{"gene":"TPT1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2001,"finding":"Fortilin (TPT1/TCTP) overexpression in HeLa and U2OS cells prevents etoposide-induced apoptosis in a dose-dependent manner and inhibits caspase-3-like activity, establishing it as a novel antiapoptotic protein structurally distinct from Bcl-2 family members and IAPs. Antisense depletion of fortilin from MCF-7 cells caused massive cell death.","method":"Transient/stable overexpression, antisense depletion, fluorogenic caspase substrate assay, immunocytochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (overexpression dose-response, stable cell lines, caspase assay, antisense knockdown) replicated across multiple cell lines in a single focused study","pmids":["11598139"],"is_preprint":false},{"year":2002,"finding":"Fortilin (TPT1) physically interacts with MCL1 both in vitro and in vivo; MCL1 acts as a chaperone that stabilizes fortilin by protecting it from rapid degradation. The fortilin(R21A) point mutant lacking MCL1-binding has a significantly shorter half-life than wild-type fortilin.","method":"Yeast two-hybrid screening, co-immunoprecipitation, siRNA knockdown, pulse-chase experiment, confocal immunostaining, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal co-IP, pulse-chase kinetics, mutagenesis (R21A), and siRNA all in one study; multiple orthogonal methods","pmids":["12149273"],"is_preprint":false},{"year":2002,"finding":"TCTP/TPT1 is the most strongly downregulated gene during tumor reversion; antisense cDNA or siRNA-mediated inhibition of TCTP expression suppresses the malignant phenotype and causes cellular reorganization similar to SIAH-1 overexpression, placing TCTP in a cellular reprogramming pathway.","method":"Differential gene expression analysis, Northern blot, quantitative PCR, antisense cDNA transfection, siRNA, phenotypic assays (tumorigenicity)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (siRNA, antisense, qPCR) in single lab; genetic placement relative to SIAH-1 pathway","pmids":["12399545"],"is_preprint":false},{"year":2004,"finding":"Fortilin and MCL1 protect cells from 5-FU-induced cytotoxicity independently of each other: when MCL1 is silenced by siRNA, fortilin retains cytoprotective activity, and vice versa. The fortilin–MCL1 interaction therefore augments, but is not required for, their individual antiapoptotic functions.","method":"siRNA-mediated gene silencing, cell viability assays in monoclonal and polyclonal U2OS populations, subcellular localization analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous siRNA dissection of epistasis between two proteins, single lab, two cell-population systems","pmids":["15262975"],"is_preprint":false},{"year":2006,"finding":"Transcription of the human TPT1 gene is regulated through two conserved CRE sites in the proximal promoter; supershift assays identified CREB I and Fra II (CREB/ATF1/AP1 family) as the interacting transcription factors. cAMP signaling via PKA-dependent CREB phosphorylation stimulates TCTP synthesis.","method":"Reporter-gene assays, gelshift (EMSA), footprinting, supershift assays, promoter deletion analysis, forskolin/PMA stimulation","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro transcription factor binding (EMSA, footprinting, supershift) combined with reporter assays and CRE-deletion constructs; multiple orthogonal methods in single study","pmids":["16859841"],"is_preprint":false},{"year":2007,"finding":"Fortilin binds Ca²⁺ with a Kd of ~10 mM (N-terminal residues 1–72 required); Ca²⁺ binding induces a conformational change in fortilin. The double point mutant fortilin(E58A/E60A) lacks Ca²⁺-binding ability and fails to protect cells against thapsigargin-induced, Ca²⁺-dependent apoptosis, establishing fortilin as an intracellular Ca²⁺ scavenger.","method":"Ca²⁺-overlay assay, flow dialysis, CD spectropolarimetry, intracellular Ca²⁺ measurement, site-directed mutagenesis, cell death assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical binding assays with Kd determination, conformational analysis, and mutagenesis validation in cells; multiple orthogonal methods","pmids":["17705784"],"is_preprint":false},{"year":2007,"finding":"Tpt1 in Xenopus oocytes activates transcription of oct4 and nanog upon nuclear transfer of somatic nuclei: depletion of tpt1 transcripts reduces oct4/nanog transcription, while elevation of tpt1 causes earlier activation of oct4 transcription.","method":"Protein isolation by binding to oct4 regulatory region, mass spectrometry identification, oocyte transcript depletion, nuclear transfer, mRNA quantification","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — depletion and overexpression in Xenopus nuclear transfer system, single lab, functional readout (oct4/nanog transcription)","pmids":["17442571"],"is_preprint":false},{"year":2008,"finding":"Crystal structure of human TCTP at 2.0 Å resolution reveals structural similarity between TCTP helices H2–H3 and Bax helices H5–H6. Site-directed mutagenesis of H2–H3 impairs TCTP's antiapoptotic function. TCTP inserts into the mitochondrial membrane and inhibits Bax dimerization. Tctp-null mice show increased spontaneous embryonic apoptosis and die between E6.5 and E9.5.","method":"X-ray crystallography (2.0 Å), site-directed mutagenesis, mitochondrial membrane insertion assay, Bax dimerization assay, Tctp knockout mice","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus in vivo knockout plus mechanistic mitochondrial assay; multiple orthogonal methods in single study","pmids":["18274553"],"is_preprint":false},{"year":2008,"finding":"Chfr checkpoint protein physically interacts with endogenous TCTP (identified by yeast two-hybrid and confirmed by co-immunoprecipitation of endogenous proteins); both co-localize to the mitotic spindle. The Chfr–TCTP interaction is stable throughout the cell cycle but is diminished by complete microtubule depolymerization, suggesting TCTP participates in the mitotic spindle checkpoint.","method":"Yeast two-hybrid screen, endogenous co-immunoprecipitation, immunofluorescence localization, microtubule depolymerization experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by endogenous co-IP and colocalization, single lab","pmids":["18504434"],"is_preprint":false},{"year":2008,"finding":"Dihydroartemisinin (DHA) binds human fortilin, increases its ubiquitination, shortens its half-life in a proteasome-dependent manner, and reduces cellular fortilin levels. DHA-induced DNA fragmentation is fortilin-dependent: fortilin-knockdown cells are less susceptible and fortilin-overexpressing cells are more susceptible to DHA-induced apoptosis.","method":"Binding assay, ubiquitination assay, pulse-chase (half-life measurement), proteasome inhibitor studies, siRNA knockdown, overexpression, DNA fragmentation assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding, ubiquitination, and half-life assays, plus genetic rescue experiment; single lab, multiple methods","pmids":["18325342"],"is_preprint":false},{"year":2008,"finding":"Fortilin interacts with TSC-22 (TGF-β stimulated clone-22) via yeast two-hybrid; fortilin overexpression reverses TSC-22-mediated apoptosis in ovarian carcinoma cells, and fortilin promotes proteasomal degradation of TSC-22.","method":"Yeast two-hybrid screening, siRNA knockdown, overexpression, apoptosis assays, protein degradation analysis","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid plus functional rescue, but no direct in-cell co-IP for the interaction; single lab","pmids":["18325344"],"is_preprint":false},{"year":2009,"finding":"Fortilin-null (fortilin⁻/⁻) mice are embryonically lethal around 3.5 dpc. In Xenopus, fortilin depletion compromises neural tissue formation, while overexpression induces partial double body axis and blocks BMP4-induced transcription of Vent1, Vent2, and Msx1. In mouse embryonic fibroblasts, fortilin siRNA depletion allows BMP4 to cause extensive DNA fragmentation and increased Msx2 expression, establishing fortilin as an inhibitor of the BMP signaling pathway.","method":"Targeted gene disruption in mice, Xenopus embryo injections (mRNA depletion/overexpression), siRNA in MEFs, BMP4 stimulation, reporter gene assays, DNA fragmentation","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mice, Xenopus gain/loss-of-function, and MEF siRNA all in one study; multiple species and orthogonal methods","pmids":["19364479"],"is_preprint":false},{"year":2011,"finding":"Fortilin binds specifically to the sequence-specific DNA-binding domain of p53, blocking p53-induced transcriptional activation of Bax. A double-point mutant of fortilin lacking p53 binding fails to inhibit p53-dependent apoptosis. Cells expressing wild-type fortilin (but not the p53-binding mutant) form large tumors in athymic mice.","method":"Co-immunoprecipitation, site-directed mutagenesis, reporter gene assay (Bax transcription), apoptosis assay, xenograft tumor assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct co-IP, mutagenesis ablating the interaction, transcriptional assay, and in vivo xenograft; multiple orthogonal methods in one study","pmids":["21795694"],"is_preprint":false},{"year":2011,"finding":"TCTP promotes p53 degradation by competing with NUMB for binding to p53-MDM2 complexes; TCTP inhibits MDM2 auto-ubiquitination and promotes MDM2-mediated ubiquitination and degradation of p53. P53 reciprocally directly represses TCTP transcription. Tctp haploinsufficient mice are sensitized to p53-dependent apoptosis.","method":"Co-immunoprecipitation, ubiquitination assays, knockdown/overexpression, promoter reporter assays, Tctp+/- mouse model, pharmacological inhibition (sertraline/thioridazine)","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple biochemical assays (co-IP, ubiquitination), genetic model (haploinsufficient mice), and pharmacological validation; independently significant findings","pmids":["22157679"],"is_preprint":false},{"year":2013,"finding":"TCTP enhances glioma cell proliferation through increased β-catenin binding to TCF-4 and elevated TOPflash transcription activity and Wnt/β-catenin target gene expression (c-Myc, cyclin D1). TCF-4 shRNA rescues the TCTP overexpression-induced proliferation, establishing TCTP as an upstream activator of Wnt/β-catenin signaling.","method":"Co-immunoprecipitation (TCTP/TCF-4/β-catenin), TOPflash/FOPflash reporter assay, shRNA knockdown, xenograft model, Western blot","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus reporter assay plus epistatic rescue by TCF-4 shRNA; single lab","pmids":["24311645"],"is_preprint":false},{"year":2015,"finding":"TCTP mRNA translation is regulated through the PI3-K/Akt/mTORC1 signalling pathway. mTOR kinase inhibitors and Akt inhibitors block serum-induced increases in TCTP protein. TSC2 knockout derepresses TCTP translation under starvation. A constitutively active 4E-BP1 mutant inhibits TCTP mRNA translation, and eIF4E overexpression increases polysomal association of TCTP mRNA.","method":"Polysome profiling, mRNA quantification by RT-qPCR, mTOR/Akt inhibitors, TSC2 knockout cells, eIF4E overexpression, 4E-BP1 constitutively active mutant, Western blot","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — polysome profiling, multiple genetic and pharmacological perturbations, TSC2 KO and dominant mutants; multiple orthogonal methods in one study","pmids":["25936523"],"is_preprint":false},{"year":2016,"finding":"TCTP contains a BH3-like domain that binds the BH3-groove of Bcl-xL. Crystal structure of a Bcl-xL deletion variant–TCTP11-31 complex at atomic resolution shows TCTP refolds into a helical conformation upon Bcl-xL binding. Unlike all other BH3-domain proteins (which inhibit Bcl-xL), TCTP activates the anti-apoptotic function of Bcl-xL. Replacing the non-conserved h1 of TCTP with that from Bax drastically increases affinity for Bcl-xL and changes biological properties.","method":"X-ray crystallography (Bcl-xL–TCTP complex), in vitro reconstitution, in vivo functional assays, TCTP+/- mouse model, mutagenesis (hybrid BH3)","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus reconstitution, mutagenesis, and mouse genetic model in one study","pmids":["26813996"],"is_preprint":false},{"year":2016,"finding":"Drosophila TCTP (Tctp) physically interacts with Rheb GTPase and acts as a guanine nucleotide exchange factor (GEF) for Rheb, activating TOR signalling for organ growth. 14-3-3 proteins physically interact with both Tctp and Rheb; knockdown of both 14-3-3 isoforms abolishes Tctp–Rheb binding, reduces phospho-S6K, phospho-4E-BP, and cyclin E, impairing tissue growth. Growth defects are suppressed by CycE overexpression.","method":"Genetic epistasis (Drosophila knockdown/synergy), co-immunoprecipitation, phospho-S6K/4E-BP Western blot, cyclin E rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, genetic epistasis across multiple genotypes, rescue experiment; consistent with prior Drosophila GEF study","pmids":["27151460"],"is_preprint":false},{"year":2016,"finding":"Drosophila Tctp binds the Brahma (Brm) chromatin remodeler and negatively modulates its activity. Tctp mutants show elevated transcription of a large gene set and transposons; brm mutations ameliorate these defects. Tctp also promotes stability of rDNA and pericentromeric heterochromatin by opposing Brm and regulating su(var)3-9 transcription.","method":"Genetic epistasis (Drosophila Tctp mutants + brm mutants), chromatin/transcription analysis, transposon assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with brm mutants and transcriptomic analysis; single lab, Drosophila model","pmids":["27687497"],"is_preprint":false},{"year":2016,"finding":"Tctp interacts with Mcl1 in the axonal compartment of Xenopus retinal ganglion cells; Tctp deficiency results in stunted retinotectal projections with mitochondrial dysfunction and impaired axon extension. Mcl1 knockdown phenocopies Tctp deficiency, placing Tctp upstream of Mcl1-mediated pro-survival signalling in axon development.","method":"Morpholino-mediated knockdown in Xenopus, co-immunoprecipitation in axonal compartment, live imaging, mitochondrial dysfunction assays, genetic epistasis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — axonal co-IP, knockdown phenotype, epistasis with Mcl1; single lab, Xenopus model","pmids":["26903505"],"is_preprint":false},{"year":2016,"finding":"Fortilin physically interacts with peroxiredoxin-1 (PRX1), protects PRX1 from proteasome-mediated degradation, and prevents its inactivating phosphorylation by Mst1 kinase. Liver-specific fortilin overexpression in transgenic mice reduces PRX1 phosphorylation and enhances PRX1 peroxidase activity, protecting against alcohol-induced ROS-mediated liver damage.","method":"Co-immunoprecipitation, proteasome inhibitor assays, kinase (Mst1) phosphorylation assay, transgenic mouse liver overexpression, PRX1 activity assay, alcohol liver-damage model","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — co-IP, in vitro kinase assay, transgenic mouse model with functional readout; multiple orthogonal methods","pmids":["26726832"],"is_preprint":false},{"year":2017,"finding":"TCTP mRNA translation is upregulated via the mTORC1 pathway in HCT116 colon cancer cells in response to the DNA-damaging drugs 5-FU and oxaliplatin; mTOR kinase inhibitors prevent this upregulation. TCTP knockdown sensitises HCT116 cells to cytotoxicity by both drugs, establishing TCTP as a contributor to drug resistance via translational regulation.","method":"Western blot, RT-qPCR, mTOR inhibitors, siRNA knockdown, RTCA system, MTS cell viability assay","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mTOR inhibitor pharmacology, mRNA vs. protein dissociation, functional knockdown; single lab","pmids":["28143584"],"is_preprint":false},{"year":2017,"finding":"Fortilin directly interacts with the cytoplasmic domain of IRE1α (the ER stress sensor), inhibits both its kinase and endoribonuclease (RNase) activities, and protects cells and whole animals from ER stress-induced apoptosis.","method":"Co-immunoprecipitation, in vitro kinase assay, in vitro RNase assay, cellular apoptosis assays, whole-animal (in vivo) ER stress model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding, two distinct enzymatic activity assays (kinase and RNase inhibition), cell-level and whole-animal functional validation in one study","pmids":["28550308"],"is_preprint":false},{"year":2018,"finding":"RNA 2'-phosphotransferase Tpt1 (the enzymatic activity encoded by the TPT1/Tpt1 gene in fungi) catalyzes NAD⁺-dependent conversion of internal RNA 2'-monophosphate to 2'-OH via a two-step mechanism forming a 2'-phospho-ADP-ribosylated RNA intermediate. A subset of Tpt1 enzymes (e.g., Aeropyrum pernix Tpt1) also catalyze NAD⁺-dependent ADP-ribosylation of 5'-monophosphate RNA/DNA termini to create a 5'-phospho-ADP-ribosylated cap.","method":"In vitro enzymatic assay with purified Tpt1 enzymes from diverse taxa, NAD⁺ substrate studies, product characterization","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of enzymatic mechanism across multiple Tpt1 enzymes; note this is the fungal/archaeal RNA ligase pathway Tpt1 activity, which is distinct from the mammalian anti-apoptotic TCTP function but encoded by the same locus family","pmids":["30202863"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of Tpt1 (1.4 Å) in a product-mimetic complex with ADP-ribose-1″-phosphate (in NAD⁺ site) and pAp (in RNA site) reveals the mechanism of 2'-PO4 RNA splice-junction recognition and RNA phospho-ADP-ribosylation. Evidence is provided that a bacterium has an endogenous phosphorylated substrate for Tpt1.","method":"X-ray crystallography (1.4 Å), product-mimetic complex, substrate binding analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with mechanistic interpretation; single study but high-quality structural data","pmids":["30644400"],"is_preprint":false},{"year":2019,"finding":"TCTP controls the G1/S transition by interacting with CSN4 (a subunit of the COP9 Signalosome); TCTP loss leads to increased fraction of deneddylated CUL1 (a substrate of the COP9 complex). This mechanism is conserved between Arabidopsis and Drosophila: dCSN4 or dTCTP knockdown in Drosophila similarly impairs cell proliferation and CUL1 neddylation.","method":"Genetic interaction studies (Arabidopsis and Drosophila), CUL1 neddylation assays, cell cycle analysis, knockdown of CSN4 and TCTP","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in two organisms plus CUL1 neddylation biochemistry; single lab, cross-species validation","pmids":["30695029"],"is_preprint":false},{"year":2019,"finding":"Cardiomyocyte-specific TCTP knockdown with siRNA induces apoptotic and autophagic cell death accompanied by mitochondrial permeability transition pore (mPTP) opening; Bnip3 mediates this TCTP-loss-induced death. Cardiomyocyte-specific TCTP overexpression in mice decreases susceptibility to doxorubicin-induced cardiac dysfunction with attenuated Bnip3 induction.","method":"siRNA knockdown, cardiomyocyte-specific transgenic overexpression, mPTP assay, Bnip3 Western blot, doxorubicin heart failure model in mice","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA mechanism (Bnip3 as mediator), transgenic mouse model with functional cardiac readout, pharmacological (DHA) validation; multiple orthogonal methods","pmids":["31320615"],"is_preprint":false},{"year":2020,"finding":"TCTP/fortilin promotes epithelial-mesenchymal transition (EMT): overexpression increases ZEB1, α-SMA, and invasiveness while decreasing E-cadherin and p53 expression in A549 lung adenocarcinoma cells, and knockdown has opposite effects. TCTP also interacts with β-catenin to stabilize it and promote nuclear localization, and induces urokinase plasminogen activator (uPA) to destabilize ECM.","method":"Stable lentiviral overexpression/knockdown, scratch and transwell migration/invasion assays, Western blot for EMT markers, co-immunoprecipitation (TCTP–β-catenin), uPA assay","journal":"OncoTargets and therapy / Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of TCTP–β-catenin plus functional EMT assays; findings consistent across two papers (PMID 28958626 and 30881019), single lab each","pmids":["28958626","30881019"],"is_preprint":false},{"year":2021,"finding":"Heart-specific fortilin knockout mice (fortilinKO-heart) die by 9 weeks with extensive cardiomyocyte apoptosis and severe heart failure; hearts show drastic upregulation of p53 target genes. Additional heart-specific p53 deletion in fortilinKO-heart mice extends lifespan from 9 to 18 weeks by mitigating cardiomyocyte apoptosis, establishing fortilin as a cardiac p53 inhibitor in vivo.","method":"Cardiomyocyte-specific conditional knockout (fortilinKO-heart), double knockout (fortilinKO-heart × p53KO-heart), cardiac phenotyping, p53 target gene expression, TUNEL/caspase apoptosis assays","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cardiac phenotype and genetic epistasis rescue by p53 KO; rigorous in vivo genetics","pmids":["34689154"],"is_preprint":false},{"year":2025,"finding":"Fortilin specifically interacts with CTNNA3 (α-T-catenin) but not with CTNNA1, CTNNA2, or CTNNB. Fortilin silencing promotes phosphorylation of CTNNA3, leading to its ubiquitination and proteasome-mediated degradation. CTNNA3 knockdown causes 293T cells to undergo apoptosis, placing fortilin as a guardian of CTNNA3 stability and cell survival.","method":"Co-immunoprecipitation Western blot, proximity ligation assay, microscale thermophoresis, biolayer interferometry, siRNA knockdown, phospho-null and phospho-mimetic CTNNA3 mutants, proteasome inhibitor assays","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple direct binding assays (Co-IP, PLA, MST, BLI), mutagenesis (phospho-null/mimetic), proteasome dependency, and functional apoptosis readout in one study","pmids":["39747445"],"is_preprint":false},{"year":2017,"finding":"TCTP activates the EGFR-AKT-MCL-1/CXCL10 pathway via phosphorylation-dependent interaction with Na,K-ATPase, conferring immune-refractory phenotypes (decreased T cell trafficking and resistance to CTL-mediated killing) in tumor cells.","method":"Transcriptome analysis, immune-refractory tumor models, pharmacological inhibition (DHA), co-immunoprecipitation (TCTP–Na,K-ATPase), phosphorylation assays, T cell killing assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus phosphorylation-dependency and functional immune assays; single lab; mechanism involving Na,K-ATPase interaction consistent with earlier reports","pmids":["35440620"],"is_preprint":false},{"year":2012,"finding":"TCTP overexpression in mouse pluripotent P19 and ES cells downregulates Oct4 transcription; the N-terminal 1–60 aa of TCTP are required for this suppression. TCTP binds the Sf1 site of the Oct4 promoter, and siRNA knockdown of TCTP increases Oct4 expression.","method":"Overexpression, siRNA knockdown, promoter reporter assay, N-terminal deletion analysis, Oct4 mRNA/protein quantification","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding mapped to Sf1 site, deletion mutagenesis, bidirectional (OE and KD) experiments; single lab","pmids":["22281008"],"is_preprint":false},{"year":2017,"finding":"TCTP regulates spindle dynamics in mouse oocytes: TCTP knockdown accelerates reduction of spindle dynamics during postovulatory aging, causing aging-related deterioration of oocyte quality, whereas TCTP overexpression preserves spindle dynamics and prevents aging-associated abnormalities, improving fertilization competency and embryo development.","method":"siRNA knockdown, mRNA overexpression injection, live spindle imaging (spindle dynamics), fertilization and embryo development assays in mouse oocytes","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional (KD and OE) experiments with live spindle imaging and functional developmental readouts; single lab","pmids":["28476647"],"is_preprint":false},{"year":2020,"finding":"DLC1 and TCTP co-localize in focal adhesions and form a protein complex; DLC1 negatively regulates TCTP levels in a RhoGAP-independent manner (both WT and GAP-dead R718A mutant reduce TCTP). Depletion of DLC1 increases TCTP expression and elevates Cdc42 and downstream JNK/NF-κB and N-WASP signaling, promoting cancer cell migration.","method":"Co-immunoprecipitation, colocalization (immunofluorescence), siRNA depletion, GFP-DLC1 WT and GAP-dead mutant transfection, Cdc42 activation assay, migration assays","journal":"Food & function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-IP, colocalization, and GAP-dead mutant dissection of mechanism; single lab","pmids":["33150340"],"is_preprint":false}],"current_model":"TPT1/TCTP (fortilin) is a multifunctional cytoprotective protein that inhibits apoptosis through several distinct mechanisms: it directly binds the DNA-binding domain of p53 (blocking Bax transcription and competing with NUMB for MDM2 complexes to promote p53 degradation), inserts into mitochondrial membranes to inhibit Bax dimerization, contains a BH3-like domain that activates Bcl-xL, sequesters intracellular Ca²⁺ via N-terminal residues to prevent Ca²⁺-dependent apoptosis, binds and inhibits both kinase and RNase activities of the ER stress sensor IRE1α, stabilizes PRX1 by blocking Mst1-mediated inactivating phosphorylation, and protects CTNNA3 from phosphorylation-ubiquitination-proteasomal degradation; its mRNA translation is regulated by the PI3-K/Akt/mTORC1 pathway via a 5'-TOP element, and its transcription is controlled by CREB/ATF1 via CRE sites in the proximal promoter; TCTP also promotes cell growth via GEF activity toward Rheb (activating TOR), interacts with the COP9 signalosome (CSN4) to regulate CUL1 neddylation and G1/S transition, co-localizes with the mitotic spindle through Chfr interaction, activates Wnt/β-catenin–TCF-4 signaling, and extracellularly (as a dimer through Cys172) acts as a histamine-releasing cytokine-like factor."},"narrative":{"mechanistic_narrative":"TPT1 (TCTP/fortilin) is a multifunctional cytoprotective protein that integrates pro-survival, growth, and developmental signaling, and whose loss is embryonically lethal in mice [PMID:11598139, PMID:18274553, PMID:19364479]. Its dominant function is suppression of apoptosis through convergent mechanisms: it inserts into the mitochondrial membrane to inhibit Bax dimerization via a Bax-like H2–H3 helical region [PMID:18274553], it contains a BH3-like domain that—unlike all other BH3 proteins—activates rather than inhibits the anti-apoptotic activity of Bcl-xL [PMID:26813996], and it sequesters intracellular Ca²⁺ through N-terminal residues to block Ca²⁺-dependent death [PMID:17705784]. TCTP is a central negative regulator of p53: it binds the p53 DNA-binding domain to block Bax transactivation [PMID:21795694] and competes with NUMB at the p53–MDM2 complex to promote MDM2-mediated p53 ubiquitination and degradation, with p53 reciprocally repressing TCTP transcription [PMID:22157679]; this axis is required for cardiomyocyte survival in vivo, as cardiac p53 deletion rescues the lethal heart failure of fortilin heart-specific knockouts [PMID:34689154]. It further restrains the ER-stress sensor IRE1α by directly inhibiting both its kinase and RNase activities [PMID:28550308], protects peroxiredoxin-1 from inactivating Mst1 phosphorylation to limit ROS damage [PMID:26726832], and stabilizes the survival factor CTNNA3 against phosphorylation-driven proteasomal degradation [PMID:39747445]. TCTP also drives cell growth and proliferation by acting as a GEF for Rheb to activate TOR signaling [PMID:27151460], by interacting with the COP9 signalosome subunit CSN4 to regulate CUL1 neddylation and the G1/S transition [PMID:30695029], and by activating Wnt/β-catenin–TCF-4 signaling [PMID:24311645]; its own abundance is controlled translationally by the PI3-K/Akt/mTORC1 pathway, including under DNA-damage stress where it promotes drug resistance [PMID:25936523, PMID:28143584]. The protein is stabilized by MCL1, which acts as a chaperone for fortilin [PMID:12149273]. A distinct enzymatic activity—NAD⁺-dependent RNA 2'-phosphotransferase that resolves internal RNA 2'-monophosphates—is encoded by Tpt1 orthologs in fungi and archaea and represents a separate, non-mammalian function of this locus family [PMID:30202863, PMID:30644400].","teleology":[{"year":2001,"claim":"Established TPT1/fortilin as a bona fide anti-apoptotic protein, distinct from the known Bcl-2 and IAP families, defining a new cytoprotective factor.","evidence":"Overexpression, antisense depletion, and caspase-3 assays across HeLa, U2OS, and MCF-7 cells","pmids":["11598139"],"confidence":"High","gaps":["Molecular target of caspase suppression not defined","Did not localize the protective step within the apoptotic cascade"]},{"year":2002,"claim":"Identified MCL1 as a binding partner that chaperones and stabilizes fortilin, linking its abundance to a known survival protein.","evidence":"Yeast two-hybrid, reciprocal co-IP, pulse-chase with the R21A binding mutant, and siRNA","pmids":["12149273"],"confidence":"High","gaps":["Whether MCL1 binding contributes to anti-apoptotic activity beyond stabilization unresolved at this stage","Structural basis of the interaction not defined"]},{"year":2002,"claim":"Placed TCTP in a tumor-reversion/reprogramming pathway, showing its downregulation reverses the malignant phenotype.","evidence":"Differential expression, antisense/siRNA, and tumorigenicity assays relative to SIAH-1","pmids":["12399545"],"confidence":"Medium","gaps":["Direct molecular link between TCTP and SIAH-1 not established","Mechanism of phenotypic reversion left undefined"]},{"year":2006,"claim":"Defined transcriptional control of TPT1 by CREB/ATF1 via proximal CRE sites, connecting cAMP/PKA signaling to TCTP synthesis.","evidence":"Reporter assays, EMSA/footprinting/supershift, promoter deletions, and forskolin stimulation","pmids":["16859841"],"confidence":"High","gaps":["Physiological stimuli driving CRE-dependent expression in vivo not defined","Interplay with later-identified p53 repression not addressed"]},{"year":2007,"claim":"Showed fortilin is an intracellular Ca²⁺ scavenger whose N-terminal Ca²⁺ binding is required for protection against Ca²⁺-dependent apoptosis.","evidence":"Ca²⁺-overlay, flow dialysis, CD spectroscopy, E58A/E60A mutant, and thapsigargin death assays","pmids":["17705784"],"confidence":"High","gaps":["Very low affinity (Kd ~10 mM) raises questions about which physiological Ca²⁺ pools are buffered","Connection to ER stress signaling not yet drawn"]},{"year":2007,"claim":"Implicated Tpt1 in pluripotency-gene activation, showing it can promote oct4/nanog transcription during somatic nuclear reprogramming.","evidence":"Oct4-region affinity purification, mass spectrometry, and transcript depletion/elevation in Xenopus oocyte nuclear transfer","pmids":["17442571"],"confidence":"Medium","gaps":["Direct vs. indirect action on pluripotency promoters unresolved","Apparent conflict with later mouse data showing Oct4 repression"]},{"year":2008,"claim":"Provided structural and in vivo basis for anti-apoptosis: a Bax-like H2–H3 region inserts into mitochondria to block Bax dimerization, and loss is embryonically lethal.","evidence":"2.0 Å crystal structure, H2–H3 mutagenesis, mitochondrial insertion/Bax dimerization assays, and Tctp-null mice","pmids":["18274553"],"confidence":"High","gaps":["Stoichiometry and lipid requirements of membrane insertion not defined","Whether mitochondrial action is the principal cause of embryonic lethality not isolated"]},{"year":2008,"claim":"Connected TCTP to the mitotic spindle checkpoint through a microtubule-dependent interaction with the Chfr checkpoint protein.","evidence":"Yeast two-hybrid, endogenous co-IP, spindle colocalization, and microtubule depolymerization","pmids":["18504434"],"confidence":"Medium","gaps":["Functional consequence of Chfr binding for checkpoint output not tested","Whether TCTP is a Chfr substrate or regulator unresolved"]},{"year":2008,"claim":"Identified fortilin as a druggable target: dihydroartemisinin binds it and triggers its ubiquitin-proteasome degradation, sensitizing cells to apoptosis.","evidence":"Binding, ubiquitination, pulse-chase, proteasome inhibition, and knockdown/overexpression DNA-fragmentation rescue","pmids":["18325342"],"confidence":"Medium","gaps":["DHA binding site on fortilin not mapped","E3 ligase mediating DHA-induced ubiquitination not identified"]},{"year":2008,"claim":"Linked fortilin to TGF-β signaling antagonism by promoting proteasomal degradation of the pro-apoptotic factor TSC-22.","evidence":"Yeast two-hybrid, knockdown/overexpression, apoptosis rescue, and degradation analysis","pmids":["18325344"],"confidence":"Low","gaps":["No in-cell co-IP confirming the direct interaction","Degradation mechanism (E3 ligase, ubiquitination site) not defined"]},{"year":2009,"claim":"Established fortilin as an inhibitor of BMP signaling required for neural development, integrating its survival role with embryonic patterning.","evidence":"Mouse knockout (lethal ~3.5 dpc), Xenopus gain/loss-of-function with BMP4 target readouts, and MEF siRNA","pmids":["19364479"],"confidence":"High","gaps":["Molecular point of BMP-pathway inhibition not identified","Discrepancy in reported lethality timing versus earlier knockout not reconciled"]},{"year":2011,"claim":"Defined a direct anti-p53 mechanism: fortilin binds the p53 DNA-binding domain to block Bax transactivation and drive tumorigenesis.","evidence":"Co-IP, p53-binding-deficient mutant, Bax reporter assay, apoptosis assay, and xenografts","pmids":["21795694"],"confidence":"High","gaps":["Whether binding affects other p53 targets beyond Bax not addressed","Structural details of the p53–fortilin interface not resolved"]},{"year":2011,"claim":"Showed TCTP promotes p53 degradation by competing with NUMB at the p53–MDM2 complex, establishing a reciprocal TCTP–p53 regulatory loop.","evidence":"Co-IP, ubiquitination assays, promoter reporters, Tctp+/- mice, and pharmacological inhibition","pmids":["22157679"],"confidence":"High","gaps":["Relative contribution of direct p53 binding (#12) versus MDM2-competition pathway not quantified","How the two opposing transcriptional arms are balanced in vivo unclear"]},{"year":2012,"claim":"Demonstrated context-dependent control of Oct4: in mouse pluripotent cells TCTP binds the Sf1 site of the Oct4 promoter and represses it, contrasting with the Xenopus activation phenotype.","evidence":"Overexpression/knockdown, promoter reporter, and N-terminal (1–60) deletion mapping","pmids":["22281008"],"confidence":"Medium","gaps":["Direct DNA binding vs. cofactor-mediated promoter occupancy not distinguished","Basis of opposite direction relative to #6 unresolved"]},{"year":2013,"claim":"Positioned TCTP as an upstream activator of Wnt/β-catenin–TCF-4 signaling driving glioma proliferation.","evidence":"Co-IP, TOPflash reporter, target-gene Western blots, TCF-4 shRNA rescue, and xenografts","pmids":["24311645"],"confidence":"Medium","gaps":["Whether TCTP acts directly on the β-catenin/TCF-4 complex or upstream not defined","Link to the separately reported β-catenin stabilization mechanism not integrated"]},{"year":2015,"claim":"Established that TCTP protein levels are set translationally by PI3-K/Akt/mTORC1 acting on its 5'-TOP mRNA.","evidence":"Polysome profiling, mTOR/Akt inhibitors, TSC2 KO, eIF4E overexpression, and constitutively active 4E-BP1","pmids":["25936523"],"confidence":"High","gaps":["Interplay between this translational control and CREB-dependent transcription not addressed","Physiological signals tuning TCTP translation in vivo not defined"]},{"year":2016,"claim":"Resolved the BH3-like mechanism: TCTP refolds into a helix in the Bcl-xL groove and uniquely activates rather than inhibits Bcl-xL.","evidence":"Crystal structure of the Bcl-xL–TCTP11-31 complex, reconstitution, hybrid-BH3 mutagenesis, and TCTP+/- mice","pmids":["26813996"],"confidence":"High","gaps":["Mechanism by which groove occupancy activates rather than inhibits Bcl-xL not fully explained","Relationship to the mitochondrial Bax-inhibition mechanism not unified"]},{"year":2016,"claim":"Defined TCTP as a Rheb GEF that activates TOR-driven growth, with 14-3-3 proteins required for the TCTP–Rheb interaction.","evidence":"Drosophila genetic epistasis, co-IP, phospho-S6K/4E-BP blots, and cyclin E rescue","pmids":["27151460"],"confidence":"High","gaps":["Whether mammalian TCTP retains Rheb-GEF activity not tested here","Relationship to TCTP being itself an mTORC1 translational target (#15) creates a feedback loop not dissected"]},{"year":2016,"claim":"Revealed a chromatin role: TCTP restrains the Brahma remodeler to silence transposons and stabilize heterochromatin.","evidence":"Drosophila Tctp/brm epistasis, transcriptome/transposon analysis, and su(var)3-9 regulation","pmids":["27687497"],"confidence":"Medium","gaps":["Direct Tctp–Brm binding in mammals not shown","Mechanism linking Brm modulation to heterochromatin stability incomplete"]},{"year":2016,"claim":"Showed the TCTP–Mcl1 axis supports axonal mitochondrial function and projection growth in neurons.","evidence":"Xenopus morpholino knockdown, axonal-compartment co-IP, live imaging, and Mcl1 epistasis","pmids":["26903505"],"confidence":"Medium","gaps":["Whether axonal effects are MCL1-stabilization–dependent or independent not resolved","Direct cause of mitochondrial dysfunction not pinpointed"]},{"year":2016,"claim":"Identified an antioxidant mechanism: fortilin stabilizes PRX1 and blocks its inactivating Mst1 phosphorylation, protecting against ROS-mediated liver damage.","evidence":"Co-IP, proteasome inhibition, Mst1 kinase assay, and liver-specific transgenic mice in an alcohol model","pmids":["26726832"],"confidence":"High","gaps":["How fortilin shields the PRX1 phospho-site mechanistically not defined","Generalizability beyond liver tissue not established"]},{"year":2017,"claim":"Showed TCTP directly inhibits the ER stress sensor IRE1α, blocking both its kinase and RNase activities to prevent ER-stress apoptosis.","evidence":"Co-IP, in vitro kinase and RNase assays, cellular apoptosis assays, and whole-animal ER-stress model","pmids":["28550308"],"confidence":"High","gaps":["Binding interface on the IRE1α cytoplasmic domain not mapped","Effect on the XBP1-splicing arm of the UPR not separately quantified"]},{"year":2017,"claim":"Linked TCTP translational upregulation to chemoresistance, showing mTORC1-driven TCTP induction protects colon cancer cells from DNA-damaging drugs.","evidence":"mTOR inhibitors, mRNA/protein dissociation, and siRNA sensitization to 5-FU/oxaliplatin","pmids":["28143584"],"confidence":"Medium","gaps":["Downstream effector responsible for resistance not isolated","Whether p53 inhibition mediates the resistance not tested"]},{"year":2017,"claim":"Demonstrated TCTP preserves oocyte spindle dynamics, linking its mitotic-spindle association to reproductive aging and embryo competency.","evidence":"siRNA/mRNA injection, live spindle imaging, and fertilization/embryo-development assays in mouse oocytes","pmids":["28476647"],"confidence":"Medium","gaps":["Molecular partner mediating spindle stabilization not identified","Relationship to the Chfr–spindle interaction (#8) not addressed"]},{"year":2018,"claim":"Characterized the distinct enzymatic Tpt1 activity—NAD⁺-dependent RNA 2'-phosphotransferase resolving internal RNA 2'-monophosphates—in fungal/archaeal orthologs.","evidence":"In vitro enzymatic assays with purified Tpt1 enzymes from diverse taxa and product characterization","pmids":["30202863"],"confidence":"High","gaps":["This RNA-repair activity is not demonstrated for the mammalian anti-apoptotic protein","Endogenous RNA substrate in higher eukaryotes not defined"]},{"year":2019,"claim":"Provided the structural mechanism of Tpt1 2'-PO4 splice-junction recognition and RNA phospho-ADP-ribosylation.","evidence":"1.4 Å crystal structure in a product-mimetic complex with ADP-ribose-1''-phosphate and pAp","pmids":["30644400"],"confidence":"High","gaps":["Relevance to mammalian TCTP biology remains separate","Physiological substrate identity in most lineages unresolved"]},{"year":2019,"claim":"Connected TCTP to cell-cycle control through CSN4/COP9 signalosome interaction regulating CUL1 neddylation at G1/S, conserved across plants and flies.","evidence":"Cross-species genetic interaction (Arabidopsis, Drosophila) and CUL1 neddylation/cell-cycle assays","pmids":["30695029"],"confidence":"Medium","gaps":["Direct biochemical effect of TCTP on COP9 deneddylase activity not measured","Human relevance not directly tested"]},{"year":2019,"claim":"Established a cardiac survival role: TCTP loss triggers Bnip3-dependent apoptotic/autophagic cardiomyocyte death with mPTP opening, and overexpression protects against doxorubicin cardiotoxicity.","evidence":"siRNA, cardiomyocyte-specific transgenic mice, mPTP assays, Bnip3 blots, and doxorubicin heart-failure model","pmids":["31320615"],"confidence":"High","gaps":["Mechanism by which TCTP suppresses Bnip3 not defined","Relationship to the p53-dependent cardiac death pathway (#28) not unified"]},{"year":2020,"claim":"Showed TCTP promotes EMT and invasion partly by binding and stabilizing β-catenin and inducing uPA, integrating its Wnt and migratory functions.","evidence":"Stable overexpression/knockdown, migration/invasion assays, EMT-marker blots, TCTP–β-catenin co-IP, and uPA assay","pmids":["28958626","30881019"],"confidence":"Medium","gaps":["Direct vs. indirect β-catenin stabilization mechanism not resolved","Whether p53 downregulation drives the EMT program not isolated"]},{"year":2020,"claim":"Identified DLC1 as a negative regulator of TCTP levels at focal adhesions, controlling Cdc42-driven migration independently of DLC1 RhoGAP activity.","evidence":"Co-IP, colocalization, siRNA, GAP-dead R718A mutant, Cdc42 activation, and migration assays","pmids":["33150340"],"confidence":"Medium","gaps":["Mechanism by which DLC1 lowers TCTP (degradation vs. translation) not defined","Direct vs. complex-mediated interaction not resolved"]},{"year":2022,"claim":"Linked TCTP to tumor immune evasion via phospho-dependent Na,K-ATPase interaction activating EGFR-AKT-MCL-1/CXCL10 signaling.","evidence":"Transcriptomics, immune-refractory tumor models, DHA inhibition, co-IP, phosphorylation, and T-cell killing assays","pmids":["35440620"],"confidence":"Medium","gaps":["Causal step from Na,K-ATPase binding to immune refractoriness not fully isolated","Whether extracellular/membrane TCTP mediates this not addressed"]},{"year":2025,"claim":"Defined a new survival mechanism: fortilin specifically binds CTNNA3 (not other catenins) and protects it from phosphorylation-driven ubiquitin-proteasome degradation to prevent apoptosis.","evidence":"Co-IP, PLA, MST, BLI, phospho-null/mimetic CTNNA3 mutants, proteasome inhibition, and apoptosis assays","pmids":["39747445"],"confidence":"High","gaps":["Kinase phosphorylating CTNNA3 not identified","Tissue contexts where CTNNA3 protection is physiologically relevant not defined"]},{"year":null,"claim":"How TCTP's many parallel pro-survival and growth mechanisms are coordinated within a single cell — and whether the mammalian protein possesses any of the RNA 2'-phosphotransferase enzymatic activity of its fungal/archaeal orthologs — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No integrated model ranks the relative in vivo contribution of the p53, Bcl-xL, IRE1α, Ca²⁺, and PRX1 pathways","Whether mammalian TCTP/fortilin has any catalytic RNA-repair role is untested","Structural basis of most protein-protein interfaces (p53, IRE1α, CSN4) unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[22,20,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,13,16,22,17]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[5]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[23,24]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[31]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7,26]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,22]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12,27]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[8,32]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,7,16,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,14,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[25,8,32]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[22,20,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,28,26]}],"complexes":["COP9 signalosome"],"partners":["MCL1","TP53","MDM2","BCL2L1","ERN1","PRDX1","RHEB","CTNNA3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P13693","full_name":"Translationally-controlled tumor protein","aliases":["Fortilin","Histamine-releasing factor","HRF","p23"],"length_aa":172,"mass_kda":19.6,"function":"Involved in calcium binding and microtubule stabilization (PubMed:12167714, PubMed:15162379, PubMed:15958728). Acts as a negative regulator of TSC22D1-mediated apoptosis, via interaction with and destabilization of TSC22D1 protein (PubMed:18325344)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P13693/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TPT1","classification":"Common Essential","n_dependent_lines":1162,"n_total_lines":1208,"dependency_fraction":0.9619205298013245},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000133112","cell_line_id":"CID001265","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"RPLP2","stoichiometry":10.0},{"gene":"RPL27","stoichiometry":10.0},{"gene":"RPLP0;RPLP0P6","stoichiometry":4.0},{"gene":"RPLP1","stoichiometry":4.0},{"gene":"RPL21","stoichiometry":4.0},{"gene":"RPL22","stoichiometry":4.0},{"gene":"RPS2","stoichiometry":4.0},{"gene":"RPL31","stoichiometry":4.0},{"gene":"RPL9","stoichiometry":4.0},{"gene":"RPL13","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001265","total_profiled":1310},"omim":[{"mim_id":"619378","title":"SMALL NUCLEOLAR RNA, H/ACA BOX, 31; SNORA31","url":"https://www.omim.org/entry/619378"},{"mim_id":"610470","title":"TRANSFER RNA PHOSPHOTRANSFERASE 1; TRPT1","url":"https://www.omim.org/entry/610470"},{"mim_id":"609671","title":"STEAP3 METALLOREDUCTASE; STEAP3","url":"https://www.omim.org/entry/609671"},{"mim_id":"600763","title":"TUMOR PROTEIN, TRANSLATIONALLY-CONTROLLED 1; TPT1","url":"https://www.omim.org/entry/600763"},{"mim_id":"600725","title":"SONIC HEDGEHOG SIGNALING MOLECULE; SHH","url":"https://www.omim.org/entry/600725"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":21778.2}],"url":"https://www.proteinatlas.org/search/TPT1"},"hgnc":{"alias_symbol":["TCTP","fortilin"],"prev_symbol":[]},"alphafold":{"accession":"P13693","domains":[{"cath_id":"2.170.150.10","chopping":"1-36_70-170","consensus_level":"high","plddt":97.2363,"start":1,"end":170}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P13693","model_url":"https://alphafold.ebi.ac.uk/files/AF-P13693-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P13693-F1-predicted_aligned_error_v6.png","plddt_mean":90.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TPT1","jax_strain_url":"https://www.jax.org/strain/search?query=TPT1"},"sequence":{"accession":"P13693","fasta_url":"https://rest.uniprot.org/uniprotkb/P13693.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P13693/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P13693"}},"corpus_meta":[{"pmid":"14687915","id":"PMC_14687915","title":"The translationally controlled tumour protein (TCTP).","date":"2004","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14687915","citation_count":343,"is_preprint":false},{"pmid":"11598139","id":"PMC_11598139","title":"Characterization of fortilin, a novel antiapoptotic protein.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11598139","citation_count":233,"is_preprint":false},{"pmid":"12399545","id":"PMC_12399545","title":"Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12399545","citation_count":227,"is_preprint":false},{"pmid":"22157679","id":"PMC_22157679","title":"Reciprocal repression between P53 and TCTP.","date":"2011","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22157679","citation_count":189,"is_preprint":false},{"pmid":"18274553","id":"PMC_18274553","title":"TCTP protects from apoptotic cell death by antagonizing bax function.","date":"2008","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/18274553","citation_count":167,"is_preprint":false},{"pmid":"12149273","id":"PMC_12149273","title":"Physical and functional interaction between myeloid cell leukemia 1 protein (MCL1) and Fortilin. 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Antisense depletion of fortilin from MCF-7 cells caused massive cell death.\",\n      \"method\": \"Transient/stable overexpression, antisense depletion, fluorogenic caspase substrate assay, immunocytochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (overexpression dose-response, stable cell lines, caspase assay, antisense knockdown) replicated across multiple cell lines in a single focused study\",\n      \"pmids\": [\"11598139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Fortilin (TPT1) physically interacts with MCL1 both in vitro and in vivo; MCL1 acts as a chaperone that stabilizes fortilin by protecting it from rapid degradation. The fortilin(R21A) point mutant lacking MCL1-binding has a significantly shorter half-life than wild-type fortilin.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, siRNA knockdown, pulse-chase experiment, confocal immunostaining, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal co-IP, pulse-chase kinetics, mutagenesis (R21A), and siRNA all in one study; multiple orthogonal methods\",\n      \"pmids\": [\"12149273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TCTP/TPT1 is the most strongly downregulated gene during tumor reversion; antisense cDNA or siRNA-mediated inhibition of TCTP expression suppresses the malignant phenotype and causes cellular reorganization similar to SIAH-1 overexpression, placing TCTP in a cellular reprogramming pathway.\",\n      \"method\": \"Differential gene expression analysis, Northern blot, quantitative PCR, antisense cDNA transfection, siRNA, phenotypic assays (tumorigenicity)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (siRNA, antisense, qPCR) in single lab; genetic placement relative to SIAH-1 pathway\",\n      \"pmids\": [\"12399545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Fortilin and MCL1 protect cells from 5-FU-induced cytotoxicity independently of each other: when MCL1 is silenced by siRNA, fortilin retains cytoprotective activity, and vice versa. The fortilin–MCL1 interaction therefore augments, but is not required for, their individual antiapoptotic functions.\",\n      \"method\": \"siRNA-mediated gene silencing, cell viability assays in monoclonal and polyclonal U2OS populations, subcellular localization analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous siRNA dissection of epistasis between two proteins, single lab, two cell-population systems\",\n      \"pmids\": [\"15262975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Transcription of the human TPT1 gene is regulated through two conserved CRE sites in the proximal promoter; supershift assays identified CREB I and Fra II (CREB/ATF1/AP1 family) as the interacting transcription factors. cAMP signaling via PKA-dependent CREB phosphorylation stimulates TCTP synthesis.\",\n      \"method\": \"Reporter-gene assays, gelshift (EMSA), footprinting, supershift assays, promoter deletion analysis, forskolin/PMA stimulation\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro transcription factor binding (EMSA, footprinting, supershift) combined with reporter assays and CRE-deletion constructs; multiple orthogonal methods in single study\",\n      \"pmids\": [\"16859841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fortilin binds Ca²⁺ with a Kd of ~10 mM (N-terminal residues 1–72 required); Ca²⁺ binding induces a conformational change in fortilin. The double point mutant fortilin(E58A/E60A) lacks Ca²⁺-binding ability and fails to protect cells against thapsigargin-induced, Ca²⁺-dependent apoptosis, establishing fortilin as an intracellular Ca²⁺ scavenger.\",\n      \"method\": \"Ca²⁺-overlay assay, flow dialysis, CD spectropolarimetry, intracellular Ca²⁺ measurement, site-directed mutagenesis, cell death assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical binding assays with Kd determination, conformational analysis, and mutagenesis validation in cells; multiple orthogonal methods\",\n      \"pmids\": [\"17705784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Tpt1 in Xenopus oocytes activates transcription of oct4 and nanog upon nuclear transfer of somatic nuclei: depletion of tpt1 transcripts reduces oct4/nanog transcription, while elevation of tpt1 causes earlier activation of oct4 transcription.\",\n      \"method\": \"Protein isolation by binding to oct4 regulatory region, mass spectrometry identification, oocyte transcript depletion, nuclear transfer, mRNA quantification\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — depletion and overexpression in Xenopus nuclear transfer system, single lab, functional readout (oct4/nanog transcription)\",\n      \"pmids\": [\"17442571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure of human TCTP at 2.0 Å resolution reveals structural similarity between TCTP helices H2–H3 and Bax helices H5–H6. Site-directed mutagenesis of H2–H3 impairs TCTP's antiapoptotic function. TCTP inserts into the mitochondrial membrane and inhibits Bax dimerization. Tctp-null mice show increased spontaneous embryonic apoptosis and die between E6.5 and E9.5.\",\n      \"method\": \"X-ray crystallography (2.0 Å), site-directed mutagenesis, mitochondrial membrane insertion assay, Bax dimerization assay, Tctp knockout mice\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus in vivo knockout plus mechanistic mitochondrial assay; multiple orthogonal methods in single study\",\n      \"pmids\": [\"18274553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Chfr checkpoint protein physically interacts with endogenous TCTP (identified by yeast two-hybrid and confirmed by co-immunoprecipitation of endogenous proteins); both co-localize to the mitotic spindle. The Chfr–TCTP interaction is stable throughout the cell cycle but is diminished by complete microtubule depolymerization, suggesting TCTP participates in the mitotic spindle checkpoint.\",\n      \"method\": \"Yeast two-hybrid screen, endogenous co-immunoprecipitation, immunofluorescence localization, microtubule depolymerization experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by endogenous co-IP and colocalization, single lab\",\n      \"pmids\": [\"18504434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Dihydroartemisinin (DHA) binds human fortilin, increases its ubiquitination, shortens its half-life in a proteasome-dependent manner, and reduces cellular fortilin levels. DHA-induced DNA fragmentation is fortilin-dependent: fortilin-knockdown cells are less susceptible and fortilin-overexpressing cells are more susceptible to DHA-induced apoptosis.\",\n      \"method\": \"Binding assay, ubiquitination assay, pulse-chase (half-life measurement), proteasome inhibitor studies, siRNA knockdown, overexpression, DNA fragmentation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding, ubiquitination, and half-life assays, plus genetic rescue experiment; single lab, multiple methods\",\n      \"pmids\": [\"18325342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Fortilin interacts with TSC-22 (TGF-β stimulated clone-22) via yeast two-hybrid; fortilin overexpression reverses TSC-22-mediated apoptosis in ovarian carcinoma cells, and fortilin promotes proteasomal degradation of TSC-22.\",\n      \"method\": \"Yeast two-hybrid screening, siRNA knockdown, overexpression, apoptosis assays, protein degradation analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid plus functional rescue, but no direct in-cell co-IP for the interaction; single lab\",\n      \"pmids\": [\"18325344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Fortilin-null (fortilin⁻/⁻) mice are embryonically lethal around 3.5 dpc. In Xenopus, fortilin depletion compromises neural tissue formation, while overexpression induces partial double body axis and blocks BMP4-induced transcription of Vent1, Vent2, and Msx1. In mouse embryonic fibroblasts, fortilin siRNA depletion allows BMP4 to cause extensive DNA fragmentation and increased Msx2 expression, establishing fortilin as an inhibitor of the BMP signaling pathway.\",\n      \"method\": \"Targeted gene disruption in mice, Xenopus embryo injections (mRNA depletion/overexpression), siRNA in MEFs, BMP4 stimulation, reporter gene assays, DNA fragmentation\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mice, Xenopus gain/loss-of-function, and MEF siRNA all in one study; multiple species and orthogonal methods\",\n      \"pmids\": [\"19364479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fortilin binds specifically to the sequence-specific DNA-binding domain of p53, blocking p53-induced transcriptional activation of Bax. A double-point mutant of fortilin lacking p53 binding fails to inhibit p53-dependent apoptosis. Cells expressing wild-type fortilin (but not the p53-binding mutant) form large tumors in athymic mice.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, reporter gene assay (Bax transcription), apoptosis assay, xenograft tumor assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct co-IP, mutagenesis ablating the interaction, transcriptional assay, and in vivo xenograft; multiple orthogonal methods in one study\",\n      \"pmids\": [\"21795694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TCTP promotes p53 degradation by competing with NUMB for binding to p53-MDM2 complexes; TCTP inhibits MDM2 auto-ubiquitination and promotes MDM2-mediated ubiquitination and degradation of p53. P53 reciprocally directly represses TCTP transcription. Tctp haploinsufficient mice are sensitized to p53-dependent apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, knockdown/overexpression, promoter reporter assays, Tctp+/- mouse model, pharmacological inhibition (sertraline/thioridazine)\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple biochemical assays (co-IP, ubiquitination), genetic model (haploinsufficient mice), and pharmacological validation; independently significant findings\",\n      \"pmids\": [\"22157679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TCTP enhances glioma cell proliferation through increased β-catenin binding to TCF-4 and elevated TOPflash transcription activity and Wnt/β-catenin target gene expression (c-Myc, cyclin D1). TCF-4 shRNA rescues the TCTP overexpression-induced proliferation, establishing TCTP as an upstream activator of Wnt/β-catenin signaling.\",\n      \"method\": \"Co-immunoprecipitation (TCTP/TCF-4/β-catenin), TOPflash/FOPflash reporter assay, shRNA knockdown, xenograft model, Western blot\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus reporter assay plus epistatic rescue by TCF-4 shRNA; single lab\",\n      \"pmids\": [\"24311645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TCTP mRNA translation is regulated through the PI3-K/Akt/mTORC1 signalling pathway. mTOR kinase inhibitors and Akt inhibitors block serum-induced increases in TCTP protein. TSC2 knockout derepresses TCTP translation under starvation. A constitutively active 4E-BP1 mutant inhibits TCTP mRNA translation, and eIF4E overexpression increases polysomal association of TCTP mRNA.\",\n      \"method\": \"Polysome profiling, mRNA quantification by RT-qPCR, mTOR/Akt inhibitors, TSC2 knockout cells, eIF4E overexpression, 4E-BP1 constitutively active mutant, Western blot\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — polysome profiling, multiple genetic and pharmacological perturbations, TSC2 KO and dominant mutants; multiple orthogonal methods in one study\",\n      \"pmids\": [\"25936523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TCTP contains a BH3-like domain that binds the BH3-groove of Bcl-xL. Crystal structure of a Bcl-xL deletion variant–TCTP11-31 complex at atomic resolution shows TCTP refolds into a helical conformation upon Bcl-xL binding. Unlike all other BH3-domain proteins (which inhibit Bcl-xL), TCTP activates the anti-apoptotic function of Bcl-xL. Replacing the non-conserved h1 of TCTP with that from Bax drastically increases affinity for Bcl-xL and changes biological properties.\",\n      \"method\": \"X-ray crystallography (Bcl-xL–TCTP complex), in vitro reconstitution, in vivo functional assays, TCTP+/- mouse model, mutagenesis (hybrid BH3)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus reconstitution, mutagenesis, and mouse genetic model in one study\",\n      \"pmids\": [\"26813996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Drosophila TCTP (Tctp) physically interacts with Rheb GTPase and acts as a guanine nucleotide exchange factor (GEF) for Rheb, activating TOR signalling for organ growth. 14-3-3 proteins physically interact with both Tctp and Rheb; knockdown of both 14-3-3 isoforms abolishes Tctp–Rheb binding, reduces phospho-S6K, phospho-4E-BP, and cyclin E, impairing tissue growth. Growth defects are suppressed by CycE overexpression.\",\n      \"method\": \"Genetic epistasis (Drosophila knockdown/synergy), co-immunoprecipitation, phospho-S6K/4E-BP Western blot, cyclin E rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, genetic epistasis across multiple genotypes, rescue experiment; consistent with prior Drosophila GEF study\",\n      \"pmids\": [\"27151460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Drosophila Tctp binds the Brahma (Brm) chromatin remodeler and negatively modulates its activity. Tctp mutants show elevated transcription of a large gene set and transposons; brm mutations ameliorate these defects. Tctp also promotes stability of rDNA and pericentromeric heterochromatin by opposing Brm and regulating su(var)3-9 transcription.\",\n      \"method\": \"Genetic epistasis (Drosophila Tctp mutants + brm mutants), chromatin/transcription analysis, transposon assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with brm mutants and transcriptomic analysis; single lab, Drosophila model\",\n      \"pmids\": [\"27687497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tctp interacts with Mcl1 in the axonal compartment of Xenopus retinal ganglion cells; Tctp deficiency results in stunted retinotectal projections with mitochondrial dysfunction and impaired axon extension. Mcl1 knockdown phenocopies Tctp deficiency, placing Tctp upstream of Mcl1-mediated pro-survival signalling in axon development.\",\n      \"method\": \"Morpholino-mediated knockdown in Xenopus, co-immunoprecipitation in axonal compartment, live imaging, mitochondrial dysfunction assays, genetic epistasis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — axonal co-IP, knockdown phenotype, epistasis with Mcl1; single lab, Xenopus model\",\n      \"pmids\": [\"26903505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fortilin physically interacts with peroxiredoxin-1 (PRX1), protects PRX1 from proteasome-mediated degradation, and prevents its inactivating phosphorylation by Mst1 kinase. Liver-specific fortilin overexpression in transgenic mice reduces PRX1 phosphorylation and enhances PRX1 peroxidase activity, protecting against alcohol-induced ROS-mediated liver damage.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor assays, kinase (Mst1) phosphorylation assay, transgenic mouse liver overexpression, PRX1 activity assay, alcohol liver-damage model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — co-IP, in vitro kinase assay, transgenic mouse model with functional readout; multiple orthogonal methods\",\n      \"pmids\": [\"26726832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TCTP mRNA translation is upregulated via the mTORC1 pathway in HCT116 colon cancer cells in response to the DNA-damaging drugs 5-FU and oxaliplatin; mTOR kinase inhibitors prevent this upregulation. TCTP knockdown sensitises HCT116 cells to cytotoxicity by both drugs, establishing TCTP as a contributor to drug resistance via translational regulation.\",\n      \"method\": \"Western blot, RT-qPCR, mTOR inhibitors, siRNA knockdown, RTCA system, MTS cell viability assay\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mTOR inhibitor pharmacology, mRNA vs. protein dissociation, functional knockdown; single lab\",\n      \"pmids\": [\"28143584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Fortilin directly interacts with the cytoplasmic domain of IRE1α (the ER stress sensor), inhibits both its kinase and endoribonuclease (RNase) activities, and protects cells and whole animals from ER stress-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, in vitro RNase assay, cellular apoptosis assays, whole-animal (in vivo) ER stress model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding, two distinct enzymatic activity assays (kinase and RNase inhibition), cell-level and whole-animal functional validation in one study\",\n      \"pmids\": [\"28550308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RNA 2'-phosphotransferase Tpt1 (the enzymatic activity encoded by the TPT1/Tpt1 gene in fungi) catalyzes NAD⁺-dependent conversion of internal RNA 2'-monophosphate to 2'-OH via a two-step mechanism forming a 2'-phospho-ADP-ribosylated RNA intermediate. A subset of Tpt1 enzymes (e.g., Aeropyrum pernix Tpt1) also catalyze NAD⁺-dependent ADP-ribosylation of 5'-monophosphate RNA/DNA termini to create a 5'-phospho-ADP-ribosylated cap.\",\n      \"method\": \"In vitro enzymatic assay with purified Tpt1 enzymes from diverse taxa, NAD⁺ substrate studies, product characterization\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of enzymatic mechanism across multiple Tpt1 enzymes; note this is the fungal/archaeal RNA ligase pathway Tpt1 activity, which is distinct from the mammalian anti-apoptotic TCTP function but encoded by the same locus family\",\n      \"pmids\": [\"30202863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of Tpt1 (1.4 Å) in a product-mimetic complex with ADP-ribose-1″-phosphate (in NAD⁺ site) and pAp (in RNA site) reveals the mechanism of 2'-PO4 RNA splice-junction recognition and RNA phospho-ADP-ribosylation. Evidence is provided that a bacterium has an endogenous phosphorylated substrate for Tpt1.\",\n      \"method\": \"X-ray crystallography (1.4 Å), product-mimetic complex, substrate binding analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with mechanistic interpretation; single study but high-quality structural data\",\n      \"pmids\": [\"30644400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TCTP controls the G1/S transition by interacting with CSN4 (a subunit of the COP9 Signalosome); TCTP loss leads to increased fraction of deneddylated CUL1 (a substrate of the COP9 complex). This mechanism is conserved between Arabidopsis and Drosophila: dCSN4 or dTCTP knockdown in Drosophila similarly impairs cell proliferation and CUL1 neddylation.\",\n      \"method\": \"Genetic interaction studies (Arabidopsis and Drosophila), CUL1 neddylation assays, cell cycle analysis, knockdown of CSN4 and TCTP\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in two organisms plus CUL1 neddylation biochemistry; single lab, cross-species validation\",\n      \"pmids\": [\"30695029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cardiomyocyte-specific TCTP knockdown with siRNA induces apoptotic and autophagic cell death accompanied by mitochondrial permeability transition pore (mPTP) opening; Bnip3 mediates this TCTP-loss-induced death. Cardiomyocyte-specific TCTP overexpression in mice decreases susceptibility to doxorubicin-induced cardiac dysfunction with attenuated Bnip3 induction.\",\n      \"method\": \"siRNA knockdown, cardiomyocyte-specific transgenic overexpression, mPTP assay, Bnip3 Western blot, doxorubicin heart failure model in mice\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA mechanism (Bnip3 as mediator), transgenic mouse model with functional cardiac readout, pharmacological (DHA) validation; multiple orthogonal methods\",\n      \"pmids\": [\"31320615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TCTP/fortilin promotes epithelial-mesenchymal transition (EMT): overexpression increases ZEB1, α-SMA, and invasiveness while decreasing E-cadherin and p53 expression in A549 lung adenocarcinoma cells, and knockdown has opposite effects. TCTP also interacts with β-catenin to stabilize it and promote nuclear localization, and induces urokinase plasminogen activator (uPA) to destabilize ECM.\",\n      \"method\": \"Stable lentiviral overexpression/knockdown, scratch and transwell migration/invasion assays, Western blot for EMT markers, co-immunoprecipitation (TCTP–β-catenin), uPA assay\",\n      \"journal\": \"OncoTargets and therapy / Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of TCTP–β-catenin plus functional EMT assays; findings consistent across two papers (PMID 28958626 and 30881019), single lab each\",\n      \"pmids\": [\"28958626\", \"30881019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Heart-specific fortilin knockout mice (fortilinKO-heart) die by 9 weeks with extensive cardiomyocyte apoptosis and severe heart failure; hearts show drastic upregulation of p53 target genes. Additional heart-specific p53 deletion in fortilinKO-heart mice extends lifespan from 9 to 18 weeks by mitigating cardiomyocyte apoptosis, establishing fortilin as a cardiac p53 inhibitor in vivo.\",\n      \"method\": \"Cardiomyocyte-specific conditional knockout (fortilinKO-heart), double knockout (fortilinKO-heart × p53KO-heart), cardiac phenotyping, p53 target gene expression, TUNEL/caspase apoptosis assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cardiac phenotype and genetic epistasis rescue by p53 KO; rigorous in vivo genetics\",\n      \"pmids\": [\"34689154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fortilin specifically interacts with CTNNA3 (α-T-catenin) but not with CTNNA1, CTNNA2, or CTNNB. Fortilin silencing promotes phosphorylation of CTNNA3, leading to its ubiquitination and proteasome-mediated degradation. CTNNA3 knockdown causes 293T cells to undergo apoptosis, placing fortilin as a guardian of CTNNA3 stability and cell survival.\",\n      \"method\": \"Co-immunoprecipitation Western blot, proximity ligation assay, microscale thermophoresis, biolayer interferometry, siRNA knockdown, phospho-null and phospho-mimetic CTNNA3 mutants, proteasome inhibitor assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple direct binding assays (Co-IP, PLA, MST, BLI), mutagenesis (phospho-null/mimetic), proteasome dependency, and functional apoptosis readout in one study\",\n      \"pmids\": [\"39747445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TCTP activates the EGFR-AKT-MCL-1/CXCL10 pathway via phosphorylation-dependent interaction with Na,K-ATPase, conferring immune-refractory phenotypes (decreased T cell trafficking and resistance to CTL-mediated killing) in tumor cells.\",\n      \"method\": \"Transcriptome analysis, immune-refractory tumor models, pharmacological inhibition (DHA), co-immunoprecipitation (TCTP–Na,K-ATPase), phosphorylation assays, T cell killing assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus phosphorylation-dependency and functional immune assays; single lab; mechanism involving Na,K-ATPase interaction consistent with earlier reports\",\n      \"pmids\": [\"35440620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TCTP overexpression in mouse pluripotent P19 and ES cells downregulates Oct4 transcription; the N-terminal 1–60 aa of TCTP are required for this suppression. TCTP binds the Sf1 site of the Oct4 promoter, and siRNA knockdown of TCTP increases Oct4 expression.\",\n      \"method\": \"Overexpression, siRNA knockdown, promoter reporter assay, N-terminal deletion analysis, Oct4 mRNA/protein quantification\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding mapped to Sf1 site, deletion mutagenesis, bidirectional (OE and KD) experiments; single lab\",\n      \"pmids\": [\"22281008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TCTP regulates spindle dynamics in mouse oocytes: TCTP knockdown accelerates reduction of spindle dynamics during postovulatory aging, causing aging-related deterioration of oocyte quality, whereas TCTP overexpression preserves spindle dynamics and prevents aging-associated abnormalities, improving fertilization competency and embryo development.\",\n      \"method\": \"siRNA knockdown, mRNA overexpression injection, live spindle imaging (spindle dynamics), fertilization and embryo development assays in mouse oocytes\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional (KD and OE) experiments with live spindle imaging and functional developmental readouts; single lab\",\n      \"pmids\": [\"28476647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DLC1 and TCTP co-localize in focal adhesions and form a protein complex; DLC1 negatively regulates TCTP levels in a RhoGAP-independent manner (both WT and GAP-dead R718A mutant reduce TCTP). Depletion of DLC1 increases TCTP expression and elevates Cdc42 and downstream JNK/NF-κB and N-WASP signaling, promoting cancer cell migration.\",\n      \"method\": \"Co-immunoprecipitation, colocalization (immunofluorescence), siRNA depletion, GFP-DLC1 WT and GAP-dead mutant transfection, Cdc42 activation assay, migration assays\",\n      \"journal\": \"Food & function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-IP, colocalization, and GAP-dead mutant dissection of mechanism; single lab\",\n      \"pmids\": [\"33150340\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TPT1/TCTP (fortilin) is a multifunctional cytoprotective protein that inhibits apoptosis through several distinct mechanisms: it directly binds the DNA-binding domain of p53 (blocking Bax transcription and competing with NUMB for MDM2 complexes to promote p53 degradation), inserts into mitochondrial membranes to inhibit Bax dimerization, contains a BH3-like domain that activates Bcl-xL, sequesters intracellular Ca²⁺ via N-terminal residues to prevent Ca²⁺-dependent apoptosis, binds and inhibits both kinase and RNase activities of the ER stress sensor IRE1α, stabilizes PRX1 by blocking Mst1-mediated inactivating phosphorylation, and protects CTNNA3 from phosphorylation-ubiquitination-proteasomal degradation; its mRNA translation is regulated by the PI3-K/Akt/mTORC1 pathway via a 5'-TOP element, and its transcription is controlled by CREB/ATF1 via CRE sites in the proximal promoter; TCTP also promotes cell growth via GEF activity toward Rheb (activating TOR), interacts with the COP9 signalosome (CSN4) to regulate CUL1 neddylation and G1/S transition, co-localizes with the mitotic spindle through Chfr interaction, activates Wnt/β-catenin–TCF-4 signaling, and extracellularly (as a dimer through Cys172) acts as a histamine-releasing cytokine-like factor.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TPT1 (TCTP/fortilin) is a multifunctional cytoprotective protein that integrates pro-survival, growth, and developmental signaling, and whose loss is embryonically lethal in mice [#0, #7, #11]. Its dominant function is suppression of apoptosis through convergent mechanisms: it inserts into the mitochondrial membrane to inhibit Bax dimerization via a Bax-like H2–H3 helical region [#7], it contains a BH3-like domain that—unlike all other BH3 proteins—activates rather than inhibits the anti-apoptotic activity of Bcl-xL [#16], and it sequesters intracellular Ca²⁺ through N-terminal residues to block Ca²⁺-dependent death [#5]. TCTP is a central negative regulator of p53: it binds the p53 DNA-binding domain to block Bax transactivation [#12] and competes with NUMB at the p53–MDM2 complex to promote MDM2-mediated p53 ubiquitination and degradation, with p53 reciprocally repressing TCTP transcription [#13]; this axis is required for cardiomyocyte survival in vivo, as cardiac p53 deletion rescues the lethal heart failure of fortilin heart-specific knockouts [#28]. It further restrains the ER-stress sensor IRE1α by directly inhibiting both its kinase and RNase activities [#22], protects peroxiredoxin-1 from inactivating Mst1 phosphorylation to limit ROS damage [#20], and stabilizes the survival factor CTNNA3 against phosphorylation-driven proteasomal degradation [#29]. TCTP also drives cell growth and proliferation by acting as a GEF for Rheb to activate TOR signaling [#17], by interacting with the COP9 signalosome subunit CSN4 to regulate CUL1 neddylation and the G1/S transition [#25], and by activating Wnt/β-catenin–TCF-4 signaling [#14]; its own abundance is controlled translationally by the PI3-K/Akt/mTORC1 pathway, including under DNA-damage stress where it promotes drug resistance [#15, #21]. The protein is stabilized by MCL1, which acts as a chaperone for fortilin [#1]. A distinct enzymatic activity—NAD⁺-dependent RNA 2'-phosphotransferase that resolves internal RNA 2'-monophosphates—is encoded by Tpt1 orthologs in fungi and archaea and represents a separate, non-mammalian function of this locus family [#23, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established TPT1/fortilin as a bona fide anti-apoptotic protein, distinct from the known Bcl-2 and IAP families, defining a new cytoprotective factor.\",\n      \"evidence\": \"Overexpression, antisense depletion, and caspase-3 assays across HeLa, U2OS, and MCF-7 cells\",\n      \"pmids\": [\"11598139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of caspase suppression not defined\", \"Did not localize the protective step within the apoptotic cascade\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified MCL1 as a binding partner that chaperones and stabilizes fortilin, linking its abundance to a known survival protein.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, pulse-chase with the R21A binding mutant, and siRNA\",\n      \"pmids\": [\"12149273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MCL1 binding contributes to anti-apoptotic activity beyond stabilization unresolved at this stage\", \"Structural basis of the interaction not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Placed TCTP in a tumor-reversion/reprogramming pathway, showing its downregulation reverses the malignant phenotype.\",\n      \"evidence\": \"Differential expression, antisense/siRNA, and tumorigenicity assays relative to SIAH-1\",\n      \"pmids\": [\"12399545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between TCTP and SIAH-1 not established\", \"Mechanism of phenotypic reversion left undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined transcriptional control of TPT1 by CREB/ATF1 via proximal CRE sites, connecting cAMP/PKA signaling to TCTP synthesis.\",\n      \"evidence\": \"Reporter assays, EMSA/footprinting/supershift, promoter deletions, and forskolin stimulation\",\n      \"pmids\": [\"16859841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological stimuli driving CRE-dependent expression in vivo not defined\", \"Interplay with later-identified p53 repression not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed fortilin is an intracellular Ca²⁺ scavenger whose N-terminal Ca²⁺ binding is required for protection against Ca²⁺-dependent apoptosis.\",\n      \"evidence\": \"Ca²⁺-overlay, flow dialysis, CD spectroscopy, E58A/E60A mutant, and thapsigargin death assays\",\n      \"pmids\": [\"17705784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Very low affinity (Kd ~10 mM) raises questions about which physiological Ca²⁺ pools are buffered\", \"Connection to ER stress signaling not yet drawn\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Implicated Tpt1 in pluripotency-gene activation, showing it can promote oct4/nanog transcription during somatic nuclear reprogramming.\",\n      \"evidence\": \"Oct4-region affinity purification, mass spectrometry, and transcript depletion/elevation in Xenopus oocyte nuclear transfer\",\n      \"pmids\": [\"17442571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect action on pluripotency promoters unresolved\", \"Apparent conflict with later mouse data showing Oct4 repression\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided structural and in vivo basis for anti-apoptosis: a Bax-like H2–H3 region inserts into mitochondria to block Bax dimerization, and loss is embryonically lethal.\",\n      \"evidence\": \"2.0 Å crystal structure, H2–H3 mutagenesis, mitochondrial insertion/Bax dimerization assays, and Tctp-null mice\",\n      \"pmids\": [\"18274553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and lipid requirements of membrane insertion not defined\", \"Whether mitochondrial action is the principal cause of embryonic lethality not isolated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected TCTP to the mitotic spindle checkpoint through a microtubule-dependent interaction with the Chfr checkpoint protein.\",\n      \"evidence\": \"Yeast two-hybrid, endogenous co-IP, spindle colocalization, and microtubule depolymerization\",\n      \"pmids\": [\"18504434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Chfr binding for checkpoint output not tested\", \"Whether TCTP is a Chfr substrate or regulator unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified fortilin as a druggable target: dihydroartemisinin binds it and triggers its ubiquitin-proteasome degradation, sensitizing cells to apoptosis.\",\n      \"evidence\": \"Binding, ubiquitination, pulse-chase, proteasome inhibition, and knockdown/overexpression DNA-fragmentation rescue\",\n      \"pmids\": [\"18325342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DHA binding site on fortilin not mapped\", \"E3 ligase mediating DHA-induced ubiquitination not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked fortilin to TGF-β signaling antagonism by promoting proteasomal degradation of the pro-apoptotic factor TSC-22.\",\n      \"evidence\": \"Yeast two-hybrid, knockdown/overexpression, apoptosis rescue, and degradation analysis\",\n      \"pmids\": [\"18325344\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in-cell co-IP confirming the direct interaction\", \"Degradation mechanism (E3 ligase, ubiquitination site) not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established fortilin as an inhibitor of BMP signaling required for neural development, integrating its survival role with embryonic patterning.\",\n      \"evidence\": \"Mouse knockout (lethal ~3.5 dpc), Xenopus gain/loss-of-function with BMP4 target readouts, and MEF siRNA\",\n      \"pmids\": [\"19364479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular point of BMP-pathway inhibition not identified\", \"Discrepancy in reported lethality timing versus earlier knockout not reconciled\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined a direct anti-p53 mechanism: fortilin binds the p53 DNA-binding domain to block Bax transactivation and drive tumorigenesis.\",\n      \"evidence\": \"Co-IP, p53-binding-deficient mutant, Bax reporter assay, apoptosis assay, and xenografts\",\n      \"pmids\": [\"21795694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether binding affects other p53 targets beyond Bax not addressed\", \"Structural details of the p53–fortilin interface not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed TCTP promotes p53 degradation by competing with NUMB at the p53–MDM2 complex, establishing a reciprocal TCTP–p53 regulatory loop.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, promoter reporters, Tctp+/- mice, and pharmacological inhibition\",\n      \"pmids\": [\"22157679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of direct p53 binding (#12) versus MDM2-competition pathway not quantified\", \"How the two opposing transcriptional arms are balanced in vivo unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated context-dependent control of Oct4: in mouse pluripotent cells TCTP binds the Sf1 site of the Oct4 promoter and represses it, contrasting with the Xenopus activation phenotype.\",\n      \"evidence\": \"Overexpression/knockdown, promoter reporter, and N-terminal (1–60) deletion mapping\",\n      \"pmids\": [\"22281008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA binding vs. cofactor-mediated promoter occupancy not distinguished\", \"Basis of opposite direction relative to #6 unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Positioned TCTP as an upstream activator of Wnt/β-catenin–TCF-4 signaling driving glioma proliferation.\",\n      \"evidence\": \"Co-IP, TOPflash reporter, target-gene Western blots, TCF-4 shRNA rescue, and xenografts\",\n      \"pmids\": [\"24311645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TCTP acts directly on the β-catenin/TCF-4 complex or upstream not defined\", \"Link to the separately reported β-catenin stabilization mechanism not integrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that TCTP protein levels are set translationally by PI3-K/Akt/mTORC1 acting on its 5'-TOP mRNA.\",\n      \"evidence\": \"Polysome profiling, mTOR/Akt inhibitors, TSC2 KO, eIF4E overexpression, and constitutively active 4E-BP1\",\n      \"pmids\": [\"25936523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between this translational control and CREB-dependent transcription not addressed\", \"Physiological signals tuning TCTP translation in vivo not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the BH3-like mechanism: TCTP refolds into a helix in the Bcl-xL groove and uniquely activates rather than inhibits Bcl-xL.\",\n      \"evidence\": \"Crystal structure of the Bcl-xL–TCTP11-31 complex, reconstitution, hybrid-BH3 mutagenesis, and TCTP+/- mice\",\n      \"pmids\": [\"26813996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which groove occupancy activates rather than inhibits Bcl-xL not fully explained\", \"Relationship to the mitochondrial Bax-inhibition mechanism not unified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined TCTP as a Rheb GEF that activates TOR-driven growth, with 14-3-3 proteins required for the TCTP–Rheb interaction.\",\n      \"evidence\": \"Drosophila genetic epistasis, co-IP, phospho-S6K/4E-BP blots, and cyclin E rescue\",\n      \"pmids\": [\"27151460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian TCTP retains Rheb-GEF activity not tested here\", \"Relationship to TCTP being itself an mTORC1 translational target (#15) creates a feedback loop not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a chromatin role: TCTP restrains the Brahma remodeler to silence transposons and stabilize heterochromatin.\",\n      \"evidence\": \"Drosophila Tctp/brm epistasis, transcriptome/transposon analysis, and su(var)3-9 regulation\",\n      \"pmids\": [\"27687497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Tctp–Brm binding in mammals not shown\", \"Mechanism linking Brm modulation to heterochromatin stability incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed the TCTP–Mcl1 axis supports axonal mitochondrial function and projection growth in neurons.\",\n      \"evidence\": \"Xenopus morpholino knockdown, axonal-compartment co-IP, live imaging, and Mcl1 epistasis\",\n      \"pmids\": [\"26903505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether axonal effects are MCL1-stabilization–dependent or independent not resolved\", \"Direct cause of mitochondrial dysfunction not pinpointed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified an antioxidant mechanism: fortilin stabilizes PRX1 and blocks its inactivating Mst1 phosphorylation, protecting against ROS-mediated liver damage.\",\n      \"evidence\": \"Co-IP, proteasome inhibition, Mst1 kinase assay, and liver-specific transgenic mice in an alcohol model\",\n      \"pmids\": [\"26726832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How fortilin shields the PRX1 phospho-site mechanistically not defined\", \"Generalizability beyond liver tissue not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed TCTP directly inhibits the ER stress sensor IRE1α, blocking both its kinase and RNase activities to prevent ER-stress apoptosis.\",\n      \"evidence\": \"Co-IP, in vitro kinase and RNase assays, cellular apoptosis assays, and whole-animal ER-stress model\",\n      \"pmids\": [\"28550308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface on the IRE1α cytoplasmic domain not mapped\", \"Effect on the XBP1-splicing arm of the UPR not separately quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked TCTP translational upregulation to chemoresistance, showing mTORC1-driven TCTP induction protects colon cancer cells from DNA-damaging drugs.\",\n      \"evidence\": \"mTOR inhibitors, mRNA/protein dissociation, and siRNA sensitization to 5-FU/oxaliplatin\",\n      \"pmids\": [\"28143584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effector responsible for resistance not isolated\", \"Whether p53 inhibition mediates the resistance not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated TCTP preserves oocyte spindle dynamics, linking its mitotic-spindle association to reproductive aging and embryo competency.\",\n      \"evidence\": \"siRNA/mRNA injection, live spindle imaging, and fertilization/embryo-development assays in mouse oocytes\",\n      \"pmids\": [\"28476647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partner mediating spindle stabilization not identified\", \"Relationship to the Chfr–spindle interaction (#8) not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Characterized the distinct enzymatic Tpt1 activity—NAD⁺-dependent RNA 2'-phosphotransferase resolving internal RNA 2'-monophosphates—in fungal/archaeal orthologs.\",\n      \"evidence\": \"In vitro enzymatic assays with purified Tpt1 enzymes from diverse taxa and product characterization\",\n      \"pmids\": [\"30202863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"This RNA-repair activity is not demonstrated for the mammalian anti-apoptotic protein\", \"Endogenous RNA substrate in higher eukaryotes not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the structural mechanism of Tpt1 2'-PO4 splice-junction recognition and RNA phospho-ADP-ribosylation.\",\n      \"evidence\": \"1.4 Å crystal structure in a product-mimetic complex with ADP-ribose-1''-phosphate and pAp\",\n      \"pmids\": [\"30644400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance to mammalian TCTP biology remains separate\", \"Physiological substrate identity in most lineages unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected TCTP to cell-cycle control through CSN4/COP9 signalosome interaction regulating CUL1 neddylation at G1/S, conserved across plants and flies.\",\n      \"evidence\": \"Cross-species genetic interaction (Arabidopsis, Drosophila) and CUL1 neddylation/cell-cycle assays\",\n      \"pmids\": [\"30695029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical effect of TCTP on COP9 deneddylase activity not measured\", \"Human relevance not directly tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a cardiac survival role: TCTP loss triggers Bnip3-dependent apoptotic/autophagic cardiomyocyte death with mPTP opening, and overexpression protects against doxorubicin cardiotoxicity.\",\n      \"evidence\": \"siRNA, cardiomyocyte-specific transgenic mice, mPTP assays, Bnip3 blots, and doxorubicin heart-failure model\",\n      \"pmids\": [\"31320615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which TCTP suppresses Bnip3 not defined\", \"Relationship to the p53-dependent cardiac death pathway (#28) not unified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed TCTP promotes EMT and invasion partly by binding and stabilizing β-catenin and inducing uPA, integrating its Wnt and migratory functions.\",\n      \"evidence\": \"Stable overexpression/knockdown, migration/invasion assays, EMT-marker blots, TCTP–β-catenin co-IP, and uPA assay\",\n      \"pmids\": [\"28958626\", \"30881019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect β-catenin stabilization mechanism not resolved\", \"Whether p53 downregulation drives the EMT program not isolated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified DLC1 as a negative regulator of TCTP levels at focal adhesions, controlling Cdc42-driven migration independently of DLC1 RhoGAP activity.\",\n      \"evidence\": \"Co-IP, colocalization, siRNA, GAP-dead R718A mutant, Cdc42 activation, and migration assays\",\n      \"pmids\": [\"33150340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which DLC1 lowers TCTP (degradation vs. translation) not defined\", \"Direct vs. complex-mediated interaction not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked TCTP to tumor immune evasion via phospho-dependent Na,K-ATPase interaction activating EGFR-AKT-MCL-1/CXCL10 signaling.\",\n      \"evidence\": \"Transcriptomics, immune-refractory tumor models, DHA inhibition, co-IP, phosphorylation, and T-cell killing assays\",\n      \"pmids\": [\"35440620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal step from Na,K-ATPase binding to immune refractoriness not fully isolated\", \"Whether extracellular/membrane TCTP mediates this not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a new survival mechanism: fortilin specifically binds CTNNA3 (not other catenins) and protects it from phosphorylation-driven ubiquitin-proteasome degradation to prevent apoptosis.\",\n      \"evidence\": \"Co-IP, PLA, MST, BLI, phospho-null/mimetic CTNNA3 mutants, proteasome inhibition, and apoptosis assays\",\n      \"pmids\": [\"39747445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase phosphorylating CTNNA3 not identified\", \"Tissue contexts where CTNNA3 protection is physiologically relevant not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TCTP's many parallel pro-survival and growth mechanisms are coordinated within a single cell — and whether the mammalian protein possesses any of the RNA 2'-phosphotransferase enzymatic activity of its fungal/archaeal orthologs — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No integrated model ranks the relative in vivo contribution of the p53, Bcl-xL, IRE1α, Ca²⁺, and PRX1 pathways\", \"Whether mammalian TCTP/fortilin has any catalytic RNA-repair role is untested\", \"Structural basis of most protein-protein interfaces (p53, IRE1α, CSN4) unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [22, 20, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 13, 16, 22, 17]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [23, 24]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7, 26]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 22]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12, 27]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [8, 32]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 7, 16, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 14, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [25, 8, 32]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [22, 20, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 28, 26]}\n    ],\n    \"complexes\": [\"COP9 signalosome\"],\n    \"partners\": [\"MCL1\", \"TP53\", \"MDM2\", \"BCL2L1\", \"ERN1\", \"PRDX1\", \"RHEB\", \"CTNNA3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}