{"gene":"HTATIP2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1998,"finding":"TIP30 (HTATIP2) interacts with HIV-1 Tat and with an SRB-containing RNA polymerase II complex both in vivo and in vitro; immunodepletion of TIP30 from nuclear extracts abolishes Tat-activated transcription without affecting Tat-independent transcription, establishing TIP30 as a specific coactivator for Tat-dependent transcription elongation.","method":"Co-immunoprecipitation (in vivo and in vitro), immunodepletion from nuclear extracts, transfection-based transcription assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in vivo and in vitro, immunodepletion with functional readout, replicated in multiple assays in one study","pmids":["9482853"],"is_preprint":false},{"year":2000,"finding":"TIP30/CC3 possesses intrinsic serine/threonine kinase activity; it phosphorylates the heptapeptide repeats of the C-terminal domain (CTD) of the largest RNA polymerase II subunit in a Tat-dependent manner. Amino acid substitutions in the putative ATP-binding motif that abolish kinase activity also abolish TIP30's ability to enhance Tat-activated transcription and to sensitize cells to apoptosis. Ectopic TIP30 induces expression of apoptosis-related genes Bad and Siva and metastasis suppressor NM23-H2.","method":"In vitro kinase assay, active-site mutagenesis, transfection-based transcription assay, gene expression profiling","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay combined with mutagenesis and functional transcription/apoptosis readouts in one rigorous study","pmids":["10698937"],"is_preprint":false},{"year":2000,"finding":"CC3/TIP30 predisposes cells to apoptosis by disrupting mitochondrial membrane potential (ΔΨm). An alternatively spliced product, TC3, which shares the N-terminal domain of CC3 but has a unique hydrophobic C-terminus, has opposing antiapoptotic activity and forms complexes with the s5α regulatory subunit of the proteasome; TC3 is rapidly degraded by the proteasome. The proapoptotic activity of CC3 resides in its N-terminal domain.","method":"Overexpression, deletion/mutagenesis of CC3/TC3, cell death assay, mitochondrial membrane potential measurement, co-immunoprecipitation with proteasome subunit, proteasome inhibitor experiments","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain mutagenesis, reconstitution of opposing functional activities, Co-IP with proteasome subunit, multiple orthogonal methods in one study","pmids":["10611237"],"is_preprint":false},{"year":2001,"finding":"Expression of CC3/TIP30 in tumor cell lines significantly reduces their angiogenic properties, as measured by inhibition of endothelial cell proliferation and migration in vitro, and alters RNA levels of several angiogenic modulators.","method":"Overexpression in tumor cell lines, in vitro endothelial cell proliferation and migration assays, RNA expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss/gain of function with defined cellular phenotype, single lab, two orthogonal readouts","pmids":["11313954"],"is_preprint":false},{"year":2003,"finding":"TIP30-deficient (Tip30−/−) mice develop hepatocellular carcinoma and other tumors at higher incidence than wild-type mice, establishing Tip30 as an in vivo tumor susceptibility gene. Loss of TIP30 also enhances susceptibility of fibroblasts to transformation by SV40 large T antigen.","method":"Genetically engineered knockout mice, tumor incidence analysis, fibroblast transformation assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout model with defined tumor phenotype, replicated across multiple tumor types, fibroblast transformation assay as orthogonal validation","pmids":["14695192"],"is_preprint":false},{"year":2004,"finding":"CC3/TIP30 directly binds karyopherins of the importin beta family in a RanGTP-insensitive manner and associates with nucleoporins in vivo. This interaction inhibits nuclear import of proteins bearing classical NLS or M9 signals. A CC3 mutant lacking proapoptotic activity shows lower affinity for transportin, is displaced by RanGTP, and fails to inhibit nuclear import. Inhibition of nuclear import correlates with proapoptotic activity.","method":"In vitro nuclear import assay, in vivo nuclear import assay, direct binding assay (pulldown), mutagenesis, RanGTP competition assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro and in vivo import assays, mutagenesis linking binding affinity to function, multiple orthogonal methods in one study","pmids":["15282309"],"is_preprint":false},{"year":2004,"finding":"TIP30 interacts with ERα-interacting coactivator CIA; both are dynamically recruited to the c-myc gene promoter and downstream regions in response to estrogen, as shown by chromatin immunoprecipitation. TIP30 overexpression represses ERα-mediated c-myc transcription, while TIP30 deficiency enhances c-myc transcription. Ectopic CIA cooperates with TIP30 to repress ERα-mediated c-myc transcription.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), overexpression/knockout cell assays, TIP30 knockout mouse mammary gland analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP with functional readout, in vivo KO validation, multiple orthogonal methods","pmids":["15073177"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of CC3/TIP30 at 1.7-Å resolution reveals a short-chain dehydrogenase/reductase (SDR) fold with binding specificity for NADPH. The protein is monomeric and unlikely to be enzymatically active in the canonical SDR sense. Structural analysis, in conjunction with prior mutagenesis data, suggests NADPH binding is important for biological activity including interaction with importins and the CIA/c-myc system.","method":"X-ray crystallography (1.7 Å resolution), structural analysis, NADPH binding","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with functional inference supported by prior mutagenesis data from multiple labs","pmids":["15728189"],"is_preprint":false},{"year":2007,"finding":"TIP30 mutants derived from HCC specimens promote cell growth and invasion while inhibiting cisplatin-induced apoptosis in HepG2 cells negative for endogenous TIP30. One mutant dramatically accelerates tumor formation in immunodeficient mice. Mutant TIP30 upregulates N-cadherin and c-MYC and downregulates p53 and E-cadherin; N-cadherin knockdown in mutant-expressing cells causes profound reduction in cell viability.","method":"Overexpression of mutant TIP30, Affymetrix GeneChip array, real-time PCR, Western blotting, siRNA knockdown of N-cadherin, in vivo xenograft","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with in vivo validation, gene expression and siRNA rescue, single lab","pmids":["17440068"],"is_preprint":false},{"year":2008,"finding":"TIP30 regulates p53 mRNA stability under oxidative stress. Under oxidative conditions, TIP30 forms an intermolecular disulfide bridge (conformational change). TIP30 blocks the nuclear import of the mRNA-binding protein HuR by disrupting HuR–importin β2 association; elevated cytoplasmic HuR then binds the p53 mRNA 3'-UTR, prolonging p53 mRNA half-life and increasing p53 expression and transcriptional activity. TIP30-induced apoptosis and mitochondrial dysfunction are blocked by p53 silencing.","method":"Overexpression, siRNA knockdown of p53/HuR, mRNA stability assay, co-immunoprecipitation (HuR–importin β2), disulfide bridge analysis under oxidative stress, antioxidant/oxidant treatment, mitochondrial dysfunction assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mRNA stability, epistasis by siRNA rescue, redox modification), mechanistic chain established in one study","pmids":["18519672"],"is_preprint":false},{"year":2008,"finding":"Abnormal overexpression of TIP30 in oligodendrocyte precursor cells (OPCs) in MS lesions traps NICD (Notch1 intracellular domain) and other NLS-bearing proteins with importin in the cytoplasm, blocking nuclear translocation required for myelinogenesis. Overexpression of TIP30 in a rat OPC cell line causes cytoplasmic entrapment of NICD and arrests differentiation upon Contactin-Fc stimulation.","method":"Immunohistochemistry in human MS tissue, overexpression in rat OPC cell line, functional differentiation assay","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human tissue correlative plus in vitro overexpression with functional readout, single lab, mechanism consistent with importin-inhibition finding from PMID 15282309","pmids":["19104151"],"is_preprint":false},{"year":2011,"finding":"TIP30 forms a protein complex with endophilin B1 and ACSL4 that interacts with Rab5a. This TIP30 complex is required for proper endocytic trafficking of EGF-EGFR. Knockdown of TIP30, ACSL4, endophilin B1, or Rab5a traps EGF-EGFR in early endosomes, causing delayed EGFR degradation and prolonged EGFR signaling. The TIP30 complex facilitates trafficking of Rab5a and V-ATPases from the trans-Golgi network to EEA1-positive early endosomes in response to EGF.","method":"Co-immunoprecipitation, siRNA knockdown, genetic knockout (Tip30−/− primary hepatocytes), endosomal trafficking assay, colocalization with V-ATPases and EEA1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple independent KD experiments, KO primary cells, multiple functional readouts, mechanistic pathway established","pmids":["21252234"],"is_preprint":false},{"year":2011,"finding":"The TIP30 protein complex (TIP30, ACSL4, endophilin B1) facilitates fusion of endocytic vesicles with Rab5a vesicles in vitro. Fusion depends on arachidonic acid, coenzyme A, and arachidonyl-CoA synthesis by ACSL4. The TIP30 complex transfers arachidonyl groups onto phosphatidic acid (PA), producing a lipid species that induces close membrane contact.","method":"In vitro vesicle fusion assay, arachidonyl-CoA synthesis assay, lipid transfer assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of membrane fusion with biochemical characterization of lipid modification, single lab","pmids":["21731680"],"is_preprint":false},{"year":2012,"finding":"TIP30 loss in lung adenocarcinoma cells results in prolonged EGFR activity in early endosomes, delayed EGFR degradation, and increased EGFR nuclear localization, leading to upregulated pAKT and pERK1/2. Tip30 deletion in mice leads to spontaneous lung adenomas and adenocarcinomas, preceded by aberrant expansion of bronchioalveolar stem/progenitor and AT2 cells and increased EGFR expression.","method":"siRNA knockdown, Tip30 knockout mice, endosomal trafficking assay, Western blotting for EGFR signaling, nuclear EGFR localization, mouse tumor pathology","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD in human cells plus in vivo KO mouse model, multiple orthogonal signaling and trafficking readouts, mechanistic link established","pmids":["22733137"],"is_preprint":false},{"year":2012,"finding":"Sorafenib downregulates HTATIP2 expression in HCC cells via JAK-STAT3 signaling, promoting invasiveness and metastatic potential. HTATIP2 knockdown reduces sorafenib-promoted invasion, while HTATIP2 overexpression enhances it; HTATIP2 expression is associated with sorafenib-induced EMT.","method":"PCR arrays, shRNA knockdown, transgenic overexpression, orthotopic mouse model, Western blotting for JAK-STAT3 pathway, EMT marker analysis","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo orthotopic model with genetic manipulation, pathway analysis, single lab","pmids":["22922424"],"is_preprint":false},{"year":2012,"finding":"TIP30 directly binds the DNA-binding domain and the C-terminal domain of p53 protein, as demonstrated by GST pull-down assay and surface plasmon resonance.","method":"GST pull-down assay, surface plasmon resonance (SPR)","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding assay with two orthogonal methods but single lab, no cellular validation","pmids":["23178973"],"is_preprint":false},{"year":2013,"finding":"miR-10b directly targets TIP30 mRNA (confirmed by luciferase reporter assay with 3'-UTR); miR-10b-mediated suppression of TIP30 enhances EGF-dependent EGFR tyrosine phosphorylation and ERK phosphorylation in pancreatic cancer cells. The effects of miR-10b are abrogated by expressing a modified TIP30 cDNA resistant to miR-10b. TIP30 silencing mimics miR-10b effects on invasion.","method":"Luciferase reporter assay, siRNA knockdown, miR-10b overexpression, EGFR/ERK phosphorylation (Western blotting), Matrigel invasion assay, rescue with miR-10b-resistant TIP30","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — luciferase reporter for direct targeting, epistatic rescue experiment, multiple signaling readouts, single lab with multiple orthogonal methods","pmids":["24096486"],"is_preprint":false},{"year":2014,"finding":"TIP30 inhibits EMT and nuclear accumulation of Snail in HCC cells by competitively interrupting the interaction of Snail with importin-β2, thereby blocking Snail nuclear import. Small interfering RNAs targeting Snail attenuate the EMT and tumor-initiating properties induced by TIP30 deficiency.","method":"Overexpression/knockdown, Co-immunoprecipitation (TIP30–importin-β2–Snail complex), nuclear fractionation, siRNA epistasis, in vitro and in vivo invasion/EMT assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of ternary complex, siRNA epistasis, multiple functional readouts, mechanistic pathway well-defined","pmids":["24681951"],"is_preprint":false},{"year":2014,"finding":"TIP30 translocates to the nucleus of lung adenocarcinoma cells in response to EGF treatment (via EGFR signaling); nuclear TIP30 negatively regulates EGF-dependent transcriptional activation of CCND1 (cyclin D1) through an HDAC1-dependent mechanism, as demonstrated by chromatin immunoprecipitation.","method":"Nuclear fractionation/localization, EGFR pathway inhibitor treatment, chromatin immunoprecipitation (ChIP), gene expression analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional readout, pharmacological epistasis, single lab","pmids":["25135222"],"is_preprint":false},{"year":2014,"finding":"TIP30 inhibits oligodendrocyte precursor cell (OPC) differentiation by sequestering the transcription factor Olig1 in the cytoplasm via direct interaction with Olig1, preventing its nuclear translocation. Overexpression of TIP30 sequesters Olig1 in the cytoplasm; knockdown of TIP30 increases nuclear Olig1 and enhances OPC differentiation. Tip30−/− mice display increased myelin protein levels at postnatal days 14 and 21.","method":"Primary OPC culture, overexpression and siRNA knockdown, Co-immunoprecipitation (TIP30–Olig1), nuclear/cytoplasmic fractionation, Tip30−/− mice, cuprizone demyelination model","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of TIP30-Olig1 complex, KO mice with phenotype, primary cell KD and OE with functional readout, multiple orthogonal methods","pmids":["25530119"],"is_preprint":false},{"year":2015,"finding":"TGF-β1 induces epigenetic silencing of TIP30 promoter via DNMT1 and DNMT3A upregulation (hypermethylation), reducing TIP30 expression during EMT. TIP30 silencing activates nuclear translocation and transcriptional activation of β-catenin in an AKT-dependent manner, promoting EMT in esophageal carcinoma cells.","method":"Promoter methylation analysis, DNMT knockdown/overexpression, Western blotting for AKT/β-catenin signaling, nuclear fractionation, in vitro and in vivo invasion assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic writer identified (DNMT1/3A), AKT/β-catenin pathway epistasis, single lab","pmids":["25544767"],"is_preprint":false},{"year":2017,"finding":"TIP30 deficiency activates the Akt/mTOR signaling pathway, leading to upregulation and nuclear accumulation of SREBP1, which promotes transcription of lipogenesis genes (fasn, scd) and elevated fatty acid synthesis in HCC cells. siRNA targeting SREBP1 reverses the fatty acid synthesis induced by TIP30 deficiency.","method":"siRNA knockdown, Western blotting for Akt/mTOR/SREBP1 signaling, nuclear fractionation, fatty acid synthesis assay, siRNA epistasis","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis via siRNA, signaling readouts, single lab with multiple methods","pmids":["28604762"],"is_preprint":false},{"year":2018,"finding":"HIV-1 Tat protein interacts with TIP30 and blocks TIP30's binding to importin-β, thereby preventing TIP30-mediated inhibition of Snail nuclear import in lung cancer cells. Loss of TIP30-importin-β interaction (via Tat) increases nuclear Snail, promoting EMT and invasion.","method":"Co-immunoprecipitation (Tat–TIP30–importin-β), nuclear fractionation of Snail, overexpression, in vivo metastasis assay, immunohistochemistry","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating competitive binding, functional epistasis, single lab","pmids":["30099830"],"is_preprint":false},{"year":2019,"finding":"TIP30 binds eukaryotic elongation factor 1A (eEF1A) and prevents its interaction with co-factor eEF1B2, thereby inhibiting translational elongation and cardiac protein synthesis. Therapeutic overexpression of TIP30 in mouse hearts inhibits cardiac hypertrophy and improves left ventricular function during pressure overload and in mdx cardiomyopathic mice. Reduced TIP30 in Tip30-reduced mice leads to exaggerated cardiac growth and dysfunction during pressure overload; pharmacological inhibition of protein synthesis rescues these defects.","method":"Co-immunoprecipitation (TIP30–eEF1A), eEF1A–eEF1B2 interaction assay, in vivo cardiac-specific overexpression and KO mouse models, protein synthesis measurement, pressure-overload model, pharmacological inhibition rescue","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of TIP30-eEF1A complex with functional disruption of eEF1B2 binding, in vivo KO and overexpression models with mechanistic pharmacological rescue, multiple orthogonal methods","pmids":["31468715"],"is_preprint":false},{"year":2023,"finding":"Epigenetic silencing of HTATIP2 in glioblastoma leads to enhanced nuclear localization of the base excision repair enzyme MPG (N-methylpurine DNA glycosylase). Induction of HTATIP2 expression shifts MPG from nuclear to cytoplasmic, while depletion of endogenous HTATIP2 increases nuclear MPG. Reduced nuclear MPG (via HTATIP2 induction or MPG depletion) yields fewer phospho-H2AX-positive cells upon alkylating agent treatment, indicating reduced BER capacity and fewer AP sites.","method":"HTATIP2 induction/knockdown, nuclear/cytoplasmic fractionation for MPG, phospho-H2AX assay after alkylating agent treatment, MPG knockdown epistasis","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — HTATIP2 gain and loss of function with localization readout and functional DNA damage assay, siRNA epistasis, single lab","pmids":["37491696"],"is_preprint":false},{"year":2023,"finding":"Increased HTATIP2 expression in proarteriogenic monocytes/macrophages from patients with chronic limb-threatening ischemia (CLTI) impairs their arteriogenic capacity. Silencing HTATIP2 in CLTI monocytes/macrophages restores expression of arteriogenic regulators Neuropilin-1 and Angiopoietin-1 and rescues their capacity to enhance angiogenic and arteriogenic processes in vitro and limb perfusion in vivo.","method":"siRNA knockdown in primary patient-derived monocytes/macrophages, endothelial tubule formation assay, smooth muscle proliferation assay, hindlimb ischemia in vivo model, Western blotting","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD in primary human cells with in vivo rescue, multiple functional readouts, single lab","pmids":["37847559"],"is_preprint":false},{"year":2010,"finding":"Silencing of CC3/TIP30 expression strongly improves tumor cell survival under glucose limitation, enabling superior metabolic adaptation. CC3-silenced HeLa cells maintain higher mitochondrial respiration, higher expression of mitochondrial respiratory complex proteins, higher c-MYC and PKM2 (M2 isoform of pyruvate kinase) in low glucose, and fail to fully activate AMPK in response to glucose limitation. Pharmacological or siRNA inhibition of AMPK similarly protects control HeLa cells from glucose-limitation-induced death.","method":"siRNA knockdown of CC3, cell survival assay under glucose limitation, mitochondrial respiration measurement, Western blotting, AMPK pharmacological and siRNA inhibition","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with functional metabolic readouts, pharmacological and siRNA epistasis for AMPK, single lab","pmids":["21150275"],"is_preprint":false},{"year":2010,"finding":"Forced expression of CC3/TIP30 in CC3-negative cells strongly delays repair of UV-induced DNA damage, negatively affects expression of DDB2/XPE and p21CIP1, and inhibits nuclear accumulation of p21CIP1 after UV. Silencing endogenous CC3 significantly reduces translesion DNA synthesis after UV. CC3 expression also inhibits repair of oxidative DNA damage and decreases nucleoredoxin levels.","method":"Overexpression, siRNA knockdown, UV-induced DNA damage repair assay, Western blotting for DDB2/p21, nuclear fractionation, oxidative damage repair assay","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function with functional DNA repair readout, multiple DNA damage contexts tested, single lab","pmids":["20374651"],"is_preprint":false},{"year":2024,"finding":"TIP30 modulates mTORC1 signaling during CVB3 infection in HeLa cells. TIP30 overexpression mitigates CVB3-induced cellular pathogenesis; rapamycin (mTOR1 inhibitor) reverses these protective effects, indicating TIP30 acts upstream of mTORC1. TIP30-knockout mice show heightened heart virus titers and cardiac damage after CVB3 infection.","method":"TIP30 lentiviral overexpression, TIP30 knockout mice, rapamycin pharmacological epistasis, viral titer assay, Western blotting for mTORC1 pathway","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice with in vivo phenotype, in vitro overexpression with pharmacological epistasis, single lab","pmids":["38981316"],"is_preprint":false},{"year":2025,"finding":"Human TIP30 functionally complements yeast Fmp52 (a short-chain dehydrogenase/reductase at the ER) in protecting against lipid-induced apoptosis triggered by the sphingolipid-derived fatty aldehyde t-2-hex, indicating an evolutionarily conserved protective role for TIP30 at the ER against lipid-mediated cytotoxicity.","method":"Functional complementation in yeast (Fmp52 deletion rescued by human TIP30 expression), yeast apoptosis assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single complementation experiment in yeast, preprint, no mammalian validation","pmids":["bio_10.1101_2025.12.01.691522"],"is_preprint":true}],"current_model":"HTATIP2/TIP30/CC3 is a multifunctional tumor and metastasis suppressor that (1) acts as an NADPH-binding SDR-fold protein (crystal structure resolved) with intrinsic serine/threonine kinase activity that phosphorylates the RNA Pol II CTD in a Tat-dependent manner to coactivate HIV-1 Tat-driven transcription; (2) inhibits nucleocytoplasmic transport by binding importin-β family members in a RanGTP-insensitive manner, thereby trapping nuclear cargo proteins (NICD, Snail, HuR, MPG) in the cytoplasm—a mechanism linked to its proapoptotic, anti-metastatic, and DNA-repair-modulatory activities; (3) forms a complex with endophilin B1 and ACSL4 that interacts with Rab5a to facilitate V-ATPase delivery to early endosomes and EGFR endocytic degradation, suppressing sustained EGFR/AKT/ERK signaling; (4) stabilizes p53 mRNA under oxidative stress by blocking HuR nuclear import; (5) represses ERα-mediated c-myc transcription via CIA coactivator interaction; (6) inhibits translational elongation by binding eEF1A and preventing its interaction with eEF1B2, thereby counteracting cardiac hypertrophy; and (7) suppresses lipid synthesis through the AKT/mTOR/SREBP1 axis, with its loss in Tip30−/− mice causing spontaneous hepatocellular carcinoma, lung adenocarcinoma, and mammary hyperplasia."},"narrative":{"mechanistic_narrative":"HTATIP2 (TIP30/CC3) is a multifunctional tumor and metastasis suppressor whose loss in knockout mice causes spontaneous hepatocellular carcinoma, lung adenocarcinoma, and enhanced tumor susceptibility [PMID:14695192, PMID:22733137]. Structurally it adopts a short-chain dehydrogenase/reductase (SDR) fold that binds NADPH but is monomeric and likely catalytically inert in the canonical SDR sense, with NADPH binding instead supporting its protein-interaction functions [PMID:15728189]. A central mechanism is inhibition of nucleocytoplasmic transport: TIP30 binds importin-β family karyopherins in a RanGTP-insensitive manner and blocks nuclear import of NLS- and M9-bearing cargo, an activity tightly coupled to its proapoptotic action [PMID:15282309]. Through this transport-blocking activity it sequesters multiple cargoes in the cytoplasm — it disrupts HuR–importin-β2 association to stabilize p53 mRNA under oxidative stress [PMID:18519672], competitively blocks Snail nuclear import to suppress EMT [PMID:24681951], and traps NICD and Olig1 in oligodendrocyte precursors to restrain differentiation [PMID:19104151, PMID:25530119]. TIP30 also assembles with endophilin B1 and ACSL4 into a Rab5a-interacting complex that delivers V-ATPases to early endosomes and drives EGF-EGFR endocytic degradation, thereby limiting sustained EGFR/AKT/ERK signaling; loss of this function prolongs EGFR signaling and promotes tumorigenesis [PMID:21252234, PMID:21731680, PMID:22733137]. Additional regulatory outputs include repression of ERα-mediated c-myc transcription via the CIA coactivator [PMID:15073177], restraint of lipogenesis through the AKT/mTOR/SREBP1 axis [PMID:28604762], and inhibition of translational elongation by binding eEF1A and preventing eEF1B2 engagement to counteract cardiac hypertrophy [PMID:31468715]. The protein was originally identified as a Tat-dependent coactivator that interacts with an RNA Pol II complex and exhibits intrinsic serine/threonine kinase activity toward the Pol II CTD [PMID:9482853, PMID:10698937].","teleology":[{"year":1998,"claim":"Established the founding molecular role of TIP30 as a specific coactivator required for HIV-1 Tat-dependent transcription, distinguishing it from general transcription machinery.","evidence":"Co-IP in vivo and in vitro plus immunodepletion with transcription readout in nuclear extracts","pmids":["9482853"],"confidence":"High","gaps":["Did not define the catalytic or structural basis of coactivation","Tat-independent functions unaddressed"]},{"year":2000,"claim":"Assigned an intrinsic serine/threonine kinase activity to TIP30 acting on the Pol II CTD and linked this activity to both transcription enhancement and apoptosis sensitization, while implicating it in apoptotic and metastasis-suppressor gene programs.","evidence":"In vitro kinase assay with ATP-binding-motif mutagenesis and gene expression profiling","pmids":["10698937"],"confidence":"High","gaps":["Kinase identity later complicated by the SDR-fold structure","Direct CTD substrate role in vivo not established"]},{"year":2000,"claim":"Localized the proapoptotic activity to the CC3 N-terminal domain and revealed an antiapoptotic splice variant (TC3) that binds the proteasome, showing functional output depends on isoform and domain structure.","evidence":"Domain mutagenesis, mitochondrial membrane potential assays, Co-IP with proteasome subunit","pmids":["10611237"],"confidence":"High","gaps":["Mechanism connecting N-terminus to mitochondrial disruption unclear","Physiological abundance of TC3 not quantified"]},{"year":2001,"claim":"Connected TIP30 expression to suppression of tumor angiogenesis, broadening its role beyond transcription/apoptosis to the tumor microenvironment.","evidence":"Overexpression in tumor lines with endothelial proliferation/migration assays and RNA profiling","pmids":["11313954"],"confidence":"Medium","gaps":["Molecular mediators of angiogenic modulation not pinned down","Single-lab in vitro readouts"]},{"year":2003,"claim":"Provided in vivo proof that Tip30 is a tumor susceptibility gene by showing knockout mice develop tumors and that loss potentiates oncogenic transformation.","evidence":"Tip30−/− knockout mice tumor incidence and SV40 large T fibroblast transformation assay","pmids":["14695192"],"confidence":"High","gaps":["Causal molecular pathway underlying tumor suppression not defined here"]},{"year":2004,"claim":"Defined a core biochemical mechanism: RanGTP-insensitive binding to importin-β karyopherins that blocks nuclear import, and tied import inhibition directly to proapoptotic function.","evidence":"In vitro and in vivo nuclear import assays, direct binding, mutagenesis and RanGTP competition","pmids":["15282309"],"confidence":"High","gaps":["Which physiological cargoes are most affected not yet identified"]},{"year":2004,"claim":"Identified a transcriptional repressor role at the c-myc promoter via the CIA coactivator, linking TIP30 to estrogen-driven proliferation control.","evidence":"Reciprocal Co-IP, ChIP, overexpression/knockout cells, KO mouse mammary analysis","pmids":["15073177"],"confidence":"High","gaps":["Mechanism of CIA cooperativity in repression not resolved"]},{"year":2005,"claim":"Resolved the protein fold, revealing an SDR architecture that binds NADPH but is monomeric and likely non-catalytic, reframing the earlier kinase claim and grounding NADPH-dependent protein interactions.","evidence":"1.7-Å X-ray crystal structure with NADPH binding and structural analysis","pmids":["15728189"],"confidence":"High","gaps":["Reconciliation with reported kinase activity unresolved","Role of NADPH in import inhibition inferred, not directly shown structurally"]},{"year":2008,"claim":"Elucidated a redox-sensitive cargo-trapping mechanism: under oxidative stress TIP30 blocks HuR import, raising cytoplasmic HuR to stabilize p53 mRNA and drive apoptosis.","evidence":"Co-IP, mRNA stability assays, siRNA epistasis, disulfide-bridge analysis under oxidants","pmids":["18519672"],"confidence":"High","gaps":["Structural basis of the oxidation-induced disulfide conformational switch not detailed"]},{"year":2008,"claim":"Extended import-trapping to a developmental context, showing pathological TIP30 overexpression sequesters NICD to block oligodendrocyte differentiation and myelinogenesis.","evidence":"MS tissue immunohistochemistry plus rat OPC overexpression with differentiation assay","pmids":["19104151"],"confidence":"Medium","gaps":["Correlative human tissue data; causal contribution to MS not established"]},{"year":2011,"claim":"Defined a distinct membrane-trafficking function: a TIP30–endophilin B1–ACSL4 complex interacts with Rab5a to deliver V-ATPases to early endosomes and promote EGFR endocytic degradation.","evidence":"Reciprocal Co-IP, multiple siRNA knockdowns, KO primary hepatocytes, trafficking and colocalization assays","pmids":["21252234","21731680"],"confidence":"High","gaps":["How NADPH/SDR fold contributes to the trafficking complex unclear","Lipid-transfer chemistry characterized only in vitro"]},{"year":2012,"claim":"Tied loss of the EGFR-degradation function to lung tumorigenesis, showing TIP30 loss prolongs EGFR activity, increases nuclear EGFR, and elevates AKT/ERK signaling with stem/progenitor expansion in vivo.","evidence":"siRNA knockdown, Tip30 KO mice tumor pathology, signaling and trafficking readouts","pmids":["22733137"],"confidence":"High","gaps":["Direct link between nuclear EGFR and transcriptional output not fully mapped"]},{"year":2012,"claim":"Identified upstream regulation showing sorafenib suppresses HTATIP2 via JAK-STAT3 to paradoxically promote invasion, and demonstrated direct TIP30–p53 protein binding.","evidence":"PCR arrays, shRNA/overexpression, orthotopic model, JAK-STAT3 analysis; GST pulldown and SPR for p53 binding","pmids":["22922424","23178973"],"confidence":"Medium","gaps":["TIP30–p53 binding shown only in vitro without cellular validation","Context-dependent pro-invasive vs suppressor roles unreconciled"]},{"year":2013,"claim":"Established miR-10b as a direct upstream repressor of TIP30, linking microRNA-mediated TIP30 loss to enhanced EGFR/ERK signaling and invasion in pancreatic cancer.","evidence":"Luciferase 3'-UTR reporter, miR-10b overexpression, miR-resistant TIP30 rescue, invasion assays","pmids":["24096486"],"confidence":"High","gaps":["Whether miR-10b acts mainly through EGFR trafficking versus other TIP30 functions not separated"]},{"year":2014,"claim":"Demonstrated TIP30 blocks EMT by competitively disrupting Snail–importin-β2 binding, integrating cargo-trapping with metastasis suppression.","evidence":"Ternary-complex Co-IP, nuclear fractionation, siRNA epistasis, in vitro/in vivo invasion assays","pmids":["24681951"],"confidence":"High","gaps":["Quantitative competition between cargoes for importin-β2 not characterized"]},{"year":2014,"claim":"Revealed an EGF-induced nuclear pool of TIP30 that represses cyclin D1 transcription via HDAC1, and a cytoplasmic Olig1-sequestering role controlling myelination.","evidence":"Nuclear fractionation and ChIP for CCND1/HDAC1; Co-IP, fractionation, KO mice and cuprizone model for Olig1","pmids":["25135222","25530119"],"confidence":"High","gaps":["Signal driving TIP30 nuclear entry versus cytoplasmic retention not fully defined"]},{"year":2015,"claim":"Placed TIP30 in an epigenetic feedback loop where TGF-β1-driven DNMT-mediated promoter silencing of TIP30 activates AKT-dependent β-catenin nuclear translocation to promote EMT.","evidence":"Promoter methylation analysis, DNMT manipulation, AKT/β-catenin signaling and invasion assays","pmids":["25544767"],"confidence":"Medium","gaps":["Direct versus indirect control of β-catenin by TIP30 not separated","Single-lab data"]},{"year":2017,"claim":"Connected TIP30 loss to metabolic reprogramming, showing AKT/mTOR-dependent SREBP1 activation drives lipogenesis upon TIP30 deficiency.","evidence":"siRNA knockdown, AKT/mTOR/SREBP1 signaling readouts, fatty acid synthesis assay, SREBP1 epistasis","pmids":["28604762"],"confidence":"Medium","gaps":["Whether TIP30 acts directly on AKT/mTOR or via EGFR trafficking unresolved"]},{"year":2018,"claim":"Showed HIV-1 Tat antagonizes TIP30 by blocking its importin-β binding, de-repressing Snail import and promoting EMT, mechanistically linking the original Tat partner to the transport-inhibition function.","evidence":"Tat–TIP30–importin-β Co-IP, Snail fractionation, in vivo metastasis and immunohistochemistry","pmids":["30099830"],"confidence":"Medium","gaps":["Physiological relevance outside HIV infection context not established"]},{"year":2019,"claim":"Defined a translational-control function whereby TIP30 binds eEF1A to block eEF1B2 engagement and limit protein synthesis, providing a therapeutic mechanism against cardiac hypertrophy.","evidence":"Co-IP, eEF1A–eEF1B2 interaction assays, cardiac KO/overexpression mice, pressure-overload model with pharmacological rescue","pmids":["31468715"],"confidence":"High","gaps":["Whether elongation control operates in tumor contexts not tested"]},{"year":2023,"claim":"Extended cargo-trapping to DNA repair, showing HTATIP2 controls nuclear versus cytoplasmic localization of the BER glycosylase MPG and thereby modulates BER capacity under alkylation stress.","evidence":"HTATIP2 induction/knockdown, MPG fractionation, phospho-H2AX assay, MPG epistasis in glioblastoma cells","pmids":["37491696"],"confidence":"Medium","gaps":["Whether MPG transport depends on the importin-β mechanism not directly shown"]},{"year":2023,"claim":"Implicated HTATIP2 in vascular biology, showing elevated levels in CLTI monocytes/macrophages impair arteriogenesis and silencing restores arteriogenic capacity.","evidence":"siRNA in primary patient cells, tubule/smooth muscle assays, hindlimb ischemia in vivo rescue","pmids":["37847559"],"confidence":"Medium","gaps":["Molecular target linking HTATIP2 to Neuropilin-1/Angiopoietin-1 unknown"]},{"year":2010,"claim":"Showed TIP30 influences metabolic stress survival and DNA repair, with loss enhancing survival under glucose limitation via AMPK and TIP30 expression impairing UV/oxidative damage repair.","evidence":"siRNA knockdown, glucose-limitation survival and respiration assays, AMPK epistasis; UV/oxidative repair and translesion synthesis assays","pmids":["21150275","20374651"],"confidence":"Medium","gaps":["Direct molecular targets in AMPK and repair pathways not defined","Single-lab readouts"]},{"year":2024,"claim":"Identified an antiviral role where TIP30 acts upstream of mTORC1 to mitigate CVB3 pathogenesis, with KO mice showing worse cardiac infection.","evidence":"Lentiviral overexpression, KO mice, rapamycin pharmacological epistasis, viral titer and mTORC1 signaling","pmids":["38981316"],"confidence":"Medium","gaps":["Direct molecular link between TIP30 and mTORC1 regulation unclear"]},{"year":2025,"claim":"Suggested an evolutionarily conserved ER-protective function against lipid-derived fatty aldehyde cytotoxicity via complementation of yeast Fmp52.","evidence":"Functional complementation in yeast Fmp52-deletion apoptosis assay (preprint)","pmids":["bio_10.1101_2025.12.01.691522"],"confidence":"Low","gaps":["Single complementation experiment in yeast, no mammalian validation","ER localization of human TIP30 not demonstrated here"]},{"year":null,"claim":"How the SDR/NADPH-binding fold mechanistically integrates TIP30's diverse activities — importin-β binding, endosomal lipid transfer, eEF1A binding, and the originally reported CTD kinase activity — into a unified biochemical function remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of TIP30 bound to importin-β or any cargo-competing partner","Reconciliation of reported kinase activity with the non-catalytic SDR fold unresolved","Mechanistic basis for cargo selectivity among many trapped proteins unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,9,17,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,17,23]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,6,18]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[23]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,17,19]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6,18]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[11,13]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,13,16,21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,9]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[5,9,17,19,24]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[11,12,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,8,13,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[23]}],"complexes":["TIP30–endophilin B1–ACSL4 complex"],"partners":["IMPORTIN-Β","HUR","SNAIL","OLIG1","EEF1A","SH3GLB1","ACSL4","RAB5A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BUP3","full_name":"Protein HTATIP2","aliases":["30 kDa HIV-1 TAT-interacting protein","HIV-1 TAT-interactive protein 2"],"length_aa":242,"mass_kda":27.0,"function":"Represses translation by preventing reactivation of elongation factor eEF1A (By similarity). May also inhibit nuclear import by competing with nuclear import substrates for binding to a subset of nuclear transport receptors (PubMed:15282309). Has additionally been proposed to act as a redox sensor involved in cellular oxidative stress surveillance (PubMed:18519672)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9BUP3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HTATIP2","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HTATIP2","total_profiled":1310},"omim":[{"mim_id":"605628","title":"HIV-1 TAT-INTERACTING PROTEIN 2, 30-KD; HTATIP2","url":"https://www.omim.org/entry/605628"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue 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The Journal of the Pakistan Medical Association","url":"https://pubmed.ncbi.nlm.nih.gov/31511712","citation_count":8,"is_preprint":false},{"pmid":"10546900","id":"PMC_10546900","title":"Heat shock-induced alterations in phosphorylation of the largest subunit of RNA polymerase II as revealed by monoclonal antibodies CC-3 and MPM-2.","date":"1999","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/10546900","citation_count":8,"is_preprint":false},{"pmid":"2166463","id":"PMC_2166463","title":"Integration of HPV-16 DNA in cervical carcinoma cell line CC3/CUHK3 and its xenografts.","date":"1990","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/2166463","citation_count":7,"is_preprint":false},{"pmid":"27065995","id":"PMC_27065995","title":"A Novel Triculture System (CC3) for Simultaneous Enzyme Production and Hydrolysis of Common Grasses through Submerged Fermentation.","date":"2016","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27065995","citation_count":6,"is_preprint":false},{"pmid":"29979475","id":"PMC_29979475","title":"Molecular modeling, biochemical characterization, and pharmacological properties of Cc3 -SPase: A platelet-aggregating thrombin-like enzyme purified from Cerastes cerastes venom.","date":"2018","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/29979475","citation_count":6,"is_preprint":false},{"pmid":"32545251","id":"PMC_32545251","title":"Absence of HTATIP2 Expression in A549 Lung Adenocarcinoma Cells Promotes Tumor Plasticity in Response to Hypoxic Stress.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32545251","citation_count":5,"is_preprint":false},{"pmid":"24853420","id":"PMC_24853420","title":"Tip30 controls differentiation of murine mammary luminal progenitor to estrogen receptor-positive luminal cell through regulating FoxA1 expression.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/24853420","citation_count":5,"is_preprint":false},{"pmid":"22490293","id":"PMC_22490293","title":"[Clinical significance of CC3/TIP30 expression in breast carcinoma and its correlation with HER-2/neu].","date":"2012","source":"Zhonghua wai ke za zhi [Chinese journal of surgery]","url":"https://pubmed.ncbi.nlm.nih.gov/22490293","citation_count":4,"is_preprint":false},{"pmid":"31917611","id":"PMC_31917611","title":"Characterization of HTATIP2 and its role during hair follicle cycles in Angora rabbit.","date":"2020","source":"Genome","url":"https://pubmed.ncbi.nlm.nih.gov/31917611","citation_count":4,"is_preprint":false},{"pmid":"30402840","id":"PMC_30402840","title":"The effects of interventional therapy on serum HTATIP2/TIP30, B7-H4 and short-term curative effect in primary hepatocellular carcinoma.","date":"2018","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30402840","citation_count":4,"is_preprint":false},{"pmid":"36817429","id":"PMC_36817429","title":"Genome-wide association study of the age of onset of type 1 diabetes reveals HTATIP2 as a novel T cell regulator.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36817429","citation_count":4,"is_preprint":false},{"pmid":"32521927","id":"PMC_32521927","title":"Clinical significance of changes in AFP, HTATIP2/TIP30, B7-H4 and inflammatory cytokines after transcatheter arterial chemoembolization.","date":"2020","source":"Journal of B.U.ON. : official journal of the Balkan Union of Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32521927","citation_count":3,"is_preprint":false},{"pmid":"40116031","id":"PMC_40116031","title":"Epidemiology of Staphylococcus haemolyticus nosocomial bacteraemia in neonatal intensive care units, France, 2019 to 2023: predominance of the ST29 (CC3) multidrug-resistant lineage.","date":"2025","source":"Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/40116031","citation_count":3,"is_preprint":false},{"pmid":"29645303","id":"PMC_29645303","title":"Unimolecular reactivity of organotrifluoroborate anions, RBF3- , and their alkali metal cluster ions, M(RBF3 )2- (M = Na, K; R = CH3 , CH3 CH2 , CH3 (CH2 )3 , CH3 (CH2 )5 , c-C3 H5 , C6 H5 , C6 H5 CH2 , CH2 CHCH2 , CH2 CH, C6 H5 CO).","date":"2018","source":"Rapid communications in mass spectrometry : RCM","url":"https://pubmed.ncbi.nlm.nih.gov/29645303","citation_count":3,"is_preprint":false},{"pmid":"26131199","id":"PMC_26131199","title":"Clinicopathologic significance and survival of TIP30 expression in laryngeal squamous cell carcinoma.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26131199","citation_count":2,"is_preprint":false},{"pmid":"37847559","id":"PMC_37847559","title":"HTATIP2 regulates arteriogenic activity in monocytes from patients with limb ischemia.","date":"2023","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/37847559","citation_count":2,"is_preprint":false},{"pmid":"36690443","id":"PMC_36690443","title":"S417 in the CC3 region of STIM1 is critical for STIM1-Orai1 binding and CRAC channel activation.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/36690443","citation_count":2,"is_preprint":false},{"pmid":"15059324","id":"PMC_15059324","title":"[Construction of adenovirus vector expressing TIP30 and its tumor suppressive effect in vitro and in vivo].","date":"2004","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/15059324","citation_count":1,"is_preprint":false},{"pmid":"38981316","id":"PMC_38981316","title":"Investigating TIP30-Mediated regulation of mTORC1 signaling as a therapeutic strategy for coxsackievirus B3-Induced viral myocarditis.","date":"2024","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/38981316","citation_count":0,"is_preprint":false},{"pmid":"25202945","id":"PMC_25202945","title":"[Effect of Tip30 expression on the invasion and metastasis of hepatoma cells].","date":"2014","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25202945","citation_count":0,"is_preprint":false},{"pmid":"15670490","id":"PMC_15670490","title":"[Effects of tumor suppressing gene TIP30/CC3 on the growth of tumor cells].","date":"2005","source":"Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/15670490","citation_count":0,"is_preprint":false},{"pmid":"23552775","id":"PMC_23552775","title":"[Gene therapy for tongue carcinoma mediated by oral administration of attenuated Salmonella harboring tip30 and IFN-γ genes in nude mouse model].","date":"2013","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/23552775","citation_count":0,"is_preprint":false},{"pmid":"34417953","id":"PMC_34417953","title":"Resonance assignment of coiled-coil 3 (CC3) domain of human STIM1.","date":"2021","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/34417953","citation_count":0,"is_preprint":false},{"pmid":"28296179","id":"PMC_28296179","title":"The 5'-AG5 CC-3' Fragment from the Human CPEB3 Ribozyme Forms an Ultrastable Parallel RNA G-Quadruplex.","date":"2017","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/28296179","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.12.01.691522","title":"Lipid-Mediated Control of ER Function During Apoptosis","date":"2025-12-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.12.01.691522","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.25.666850","title":"Characterization of  <i>Staphylococcus lugdunensis</i>  biofilm reveals key differences according to clonal lineage and iron availability","date":"2025-07-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.25.666850","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.16.654474","title":"Parkin-dependent ubiquitination of TAX1BP1 affects the degradation pathway of defective mitochondria","date":"2025-05-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.16.654474","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.17.25336024","title":"Inhibiting LRRK2 kinase activity protects against the pathology associated with the presenilin 1 Ile416Thr mutation in cholinergic neurons","date":"2025-09-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.17.25336024","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.08.669439","title":"MORC2 Mediates Transcriptional Regulation Through Liquid-Liquid Phase Separation","date":"2025-08-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.08.669439","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.20.655205","title":"Multiple weak brakes act in concert to regulate STIM1 and control store-operated calcium entry","date":"2025-05-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.20.655205","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.11.632512","title":"BicD and MAP7 collaborate to activate homodimeric  <i>Drosophila</i>  kinesin-1 by complementary mechanisms","date":"2025-01-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.11.632512","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.08.607206","title":"<i>Tritrichomonas muris</i>  sensitizes the intestinal epithelium to doxorubicin-induced apoptosis","date":"2024-08-09","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.08.607206","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47030,"output_tokens":8223,"usd":0.132217,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18129,"output_tokens":7196,"usd":0.135272,"stage2_stop_reason":"end_turn"},"total_usd":0.267489,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"TIP30 (HTATIP2) interacts with HIV-1 Tat and with an SRB-containing RNA polymerase II complex both in vivo and in vitro; immunodepletion of TIP30 from nuclear extracts abolishes Tat-activated transcription without affecting Tat-independent transcription, establishing TIP30 as a specific coactivator for Tat-dependent transcription elongation.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), immunodepletion from nuclear extracts, transfection-based transcription assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in vivo and in vitro, immunodepletion with functional readout, replicated in multiple assays in one study\",\n      \"pmids\": [\"9482853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TIP30/CC3 possesses intrinsic serine/threonine kinase activity; it phosphorylates the heptapeptide repeats of the C-terminal domain (CTD) of the largest RNA polymerase II subunit in a Tat-dependent manner. Amino acid substitutions in the putative ATP-binding motif that abolish kinase activity also abolish TIP30's ability to enhance Tat-activated transcription and to sensitize cells to apoptosis. Ectopic TIP30 induces expression of apoptosis-related genes Bad and Siva and metastasis suppressor NM23-H2.\",\n      \"method\": \"In vitro kinase assay, active-site mutagenesis, transfection-based transcription assay, gene expression profiling\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay combined with mutagenesis and functional transcription/apoptosis readouts in one rigorous study\",\n      \"pmids\": [\"10698937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CC3/TIP30 predisposes cells to apoptosis by disrupting mitochondrial membrane potential (ΔΨm). An alternatively spliced product, TC3, which shares the N-terminal domain of CC3 but has a unique hydrophobic C-terminus, has opposing antiapoptotic activity and forms complexes with the s5α regulatory subunit of the proteasome; TC3 is rapidly degraded by the proteasome. The proapoptotic activity of CC3 resides in its N-terminal domain.\",\n      \"method\": \"Overexpression, deletion/mutagenesis of CC3/TC3, cell death assay, mitochondrial membrane potential measurement, co-immunoprecipitation with proteasome subunit, proteasome inhibitor experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain mutagenesis, reconstitution of opposing functional activities, Co-IP with proteasome subunit, multiple orthogonal methods in one study\",\n      \"pmids\": [\"10611237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Expression of CC3/TIP30 in tumor cell lines significantly reduces their angiogenic properties, as measured by inhibition of endothelial cell proliferation and migration in vitro, and alters RNA levels of several angiogenic modulators.\",\n      \"method\": \"Overexpression in tumor cell lines, in vitro endothelial cell proliferation and migration assays, RNA expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss/gain of function with defined cellular phenotype, single lab, two orthogonal readouts\",\n      \"pmids\": [\"11313954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TIP30-deficient (Tip30−/−) mice develop hepatocellular carcinoma and other tumors at higher incidence than wild-type mice, establishing Tip30 as an in vivo tumor susceptibility gene. Loss of TIP30 also enhances susceptibility of fibroblasts to transformation by SV40 large T antigen.\",\n      \"method\": \"Genetically engineered knockout mice, tumor incidence analysis, fibroblast transformation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout model with defined tumor phenotype, replicated across multiple tumor types, fibroblast transformation assay as orthogonal validation\",\n      \"pmids\": [\"14695192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CC3/TIP30 directly binds karyopherins of the importin beta family in a RanGTP-insensitive manner and associates with nucleoporins in vivo. This interaction inhibits nuclear import of proteins bearing classical NLS or M9 signals. A CC3 mutant lacking proapoptotic activity shows lower affinity for transportin, is displaced by RanGTP, and fails to inhibit nuclear import. Inhibition of nuclear import correlates with proapoptotic activity.\",\n      \"method\": \"In vitro nuclear import assay, in vivo nuclear import assay, direct binding assay (pulldown), mutagenesis, RanGTP competition assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro and in vivo import assays, mutagenesis linking binding affinity to function, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15282309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TIP30 interacts with ERα-interacting coactivator CIA; both are dynamically recruited to the c-myc gene promoter and downstream regions in response to estrogen, as shown by chromatin immunoprecipitation. TIP30 overexpression represses ERα-mediated c-myc transcription, while TIP30 deficiency enhances c-myc transcription. Ectopic CIA cooperates with TIP30 to repress ERα-mediated c-myc transcription.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), overexpression/knockout cell assays, TIP30 knockout mouse mammary gland analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP with functional readout, in vivo KO validation, multiple orthogonal methods\",\n      \"pmids\": [\"15073177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of CC3/TIP30 at 1.7-Å resolution reveals a short-chain dehydrogenase/reductase (SDR) fold with binding specificity for NADPH. The protein is monomeric and unlikely to be enzymatically active in the canonical SDR sense. Structural analysis, in conjunction with prior mutagenesis data, suggests NADPH binding is important for biological activity including interaction with importins and the CIA/c-myc system.\",\n      \"method\": \"X-ray crystallography (1.7 Å resolution), structural analysis, NADPH binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with functional inference supported by prior mutagenesis data from multiple labs\",\n      \"pmids\": [\"15728189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TIP30 mutants derived from HCC specimens promote cell growth and invasion while inhibiting cisplatin-induced apoptosis in HepG2 cells negative for endogenous TIP30. One mutant dramatically accelerates tumor formation in immunodeficient mice. Mutant TIP30 upregulates N-cadherin and c-MYC and downregulates p53 and E-cadherin; N-cadherin knockdown in mutant-expressing cells causes profound reduction in cell viability.\",\n      \"method\": \"Overexpression of mutant TIP30, Affymetrix GeneChip array, real-time PCR, Western blotting, siRNA knockdown of N-cadherin, in vivo xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with in vivo validation, gene expression and siRNA rescue, single lab\",\n      \"pmids\": [\"17440068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TIP30 regulates p53 mRNA stability under oxidative stress. Under oxidative conditions, TIP30 forms an intermolecular disulfide bridge (conformational change). TIP30 blocks the nuclear import of the mRNA-binding protein HuR by disrupting HuR–importin β2 association; elevated cytoplasmic HuR then binds the p53 mRNA 3'-UTR, prolonging p53 mRNA half-life and increasing p53 expression and transcriptional activity. TIP30-induced apoptosis and mitochondrial dysfunction are blocked by p53 silencing.\",\n      \"method\": \"Overexpression, siRNA knockdown of p53/HuR, mRNA stability assay, co-immunoprecipitation (HuR–importin β2), disulfide bridge analysis under oxidative stress, antioxidant/oxidant treatment, mitochondrial dysfunction assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mRNA stability, epistasis by siRNA rescue, redox modification), mechanistic chain established in one study\",\n      \"pmids\": [\"18519672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Abnormal overexpression of TIP30 in oligodendrocyte precursor cells (OPCs) in MS lesions traps NICD (Notch1 intracellular domain) and other NLS-bearing proteins with importin in the cytoplasm, blocking nuclear translocation required for myelinogenesis. Overexpression of TIP30 in a rat OPC cell line causes cytoplasmic entrapment of NICD and arrests differentiation upon Contactin-Fc stimulation.\",\n      \"method\": \"Immunohistochemistry in human MS tissue, overexpression in rat OPC cell line, functional differentiation assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human tissue correlative plus in vitro overexpression with functional readout, single lab, mechanism consistent with importin-inhibition finding from PMID 15282309\",\n      \"pmids\": [\"19104151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIP30 forms a protein complex with endophilin B1 and ACSL4 that interacts with Rab5a. This TIP30 complex is required for proper endocytic trafficking of EGF-EGFR. Knockdown of TIP30, ACSL4, endophilin B1, or Rab5a traps EGF-EGFR in early endosomes, causing delayed EGFR degradation and prolonged EGFR signaling. The TIP30 complex facilitates trafficking of Rab5a and V-ATPases from the trans-Golgi network to EEA1-positive early endosomes in response to EGF.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, genetic knockout (Tip30−/− primary hepatocytes), endosomal trafficking assay, colocalization with V-ATPases and EEA1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple independent KD experiments, KO primary cells, multiple functional readouts, mechanistic pathway established\",\n      \"pmids\": [\"21252234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The TIP30 protein complex (TIP30, ACSL4, endophilin B1) facilitates fusion of endocytic vesicles with Rab5a vesicles in vitro. Fusion depends on arachidonic acid, coenzyme A, and arachidonyl-CoA synthesis by ACSL4. The TIP30 complex transfers arachidonyl groups onto phosphatidic acid (PA), producing a lipid species that induces close membrane contact.\",\n      \"method\": \"In vitro vesicle fusion assay, arachidonyl-CoA synthesis assay, lipid transfer assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of membrane fusion with biochemical characterization of lipid modification, single lab\",\n      \"pmids\": [\"21731680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TIP30 loss in lung adenocarcinoma cells results in prolonged EGFR activity in early endosomes, delayed EGFR degradation, and increased EGFR nuclear localization, leading to upregulated pAKT and pERK1/2. Tip30 deletion in mice leads to spontaneous lung adenomas and adenocarcinomas, preceded by aberrant expansion of bronchioalveolar stem/progenitor and AT2 cells and increased EGFR expression.\",\n      \"method\": \"siRNA knockdown, Tip30 knockout mice, endosomal trafficking assay, Western blotting for EGFR signaling, nuclear EGFR localization, mouse tumor pathology\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD in human cells plus in vivo KO mouse model, multiple orthogonal signaling and trafficking readouts, mechanistic link established\",\n      \"pmids\": [\"22733137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sorafenib downregulates HTATIP2 expression in HCC cells via JAK-STAT3 signaling, promoting invasiveness and metastatic potential. HTATIP2 knockdown reduces sorafenib-promoted invasion, while HTATIP2 overexpression enhances it; HTATIP2 expression is associated with sorafenib-induced EMT.\",\n      \"method\": \"PCR arrays, shRNA knockdown, transgenic overexpression, orthotopic mouse model, Western blotting for JAK-STAT3 pathway, EMT marker analysis\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo orthotopic model with genetic manipulation, pathway analysis, single lab\",\n      \"pmids\": [\"22922424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TIP30 directly binds the DNA-binding domain and the C-terminal domain of p53 protein, as demonstrated by GST pull-down assay and surface plasmon resonance.\",\n      \"method\": \"GST pull-down assay, surface plasmon resonance (SPR)\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding assay with two orthogonal methods but single lab, no cellular validation\",\n      \"pmids\": [\"23178973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-10b directly targets TIP30 mRNA (confirmed by luciferase reporter assay with 3'-UTR); miR-10b-mediated suppression of TIP30 enhances EGF-dependent EGFR tyrosine phosphorylation and ERK phosphorylation in pancreatic cancer cells. The effects of miR-10b are abrogated by expressing a modified TIP30 cDNA resistant to miR-10b. TIP30 silencing mimics miR-10b effects on invasion.\",\n      \"method\": \"Luciferase reporter assay, siRNA knockdown, miR-10b overexpression, EGFR/ERK phosphorylation (Western blotting), Matrigel invasion assay, rescue with miR-10b-resistant TIP30\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — luciferase reporter for direct targeting, epistatic rescue experiment, multiple signaling readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24096486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIP30 inhibits EMT and nuclear accumulation of Snail in HCC cells by competitively interrupting the interaction of Snail with importin-β2, thereby blocking Snail nuclear import. Small interfering RNAs targeting Snail attenuate the EMT and tumor-initiating properties induced by TIP30 deficiency.\",\n      \"method\": \"Overexpression/knockdown, Co-immunoprecipitation (TIP30–importin-β2–Snail complex), nuclear fractionation, siRNA epistasis, in vitro and in vivo invasion/EMT assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of ternary complex, siRNA epistasis, multiple functional readouts, mechanistic pathway well-defined\",\n      \"pmids\": [\"24681951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIP30 translocates to the nucleus of lung adenocarcinoma cells in response to EGF treatment (via EGFR signaling); nuclear TIP30 negatively regulates EGF-dependent transcriptional activation of CCND1 (cyclin D1) through an HDAC1-dependent mechanism, as demonstrated by chromatin immunoprecipitation.\",\n      \"method\": \"Nuclear fractionation/localization, EGFR pathway inhibitor treatment, chromatin immunoprecipitation (ChIP), gene expression analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional readout, pharmacological epistasis, single lab\",\n      \"pmids\": [\"25135222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIP30 inhibits oligodendrocyte precursor cell (OPC) differentiation by sequestering the transcription factor Olig1 in the cytoplasm via direct interaction with Olig1, preventing its nuclear translocation. Overexpression of TIP30 sequesters Olig1 in the cytoplasm; knockdown of TIP30 increases nuclear Olig1 and enhances OPC differentiation. Tip30−/− mice display increased myelin protein levels at postnatal days 14 and 21.\",\n      \"method\": \"Primary OPC culture, overexpression and siRNA knockdown, Co-immunoprecipitation (TIP30–Olig1), nuclear/cytoplasmic fractionation, Tip30−/− mice, cuprizone demyelination model\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of TIP30-Olig1 complex, KO mice with phenotype, primary cell KD and OE with functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"25530119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TGF-β1 induces epigenetic silencing of TIP30 promoter via DNMT1 and DNMT3A upregulation (hypermethylation), reducing TIP30 expression during EMT. TIP30 silencing activates nuclear translocation and transcriptional activation of β-catenin in an AKT-dependent manner, promoting EMT in esophageal carcinoma cells.\",\n      \"method\": \"Promoter methylation analysis, DNMT knockdown/overexpression, Western blotting for AKT/β-catenin signaling, nuclear fractionation, in vitro and in vivo invasion assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic writer identified (DNMT1/3A), AKT/β-catenin pathway epistasis, single lab\",\n      \"pmids\": [\"25544767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIP30 deficiency activates the Akt/mTOR signaling pathway, leading to upregulation and nuclear accumulation of SREBP1, which promotes transcription of lipogenesis genes (fasn, scd) and elevated fatty acid synthesis in HCC cells. siRNA targeting SREBP1 reverses the fatty acid synthesis induced by TIP30 deficiency.\",\n      \"method\": \"siRNA knockdown, Western blotting for Akt/mTOR/SREBP1 signaling, nuclear fractionation, fatty acid synthesis assay, siRNA epistasis\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis via siRNA, signaling readouts, single lab with multiple methods\",\n      \"pmids\": [\"28604762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HIV-1 Tat protein interacts with TIP30 and blocks TIP30's binding to importin-β, thereby preventing TIP30-mediated inhibition of Snail nuclear import in lung cancer cells. Loss of TIP30-importin-β interaction (via Tat) increases nuclear Snail, promoting EMT and invasion.\",\n      \"method\": \"Co-immunoprecipitation (Tat–TIP30–importin-β), nuclear fractionation of Snail, overexpression, in vivo metastasis assay, immunohistochemistry\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating competitive binding, functional epistasis, single lab\",\n      \"pmids\": [\"30099830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TIP30 binds eukaryotic elongation factor 1A (eEF1A) and prevents its interaction with co-factor eEF1B2, thereby inhibiting translational elongation and cardiac protein synthesis. Therapeutic overexpression of TIP30 in mouse hearts inhibits cardiac hypertrophy and improves left ventricular function during pressure overload and in mdx cardiomyopathic mice. Reduced TIP30 in Tip30-reduced mice leads to exaggerated cardiac growth and dysfunction during pressure overload; pharmacological inhibition of protein synthesis rescues these defects.\",\n      \"method\": \"Co-immunoprecipitation (TIP30–eEF1A), eEF1A–eEF1B2 interaction assay, in vivo cardiac-specific overexpression and KO mouse models, protein synthesis measurement, pressure-overload model, pharmacological inhibition rescue\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of TIP30-eEF1A complex with functional disruption of eEF1B2 binding, in vivo KO and overexpression models with mechanistic pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"31468715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Epigenetic silencing of HTATIP2 in glioblastoma leads to enhanced nuclear localization of the base excision repair enzyme MPG (N-methylpurine DNA glycosylase). Induction of HTATIP2 expression shifts MPG from nuclear to cytoplasmic, while depletion of endogenous HTATIP2 increases nuclear MPG. Reduced nuclear MPG (via HTATIP2 induction or MPG depletion) yields fewer phospho-H2AX-positive cells upon alkylating agent treatment, indicating reduced BER capacity and fewer AP sites.\",\n      \"method\": \"HTATIP2 induction/knockdown, nuclear/cytoplasmic fractionation for MPG, phospho-H2AX assay after alkylating agent treatment, MPG knockdown epistasis\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — HTATIP2 gain and loss of function with localization readout and functional DNA damage assay, siRNA epistasis, single lab\",\n      \"pmids\": [\"37491696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Increased HTATIP2 expression in proarteriogenic monocytes/macrophages from patients with chronic limb-threatening ischemia (CLTI) impairs their arteriogenic capacity. Silencing HTATIP2 in CLTI monocytes/macrophages restores expression of arteriogenic regulators Neuropilin-1 and Angiopoietin-1 and rescues their capacity to enhance angiogenic and arteriogenic processes in vitro and limb perfusion in vivo.\",\n      \"method\": \"siRNA knockdown in primary patient-derived monocytes/macrophages, endothelial tubule formation assay, smooth muscle proliferation assay, hindlimb ischemia in vivo model, Western blotting\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD in primary human cells with in vivo rescue, multiple functional readouts, single lab\",\n      \"pmids\": [\"37847559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Silencing of CC3/TIP30 expression strongly improves tumor cell survival under glucose limitation, enabling superior metabolic adaptation. CC3-silenced HeLa cells maintain higher mitochondrial respiration, higher expression of mitochondrial respiratory complex proteins, higher c-MYC and PKM2 (M2 isoform of pyruvate kinase) in low glucose, and fail to fully activate AMPK in response to glucose limitation. Pharmacological or siRNA inhibition of AMPK similarly protects control HeLa cells from glucose-limitation-induced death.\",\n      \"method\": \"siRNA knockdown of CC3, cell survival assay under glucose limitation, mitochondrial respiration measurement, Western blotting, AMPK pharmacological and siRNA inhibition\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with functional metabolic readouts, pharmacological and siRNA epistasis for AMPK, single lab\",\n      \"pmids\": [\"21150275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Forced expression of CC3/TIP30 in CC3-negative cells strongly delays repair of UV-induced DNA damage, negatively affects expression of DDB2/XPE and p21CIP1, and inhibits nuclear accumulation of p21CIP1 after UV. Silencing endogenous CC3 significantly reduces translesion DNA synthesis after UV. CC3 expression also inhibits repair of oxidative DNA damage and decreases nucleoredoxin levels.\",\n      \"method\": \"Overexpression, siRNA knockdown, UV-induced DNA damage repair assay, Western blotting for DDB2/p21, nuclear fractionation, oxidative damage repair assay\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function with functional DNA repair readout, multiple DNA damage contexts tested, single lab\",\n      \"pmids\": [\"20374651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TIP30 modulates mTORC1 signaling during CVB3 infection in HeLa cells. TIP30 overexpression mitigates CVB3-induced cellular pathogenesis; rapamycin (mTOR1 inhibitor) reverses these protective effects, indicating TIP30 acts upstream of mTORC1. TIP30-knockout mice show heightened heart virus titers and cardiac damage after CVB3 infection.\",\n      \"method\": \"TIP30 lentiviral overexpression, TIP30 knockout mice, rapamycin pharmacological epistasis, viral titer assay, Western blotting for mTORC1 pathway\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with in vivo phenotype, in vitro overexpression with pharmacological epistasis, single lab\",\n      \"pmids\": [\"38981316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Human TIP30 functionally complements yeast Fmp52 (a short-chain dehydrogenase/reductase at the ER) in protecting against lipid-induced apoptosis triggered by the sphingolipid-derived fatty aldehyde t-2-hex, indicating an evolutionarily conserved protective role for TIP30 at the ER against lipid-mediated cytotoxicity.\",\n      \"method\": \"Functional complementation in yeast (Fmp52 deletion rescued by human TIP30 expression), yeast apoptosis assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single complementation experiment in yeast, preprint, no mammalian validation\",\n      \"pmids\": [\"bio_10.1101_2025.12.01.691522\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"HTATIP2/TIP30/CC3 is a multifunctional tumor and metastasis suppressor that (1) acts as an NADPH-binding SDR-fold protein (crystal structure resolved) with intrinsic serine/threonine kinase activity that phosphorylates the RNA Pol II CTD in a Tat-dependent manner to coactivate HIV-1 Tat-driven transcription; (2) inhibits nucleocytoplasmic transport by binding importin-β family members in a RanGTP-insensitive manner, thereby trapping nuclear cargo proteins (NICD, Snail, HuR, MPG) in the cytoplasm—a mechanism linked to its proapoptotic, anti-metastatic, and DNA-repair-modulatory activities; (3) forms a complex with endophilin B1 and ACSL4 that interacts with Rab5a to facilitate V-ATPase delivery to early endosomes and EGFR endocytic degradation, suppressing sustained EGFR/AKT/ERK signaling; (4) stabilizes p53 mRNA under oxidative stress by blocking HuR nuclear import; (5) represses ERα-mediated c-myc transcription via CIA coactivator interaction; (6) inhibits translational elongation by binding eEF1A and preventing its interaction with eEF1B2, thereby counteracting cardiac hypertrophy; and (7) suppresses lipid synthesis through the AKT/mTOR/SREBP1 axis, with its loss in Tip30−/− mice causing spontaneous hepatocellular carcinoma, lung adenocarcinoma, and mammary hyperplasia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HTATIP2 (TIP30/CC3) is a multifunctional tumor and metastasis suppressor whose loss in knockout mice causes spontaneous hepatocellular carcinoma, lung adenocarcinoma, and enhanced tumor susceptibility [#4, #13]. Structurally it adopts a short-chain dehydrogenase/reductase (SDR) fold that binds NADPH but is monomeric and likely catalytically inert in the canonical SDR sense, with NADPH binding instead supporting its protein-interaction functions [#7]. A central mechanism is inhibition of nucleocytoplasmic transport: TIP30 binds importin-\\u03b2 family karyopherins in a RanGTP-insensitive manner and blocks nuclear import of NLS- and M9-bearing cargo, an activity tightly coupled to its proapoptotic action [#5]. Through this transport-blocking activity it sequesters multiple cargoes in the cytoplasm \\u2014 it disrupts HuR\\u2013importin-\\u03b22 association to stabilize p53 mRNA under oxidative stress [#9], competitively blocks Snail nuclear import to suppress EMT [#17], and traps NICD and Olig1 in oligodendrocyte precursors to restrain differentiation [#10, #19]. TIP30 also assembles with endophilin B1 and ACSL4 into a Rab5a-interacting complex that delivers V-ATPases to early endosomes and drives EGF-EGFR endocytic degradation, thereby limiting sustained EGFR/AKT/ERK signaling; loss of this function prolongs EGFR signaling and promotes tumorigenesis [#11, #12, #13]. Additional regulatory outputs include repression of ER\\u03b1-mediated c-myc transcription via the CIA coactivator [#6], restraint of lipogenesis through the AKT/mTOR/SREBP1 axis [#21], and inhibition of translational elongation by binding eEF1A and preventing eEF1B2 engagement to counteract cardiac hypertrophy [#23]. The protein was originally identified as a Tat-dependent coactivator that interacts with an RNA Pol II complex and exhibits intrinsic serine/threonine kinase activity toward the Pol II CTD [#0, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the founding molecular role of TIP30 as a specific coactivator required for HIV-1 Tat-dependent transcription, distinguishing it from general transcription machinery.\",\n      \"evidence\": \"Co-IP in vivo and in vitro plus immunodepletion with transcription readout in nuclear extracts\",\n      \"pmids\": [\"9482853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the catalytic or structural basis of coactivation\", \"Tat-independent functions unaddressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Assigned an intrinsic serine/threonine kinase activity to TIP30 acting on the Pol II CTD and linked this activity to both transcription enhancement and apoptosis sensitization, while implicating it in apoptotic and metastasis-suppressor gene programs.\",\n      \"evidence\": \"In vitro kinase assay with ATP-binding-motif mutagenesis and gene expression profiling\",\n      \"pmids\": [\"10698937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase identity later complicated by the SDR-fold structure\", \"Direct CTD substrate role in vivo not established\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Localized the proapoptotic activity to the CC3 N-terminal domain and revealed an antiapoptotic splice variant (TC3) that binds the proteasome, showing functional output depends on isoform and domain structure.\",\n      \"evidence\": \"Domain mutagenesis, mitochondrial membrane potential assays, Co-IP with proteasome subunit\",\n      \"pmids\": [\"10611237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting N-terminus to mitochondrial disruption unclear\", \"Physiological abundance of TC3 not quantified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected TIP30 expression to suppression of tumor angiogenesis, broadening its role beyond transcription/apoptosis to the tumor microenvironment.\",\n      \"evidence\": \"Overexpression in tumor lines with endothelial proliferation/migration assays and RNA profiling\",\n      \"pmids\": [\"11313954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mediators of angiogenic modulation not pinned down\", \"Single-lab in vitro readouts\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided in vivo proof that Tip30 is a tumor susceptibility gene by showing knockout mice develop tumors and that loss potentiates oncogenic transformation.\",\n      \"evidence\": \"Tip30\\u2212/\\u2212 knockout mice tumor incidence and SV40 large T fibroblast transformation assay\",\n      \"pmids\": [\"14695192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal molecular pathway underlying tumor suppression not defined here\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined a core biochemical mechanism: RanGTP-insensitive binding to importin-\\u03b2 karyopherins that blocks nuclear import, and tied import inhibition directly to proapoptotic function.\",\n      \"evidence\": \"In vitro and in vivo nuclear import assays, direct binding, mutagenesis and RanGTP competition\",\n      \"pmids\": [\"15282309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which physiological cargoes are most affected not yet identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified a transcriptional repressor role at the c-myc promoter via the CIA coactivator, linking TIP30 to estrogen-driven proliferation control.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, overexpression/knockout cells, KO mouse mammary analysis\",\n      \"pmids\": [\"15073177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CIA cooperativity in repression not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the protein fold, revealing an SDR architecture that binds NADPH but is monomeric and likely non-catalytic, reframing the earlier kinase claim and grounding NADPH-dependent protein interactions.\",\n      \"evidence\": \"1.7-\\u00c5 X-ray crystal structure with NADPH binding and structural analysis\",\n      \"pmids\": [\"15728189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with reported kinase activity unresolved\", \"Role of NADPH in import inhibition inferred, not directly shown structurally\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Elucidated a redox-sensitive cargo-trapping mechanism: under oxidative stress TIP30 blocks HuR import, raising cytoplasmic HuR to stabilize p53 mRNA and drive apoptosis.\",\n      \"evidence\": \"Co-IP, mRNA stability assays, siRNA epistasis, disulfide-bridge analysis under oxidants\",\n      \"pmids\": [\"18519672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the oxidation-induced disulfide conformational switch not detailed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended import-trapping to a developmental context, showing pathological TIP30 overexpression sequesters NICD to block oligodendrocyte differentiation and myelinogenesis.\",\n      \"evidence\": \"MS tissue immunohistochemistry plus rat OPC overexpression with differentiation assay\",\n      \"pmids\": [\"19104151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative human tissue data; causal contribution to MS not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined a distinct membrane-trafficking function: a TIP30\\u2013endophilin B1\\u2013ACSL4 complex interacts with Rab5a to deliver V-ATPases to early endosomes and promote EGFR endocytic degradation.\",\n      \"evidence\": \"Reciprocal Co-IP, multiple siRNA knockdowns, KO primary hepatocytes, trafficking and colocalization assays\",\n      \"pmids\": [\"21252234\", \"21731680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NADPH/SDR fold contributes to the trafficking complex unclear\", \"Lipid-transfer chemistry characterized only in vitro\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Tied loss of the EGFR-degradation function to lung tumorigenesis, showing TIP30 loss prolongs EGFR activity, increases nuclear EGFR, and elevates AKT/ERK signaling with stem/progenitor expansion in vivo.\",\n      \"evidence\": \"siRNA knockdown, Tip30 KO mice tumor pathology, signaling and trafficking readouts\",\n      \"pmids\": [\"22733137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between nuclear EGFR and transcriptional output not fully mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified upstream regulation showing sorafenib suppresses HTATIP2 via JAK-STAT3 to paradoxically promote invasion, and demonstrated direct TIP30\\u2013p53 protein binding.\",\n      \"evidence\": \"PCR arrays, shRNA/overexpression, orthotopic model, JAK-STAT3 analysis; GST pulldown and SPR for p53 binding\",\n      \"pmids\": [\"22922424\", \"23178973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TIP30\\u2013p53 binding shown only in vitro without cellular validation\", \"Context-dependent pro-invasive vs suppressor roles unreconciled\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established miR-10b as a direct upstream repressor of TIP30, linking microRNA-mediated TIP30 loss to enhanced EGFR/ERK signaling and invasion in pancreatic cancer.\",\n      \"evidence\": \"Luciferase 3'-UTR reporter, miR-10b overexpression, miR-resistant TIP30 rescue, invasion assays\",\n      \"pmids\": [\"24096486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether miR-10b acts mainly through EGFR trafficking versus other TIP30 functions not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated TIP30 blocks EMT by competitively disrupting Snail\\u2013importin-\\u03b22 binding, integrating cargo-trapping with metastasis suppression.\",\n      \"evidence\": \"Ternary-complex Co-IP, nuclear fractionation, siRNA epistasis, in vitro/in vivo invasion assays\",\n      \"pmids\": [\"24681951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative competition between cargoes for importin-\\u03b22 not characterized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed an EGF-induced nuclear pool of TIP30 that represses cyclin D1 transcription via HDAC1, and a cytoplasmic Olig1-sequestering role controlling myelination.\",\n      \"evidence\": \"Nuclear fractionation and ChIP for CCND1/HDAC1; Co-IP, fractionation, KO mice and cuprizone model for Olig1\",\n      \"pmids\": [\"25135222\", \"25530119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal driving TIP30 nuclear entry versus cytoplasmic retention not fully defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed TIP30 in an epigenetic feedback loop where TGF-\\u03b21-driven DNMT-mediated promoter silencing of TIP30 activates AKT-dependent \\u03b2-catenin nuclear translocation to promote EMT.\",\n      \"evidence\": \"Promoter methylation analysis, DNMT manipulation, AKT/\\u03b2-catenin signaling and invasion assays\",\n      \"pmids\": [\"25544767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect control of \\u03b2-catenin by TIP30 not separated\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected TIP30 loss to metabolic reprogramming, showing AKT/mTOR-dependent SREBP1 activation drives lipogenesis upon TIP30 deficiency.\",\n      \"evidence\": \"siRNA knockdown, AKT/mTOR/SREBP1 signaling readouts, fatty acid synthesis assay, SREBP1 epistasis\",\n      \"pmids\": [\"28604762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TIP30 acts directly on AKT/mTOR or via EGFR trafficking unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed HIV-1 Tat antagonizes TIP30 by blocking its importin-\\u03b2 binding, de-repressing Snail import and promoting EMT, mechanistically linking the original Tat partner to the transport-inhibition function.\",\n      \"evidence\": \"Tat\\u2013TIP30\\u2013importin-\\u03b2 Co-IP, Snail fractionation, in vivo metastasis and immunohistochemistry\",\n      \"pmids\": [\"30099830\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance outside HIV infection context not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a translational-control function whereby TIP30 binds eEF1A to block eEF1B2 engagement and limit protein synthesis, providing a therapeutic mechanism against cardiac hypertrophy.\",\n      \"evidence\": \"Co-IP, eEF1A\\u2013eEF1B2 interaction assays, cardiac KO/overexpression mice, pressure-overload model with pharmacological rescue\",\n      \"pmids\": [\"31468715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether elongation control operates in tumor contexts not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended cargo-trapping to DNA repair, showing HTATIP2 controls nuclear versus cytoplasmic localization of the BER glycosylase MPG and thereby modulates BER capacity under alkylation stress.\",\n      \"evidence\": \"HTATIP2 induction/knockdown, MPG fractionation, phospho-H2AX assay, MPG epistasis in glioblastoma cells\",\n      \"pmids\": [\"37491696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MPG transport depends on the importin-\\u03b2 mechanism not directly shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated HTATIP2 in vascular biology, showing elevated levels in CLTI monocytes/macrophages impair arteriogenesis and silencing restores arteriogenic capacity.\",\n      \"evidence\": \"siRNA in primary patient cells, tubule/smooth muscle assays, hindlimb ischemia in vivo rescue\",\n      \"pmids\": [\"37847559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target linking HTATIP2 to Neuropilin-1/Angiopoietin-1 unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed TIP30 influences metabolic stress survival and DNA repair, with loss enhancing survival under glucose limitation via AMPK and TIP30 expression impairing UV/oxidative damage repair.\",\n      \"evidence\": \"siRNA knockdown, glucose-limitation survival and respiration assays, AMPK epistasis; UV/oxidative repair and translesion synthesis assays\",\n      \"pmids\": [\"21150275\", \"20374651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets in AMPK and repair pathways not defined\", \"Single-lab readouts\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified an antiviral role where TIP30 acts upstream of mTORC1 to mitigate CVB3 pathogenesis, with KO mice showing worse cardiac infection.\",\n      \"evidence\": \"Lentiviral overexpression, KO mice, rapamycin pharmacological epistasis, viral titer and mTORC1 signaling\",\n      \"pmids\": [\"38981316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between TIP30 and mTORC1 regulation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Suggested an evolutionarily conserved ER-protective function against lipid-derived fatty aldehyde cytotoxicity via complementation of yeast Fmp52.\",\n      \"evidence\": \"Functional complementation in yeast Fmp52-deletion apoptosis assay (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.12.01.691522\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single complementation experiment in yeast, no mammalian validation\", \"ER localization of human TIP30 not demonstrated here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the SDR/NADPH-binding fold mechanistically integrates TIP30's diverse activities \\u2014 importin-\\u03b2 binding, endosomal lipid transfer, eEF1A binding, and the originally reported CTD kinase activity \\u2014 into a unified biochemical function remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of TIP30 bound to importin-\\u03b2 or any cargo-competing partner\", \"Reconciliation of reported kinase activity with the non-catalytic SDR fold unresolved\", \"Mechanistic basis for cargo selectivity among many trapped proteins unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 9, 17, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 17, 23]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 6, 18]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 17, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6, 18]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [11, 13]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 13, 16, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [5, 9, 17, 19, 24]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [11, 12, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 8, 13, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"complexes\": [\n      \"TIP30\\u2013endophilin B1\\u2013ACSL4 complex\"\n    ],\n    \"partners\": [\n      \"importin-\\u03b2\",\n      \"HuR\",\n      \"Snail\",\n      \"Olig1\",\n      \"eEF1A\",\n      \"SH3GLB1\",\n      \"ACSL4\",\n      \"RAB5A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}