"Direct enzymatic versus scaffolding contribution to microtubule nucleation undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Positioned PTTG1 as a downstream effector of oncogenic transcription factors (STAT3, FoxM1) and metastatic secretory programs (galectin-1/c-Myc, MMP-2, integrin-\\u03b1V/FAK).\",\n      \"evidence\": \"ChIP, reporter assays, siRNA epistasis and in vivo metastasis models across colorectal, esophageal, and lung cancer systems\",\n      \"pmids\": [\"23416975\", \"26264222\", \"19351864\", \"17096843\", \"22081074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these effects require nuclear PTTG1, the PXXP motif, or partner recruitment is not uniformly resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the high-resolution structural mechanism of separase inhibition and showed securin is functionally redundant with SGO2-MAD2.\",\n      \"evidence\": \"Cryo-EM of human separase\\u2013securin and separase\\u2013CDK1\\u2013cyclinB1\\u2013CKS1 complexes; in vitro separase liberation and securin/SGO2 co-depletion epistasis\",\n      \"pmids\": [\"34290405\", \"32322060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PTTG1's non-mitotic interactions (p53, \\u03b2-catenin, Golgi complex) not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined new oncogenic mechanisms: \\u03b2-catenin stabilization through PP2A competition with GSK3\\u03b2, and metabolic reprogramming via ASNS-driven asparagine/mTOR signaling.\",\n      \"evidence\": \"Co-IP, phospho-mutant and PP2A-inhibitor analysis; in vivo HCC models with ChIP, metabolomics, and asparaginase rescue\",\n      \"pmids\": [\"37400529\", \"37159932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings without independent replication\", \"Integration of metabolic, Wnt, and mitotic roles within one cell undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTTG1's intrinsically disordered structure encodes its diverse, mutually exclusive interactions and how its subcellular partitioning (spindle, Golgi, nucleus) is governed remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model for non-separase partners\", \"Determinants directing PTTG1 between mitotic, migratory, and transcriptional pools unknown\", \"Reconciliation of in-cell p53 binding with negative in vitro biophysics outstanding\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 4, 41]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [33, 6, 35]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [33, 34]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [24, 42]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 24]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 43]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5, 24]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [24, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 6, 9, 33]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 14, 29, 30]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [42, 39]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 18, 25]}\n    ],\n    \"complexes\": [\"separase-securin complex\", \"Golgi microtubule nucleation complex (GM130/AKAP450/\\u03b3-tubulin)\"],\n    \"partners\": [\"ESPL1\", \"TP53\", \"XRCC6\", \"PRKDC\", \"GM130\", \"CTNNB1\", \"PPP2CA\", \"GSK3B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}