Affinage

HTATIP2

Protein HTATIP2 · UniProt Q9BUP3

Length
242 aa
Mass
27.0 kDa
Annotated
2026-06-10
83 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1998 High

    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

    PMID:9482853

    Open questions at the time
    • Did not define the catalytic or structural basis of coactivation
    • Tat-independent functions unaddressed
  2. 2000 High

    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

    PMID:10698937

    Open questions at the time
    • Kinase identity later complicated by the SDR-fold structure
    • Direct CTD substrate role in vivo not established
  3. 2000 High

    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

    PMID:10611237

    Open questions at the time
    • Mechanism connecting N-terminus to mitochondrial disruption unclear
    • Physiological abundance of TC3 not quantified
  4. 2001 Medium

    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

    PMID:11313954

    Open questions at the time
    • Molecular mediators of angiogenic modulation not pinned down
    • Single-lab in vitro readouts
  5. 2003 High

    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

    PMID:14695192

    Open questions at the time
    • Causal molecular pathway underlying tumor suppression not defined here
  6. 2004 High

    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

    PMID:15282309

    Open questions at the time
    • Which physiological cargoes are most affected not yet identified
  7. 2004 High

    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

    PMID:15073177

    Open questions at the time
    • Mechanism of CIA cooperativity in repression not resolved
  8. 2005 High

    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

    PMID:15728189

    Open questions at the time
    • Reconciliation with reported kinase activity unresolved
    • Role of NADPH in import inhibition inferred, not directly shown structurally
  9. 2008 High

    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

    PMID:18519672

    Open questions at the time
    • Structural basis of the oxidation-induced disulfide conformational switch not detailed
  10. 2008 Medium

    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

    PMID:19104151

    Open questions at the time
    • Correlative human tissue data; causal contribution to MS not established
  11. 2011 High

    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

    PMID:21252234 PMID:21731680

    Open questions at the time
    • How NADPH/SDR fold contributes to the trafficking complex unclear
    • Lipid-transfer chemistry characterized only in vitro
  12. 2012 High

    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

    PMID:22733137

    Open questions at the time
    • Direct link between nuclear EGFR and transcriptional output not fully mapped
  13. 2012 Medium

    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

    PMID:22922424 PMID:23178973

    Open questions at the time
    • TIP30–p53 binding shown only in vitro without cellular validation
    • Context-dependent pro-invasive vs suppressor roles unreconciled
  14. 2013 High

    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

    PMID:24096486

    Open questions at the time
    • Whether miR-10b acts mainly through EGFR trafficking versus other TIP30 functions not separated
  15. 2014 High

    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

    PMID:24681951

    Open questions at the time
    • Quantitative competition between cargoes for importin-β2 not characterized
  16. 2014 High

    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

    PMID:25135222 PMID:25530119

    Open questions at the time
    • Signal driving TIP30 nuclear entry versus cytoplasmic retention not fully defined
  17. 2015 Medium

    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

    PMID:25544767

    Open questions at the time
    • Direct versus indirect control of β-catenin by TIP30 not separated
    • Single-lab data
  18. 2017 Medium

    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

    PMID:28604762

    Open questions at the time
    • Whether TIP30 acts directly on AKT/mTOR or via EGFR trafficking unresolved
  19. 2018 Medium

    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

    PMID:30099830

    Open questions at the time
    • Physiological relevance outside HIV infection context not established
  20. 2019 High

    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

    PMID:31468715

    Open questions at the time
    • Whether elongation control operates in tumor contexts not tested
  21. 2023 Medium

    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

    PMID:37491696

    Open questions at the time
    • Whether MPG transport depends on the importin-β mechanism not directly shown
  22. 2023 Medium

    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

    PMID:37847559

    Open questions at the time
    • Molecular target linking HTATIP2 to Neuropilin-1/Angiopoietin-1 unknown
  23. 2010 Medium

    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

    PMID:20374651 PMID:21150275

    Open questions at the time
    • Direct molecular targets in AMPK and repair pathways not defined
    • Single-lab readouts
  24. 2024 Medium

    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

    PMID:38981316

    Open questions at the time
    • Direct molecular link between TIP30 and mTORC1 regulation unclear
  25. 2025 Low

    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)

    PMID:bio_10.1101_2025.12.01.691522

    Open questions at the time
    • Single complementation experiment in yeast, no mammalian validation
    • ER localization of human TIP30 not demonstrated here

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 3 GO:0045182 translation regulator activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005739 mitochondrion 2 GO:0005768 endosome 2
Pathway
R-HSA-9609507 Protein localization 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-392499 Metabolism of proteins 1
Partners
ACSL4EEF1AHURIMPORTIN-ΒOLIG1RAB5ASH3GLB1SNAIL
Complex memberships
TIP30–endophilin B1–ACSL4 complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. Co-immunoprecipitation (in vivo and in vitro), immunodepletion from nuclear extracts, transfection-based transcription assay Proceedings of the National Academy of Sciences of the United States of America High 9482853
2000 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. In vitro kinase assay, active-site mutagenesis, transfection-based transcription assay, gene expression profiling The EMBO journal High 10698937
2000 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. Overexpression, deletion/mutagenesis of CC3/TC3, cell death assay, mitochondrial membrane potential measurement, co-immunoprecipitation with proteasome subunit, proteasome inhibitor experiments Molecular and cellular biology High 10611237
2001 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. Overexpression in tumor cell lines, in vitro endothelial cell proliferation and migration assays, RNA expression analysis Oncogene Medium 11313954
2003 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. Genetically engineered knockout mice, tumor incidence analysis, fibroblast transformation assay Cancer research High 14695192
2004 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. In vitro nuclear import assay, in vivo nuclear import assay, direct binding assay (pulldown), mutagenesis, RanGTP competition assay Molecular and cellular biology High 15282309
2004 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. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), overexpression/knockout cell assays, TIP30 knockout mouse mammary gland analysis The Journal of biological chemistry High 15073177
2005 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. X-ray crystallography (1.7 Å resolution), structural analysis, NADPH binding The Journal of biological chemistry High 15728189
2007 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. Overexpression of mutant TIP30, Affymetrix GeneChip array, real-time PCR, Western blotting, siRNA knockdown of N-cadherin, in vivo xenograft Cancer research Medium 17440068
2008 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. 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 Cancer research High 18519672
2008 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. Immunohistochemistry in human MS tissue, overexpression in rat OPC cell line, functional differentiation assay The Journal of clinical investigation Medium 19104151
2011 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. Co-immunoprecipitation, siRNA knockdown, genetic knockout (Tip30−/− primary hepatocytes), endosomal trafficking assay, colocalization with V-ATPases and EEA1 The Journal of biological chemistry High 21252234
2011 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. In vitro vesicle fusion assay, arachidonyl-CoA synthesis assay, lipid transfer assay PloS one High 21731680
2012 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. siRNA knockdown, Tip30 knockout mice, endosomal trafficking assay, Western blotting for EGFR signaling, nuclear EGFR localization, mouse tumor pathology Oncogene High 22733137
2012 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. PCR arrays, shRNA knockdown, transgenic overexpression, orthotopic mouse model, Western blotting for JAK-STAT3 pathway, EMT marker analysis Gastroenterology Medium 22922424
2012 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. GST pull-down assay, surface plasmon resonance (SPR) Molecules and cells Medium 23178973
2013 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. Luciferase reporter assay, siRNA knockdown, miR-10b overexpression, EGFR/ERK phosphorylation (Western blotting), Matrigel invasion assay, rescue with miR-10b-resistant TIP30 Oncogene High 24096486
2014 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. Overexpression/knockdown, Co-immunoprecipitation (TIP30–importin-β2–Snail complex), nuclear fractionation, siRNA epistasis, in vitro and in vivo invasion/EMT assays Oncogene High 24681951
2014 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. Nuclear fractionation/localization, EGFR pathway inhibitor treatment, chromatin immunoprecipitation (ChIP), gene expression analysis Cancer letters Medium 25135222
2014 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. Primary OPC culture, overexpression and siRNA knockdown, Co-immunoprecipitation (TIP30–Olig1), nuclear/cytoplasmic fractionation, Tip30−/− mice, cuprizone demyelination model Glia High 25530119
2015 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. Promoter methylation analysis, DNMT knockdown/overexpression, Western blotting for AKT/β-catenin signaling, nuclear fractionation, in vitro and in vivo invasion assays Oncotarget Medium 25544767
2017 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. siRNA knockdown, Western blotting for Akt/mTOR/SREBP1 signaling, nuclear fractionation, fatty acid synthesis assay, siRNA epistasis Oncogenesis Medium 28604762
2018 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. Co-immunoprecipitation (Tat–TIP30–importin-β), nuclear fractionation of Snail, overexpression, in vivo metastasis assay, immunohistochemistry Cancer science Medium 30099830
2019 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. 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 EMBO molecular medicine High 31468715
2023 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. HTATIP2 induction/knockdown, nuclear/cytoplasmic fractionation for MPG, phospho-H2AX assay after alkylating agent treatment, MPG knockdown epistasis Molecular oncology Medium 37491696
2023 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. siRNA knockdown in primary patient-derived monocytes/macrophages, endothelial tubule formation assay, smooth muscle proliferation assay, hindlimb ischemia in vivo model, Western blotting JCI insight Medium 37847559
2010 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. siRNA knockdown of CC3, cell survival assay under glucose limitation, mitochondrial respiration measurement, Western blotting, AMPK pharmacological and siRNA inhibition Cell cycle (Georgetown, Tex.) Medium 21150275
2010 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. Overexpression, siRNA knockdown, UV-induced DNA damage repair assay, Western blotting for DDB2/p21, nuclear fractionation, oxidative damage repair assay BMC cell biology Medium 20374651
2024 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. TIP30 lentiviral overexpression, TIP30 knockout mice, rapamycin pharmacological epistasis, viral titer assay, Western blotting for mTORC1 pathway Virology Medium 38981316
2025 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. Functional complementation in yeast (Fmp52 deletion rescued by human TIP30 expression), yeast apoptosis assay bioRxivpreprint Low bio_10.1101_2025.12.01.691522

Source papers

Stage 0 corpus · 83 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-β actions. Oncogene 127 24096486
2008 Abnormal expression of TIP30 and arrested nucleocytoplasmic transport within oligodendrocyte precursor cells in multiple sclerosis. The Journal of clinical investigation 90 19104151
2012 Sorafenib down-regulates expression of HTATIP2 to promote invasiveness and metastasis of orthotopic hepatocellular carcinoma tumors in mice. Gastroenterology 87 22922424
2000 TIP30 has an intrinsic kinase activity required for up-regulation of a subset of apoptotic genes. The EMBO journal 84 10698937
2003 TIP30 deficiency increases susceptibility to tumorigenesis. Cancer research 79 14695192
1998 A cofactor, TIP30, specifically enhances HIV-1 Tat-activated transcription. Proceedings of the National Academy of Sciences of the United States of America 73 9482853
2004 TIP30 interacts with an estrogen receptor alpha-interacting coactivator CIA and regulates c-myc transcription. The Journal of biological chemistry 67 15073177
2009 Decreased TIP30 expression promotes tumor metastasis in lung cancer. The American journal of pathology 59 19349353
2008 TIP30 induces apoptosis under oxidative stress through stabilization of p53 messenger RNA in human hepatocellular carcinoma. Cancer research 59 18519672
2015 Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation. Proceedings of the National Academy of Sciences of the United States of America 55 25918394
2001 Metastasis suppressor CC3 inhibits angiogenic properties of tumor cells in vitro. Oncogene 50 11313954
2011 A novel TIP30 protein complex regulates EGF receptor signaling and endocytic degradation. The Journal of biological chemistry 48 21252234
2004 Inhibition of nuclear import by the proapoptotic protein CC3. Molecular and cellular biology 46 15282309
2017 TIP30 regulates lipid metabolism in hepatocellular carcinoma by regulating SREBP1 through the Akt/mTOR signaling pathway. Oncogenesis 44 28604762
2006 TIP30/CC3 expression in breast carcinoma: relation to metastasis, clinicopathologic parameters, and P53 expression. Human pathology 44 17097132
2013 Aspirin minimized the pro-metastasis effect of sorafenib and improved survival by up-regulating HTATIP2 in hepatocellular carcinoma. PloS one 42 23741443
2015 MicroRNA-10b Induces Vascular Muscle Cell Proliferation Through Akt Pathway by Targeting TIP30. Current vascular pharmacology 41 25612666
2006 TIP30 inhibits growth of HCC cell lines and inhibits HCC xenografts in mice in combination with 5-FU. Hepatology (Baltimore, Md.) 39 16799960
2012 TIP30 loss enhances cytoplasmic and nuclear EGFR signaling and promotes lung adenocarcinogenesis in mice. Oncogene 38 22733137
2010 CC3/TIP30 regulates metabolic adaptation of tumor cells to glucose limitation. Cell cycle (Georgetown, Tex.) 35 21150275
2016 Metformin inhibits the prometastatic effect of sorafenib in hepatocellular carcinoma by upregulating the expression of TIP30. Cancer science 33 26752068
2014 Decreased TIP30 promotes Snail-mediated epithelial-mesenchymal transition and tumor-initiating properties in hepatocellular carcinoma. Oncogene 33 24681951
2000 Alternatively spliced products CC3 and TC3 have opposing effects on apoptosis. Molecular and cellular biology 32 10611237
1991 Monoclonal antibody CC-3 recognizes phosphoproteins in interphase and mitotic cells. Experimental cell research 30 2055264
2007 TIP30 mutant derived from hepatocellular carcinoma specimens promotes growth of HepG2 cells through up-regulation of N-cadherin. Cancer research 29 17440068
2005 Crystal structure of CC3 (TIP30): implications for its role as a tumor suppressor. The Journal of biological chemistry 28 15728189
2015 TGF-β1 induces epigenetic silence of TIP30 to promote tumor metastasis in esophageal carcinoma. Oncotarget 27 25544767
2004 Multisite phosphorylation of Pin1-associated mitotic phosphoproteins revealed by monoclonal antibodies MPM-2 and CC-3. BMC cell biology 26 15171797
2019 TIP30 counteracts cardiac hypertrophy and failure by inhibiting translational elongation. EMBO molecular medicine 25 31468715
2009 Expression of TIP30 tumor suppressor gene is down-regulated in human colorectal carcinoma. Digestive diseases and sciences 25 19798571
2000 Three-dimensional model of human TIP30, a coactivator for HIV-1 Tat-activated transcription, and CC3, a protein associated with metastasis suppression. Cellular and molecular life sciences : CMLS 25 10892349
2016 Lnc-CC3 increases metastasis in cervical cancer by increasing Slug expression. Oncotarget 24 27223436
2007 Deletion of Tip30 leads to rapid immortalization of murine mammary epithelial cells and ductal hyperplasia in the mammary gland. Oncogene 24 17533366
2011 The TIP30 protein complex, arachidonic acid and coenzyme A are required for vesicle membrane fusion. PloS one 21 21731680
2017 microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-β actions. Oncogene 20 28604742
2014 Proteomic analysis of livers from fat-fed mice deficient in either PKCδ or PKCε identifies Htatip2 as a regulator of lipid metabolism. Proteomics 20 25175814
2010 Tip30 deletion in MMTV-Neu mice leads to enhanced EGFR signaling and development of estrogen receptor-positive and progesterone receptor-negative mammary tumors. Cancer research 20 21159643
2014 The combination of HTATIP2 expression and microvessel density predicts converse survival of hepatocellular carcinoma with or without sorafenib. Oncotarget 18 25008315
2008 TIP30 is associated with progression and metastasis of prostate cancer. International journal of cancer 18 18528861
2014 Contribution of TIP30 to chemoresistance in laryngeal carcinoma. Cell death & disease 17 25321475
2005 TIP30 regulates apoptosis-related genes in its apoptotic signal transduction pathway. World journal of gastroenterology 16 15633220
2018 Metformin Enhances the Effect of Regorafenib and Inhibits Recurrence and Metastasis of Hepatic Carcinoma After Liver Resection via Regulating Expression of Hypoxia Inducible Factors 2α (HIF-2α) and 30 kDa HIV Tat-Interacting Protein (TIP30). Medical science monitor : international medical journal of experimental and clinical research 15 29654226
2007 Tip30-induced apoptosis requires translocation of Bax and involves mitochondrial release of cytochrome c and Smac/DIABLO in hepatocellular carcinoma cells. Biochimica et biophysica acta 15 17997990
2014 TIP30 inhibits oligodendrocyte precursor cell differentiation via cytoplasmic sequestration of Olig1. Glia 14 25530119
2015 Overexpression of TIP30 inhibits the growth and invasion of glioma cells. Molecular medicine reports 12 26718891
2014 TIP30: A Novel Tumor-Suppressor Gene. Oncology research 12 26629947
2009 Factors that retard remyelination in multiple sclerosis with a focus on TIP30: a novel therapeutic target. Expert opinion on therapeutic targets 12 19839715
2018 Human immunodeficiency virus Tat-TIP30 interaction promotes metastasis by enhancing the nuclear translocation of Snail in lung cancer cell lines. Cancer science 11 30099830
2017 Aberrant methylation of HTATIP2 and UCHL1 as a predictive biomarker for cholangiocarcinoma. Molecular medicine reports 11 29359783
2014 TIP30 nuclear translocation negatively regulates EGF-dependent cyclin D1 transcription in human lung adenocarcinoma. Cancer letters 11 25135222
2001 Differentially expressed CC3/TIP30 and rab11 along in vivo and in vitro intestinal epithelial cell crypt-villus axis. Life sciences 11 11531160
2015 Photodissociation dynamics of cyclopropenylidene, c-C3 H2. Chemistry (Weinheim an der Bergstrasse, Germany) 10 26385048
2024 The bispecific B7H3xCD3 antibody CC-3 induces T cell immunity against bone and soft tissue sarcomas. Frontiers in immunology 9 38765008
2014 Reduction of TIP30 in esophageal squamous cell carcinoma cells involves promoter methylation and microRNA-10b. Biochemical and biophysical research communications 9 25312779
2012 TIP30 directly binds p53 tumor suppressor protein in vitro. Molecules and cells 9 23178973
2010 CC3/TIP30 affects DNA damage repair. BMC cell biology 9 20374651
2005 Overexpression of CC3/TIP30 is associated with HER-2/neu status in breast cancer. Journal of cancer research and clinical oncology 9 15931508
2023 Epigenetic silencing of HTATIP2 in glioblastoma contributes to treatment resistance by enhancing nuclear translocation of the DNA repair protein MPG. Molecular oncology 8 37491696
2021 TIP30 overcomes gefitinib resistance by regulating cytoplasmic and nuclear EGFR signaling in non-small-cell lung cancer. Cancer science 8 34058054
2019 Combined detection of AFP-L3, GP73 and TIP30 enhances diagnostic accuracy for HBV-related cirrhosis and hepatocellular carcinoma. JPMA. The Journal of the Pakistan Medical Association 8 31511712
1999 Heat shock-induced alterations in phosphorylation of the largest subunit of RNA polymerase II as revealed by monoclonal antibodies CC-3 and MPM-2. Biochemistry and cell biology = Biochimie et biologie cellulaire 8 10546900
1990 Integration of HPV-16 DNA in cervical carcinoma cell line CC3/CUHK3 and its xenografts. Anticancer research 7 2166463
2018 Molecular modeling, biochemical characterization, and pharmacological properties of Cc3 -SPase: A platelet-aggregating thrombin-like enzyme purified from Cerastes cerastes venom. Journal of biochemical and molecular toxicology 6 29979475
2016 A Novel Triculture System (CC3) for Simultaneous Enzyme Production and Hydrolysis of Common Grasses through Submerged Fermentation. Frontiers in microbiology 6 27065995
2020 Absence of HTATIP2 Expression in A549 Lung Adenocarcinoma Cells Promotes Tumor Plasticity in Response to Hypoxic Stress. Cancers 5 32545251
2014 Tip30 controls differentiation of murine mammary luminal progenitor to estrogen receptor-positive luminal cell through regulating FoxA1 expression. Cell death & disease 5 24853420
2023 Genome-wide association study of the age of onset of type 1 diabetes reveals HTATIP2 as a novel T cell regulator. Frontiers in immunology 4 36817429
2020 Characterization of HTATIP2 and its role during hair follicle cycles in Angora rabbit. Genome 4 31917611
2018 The effects of interventional therapy on serum HTATIP2/TIP30, B7-H4 and short-term curative effect in primary hepatocellular carcinoma. European review for medical and pharmacological sciences 4 30402840
2012 [Clinical significance of CC3/TIP30 expression in breast carcinoma and its correlation with HER-2/neu]. Zhonghua wai ke za zhi [Chinese journal of surgery] 4 22490293
2025 Epidemiology of Staphylococcus haemolyticus nosocomial bacteraemia in neonatal intensive care units, France, 2019 to 2023: predominance of the ST29 (CC3) multidrug-resistant lineage. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 3 40116031
2020 Clinical significance of changes in AFP, HTATIP2/TIP30, B7-H4 and inflammatory cytokines after transcatheter arterial chemoembolization. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 3 32521927
2018 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). Rapid communications in mass spectrometry : RCM 3 29645303
2023 S417 in the CC3 region of STIM1 is critical for STIM1-Orai1 binding and CRAC channel activation. Life science alliance 2 36690443
2023 HTATIP2 regulates arteriogenic activity in monocytes from patients with limb ischemia. JCI insight 2 37847559
2015 Clinicopathologic significance and survival of TIP30 expression in laryngeal squamous cell carcinoma. International journal of clinical and experimental medicine 2 26131199
2004 [Construction of adenovirus vector expressing TIP30 and its tumor suppressive effect in vitro and in vivo]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 1 15059324
2024 Investigating TIP30-Mediated regulation of mTORC1 signaling as a therapeutic strategy for coxsackievirus B3-Induced viral myocarditis. Virology 0 38981316
2021 Resonance assignment of coiled-coil 3 (CC3) domain of human STIM1. Biomolecular NMR assignments 0 34417953
2017 The 5'-AG5 CC-3' Fragment from the Human CPEB3 Ribozyme Forms an Ultrastable Parallel RNA G-Quadruplex. Chembiochem : a European journal of chemical biology 0 28296179
2014 [Effect of Tip30 expression on the invasion and metastasis of hepatoma cells]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 0 25202945
2013 [Gene therapy for tongue carcinoma mediated by oral administration of attenuated Salmonella harboring tip30 and IFN-γ genes in nude mouse model]. Shanghai kou qiang yi xue = Shanghai journal of stomatology 0 23552775
2005 [Effects of tumor suppressing gene TIP30/CC3 on the growth of tumor cells]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 0 15670490

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