{"gene":"JPT1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2004,"finding":"HN1 (JPT1) encodes a 16.5-kDa protein that localizes to the nucleus, as determined by GFP fusion expression and Western blot in transfected cells.","method":"GFP fusion expression, Western blot, subcellular localization imaging","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with GFP fusion in a single study, confirmed by Western blot; no functional consequence linked","pmids":["15094197"],"is_preprint":false},{"year":2009,"finding":"Hn1 depletion in B16.F10 melanoma cells promotes differentiation, including increased melanogenesis (elevated tyrosinase and Trp2), increased actin–Rab27a interaction, G1/S cell cycle arrest (reduced pRb phosphorylation, lower p27, increased p21), reduced c-Met expression, reduced basal ERK phosphorylation, increased basal p38 MAPK phosphorylation, and reduced transcription factors MITF and USF-1 with increased TFE3.","method":"siRNA knockdown, flow cytometry, Western blot, immunofluorescence in murine melanoma cells","journal":"Differentiation; research in biological diversity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean siRNA KD with multiple orthogonal readouts in a single study; single lab","pmids":["19427096"],"is_preprint":false},{"year":2011,"finding":"HN1 is regulated by androgens via androgen response elements in its promoter. HN1 overexpression promotes ubiquitination-mediated proteasomal degradation of androgen receptor (AR) by reducing AR S213/210 phosphorylation, thereby downregulating AR target genes (KLK3, KLK4, NKX3.1, STAMP2). HN1 knockdown increases Akt(S473) phosphorylation and promotes AR nuclear translocation, an effect blocked by the Akt inhibitor LY294002 but not ERK inhibitor PD98059.","method":"siRNA knockdown, overexpression, Western blot, qRT-PCR, co-treatment with kinase inhibitors in prostate cancer cell lines","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (siRNA, OE, pharmacological inhibition, gene expression); single lab","pmids":["22155408"],"is_preprint":false},{"year":2015,"finding":"HN1 physically associates with the GSK3β/β-catenin destruction complex and is predominantly cytoplasmic when GSK3β is phosphorylated at S9. Ectopic HN1 expression increases β-catenin degradation, leading to loss of E-cadherin interaction, actin reorganization, colony formation and migration in PC-3 and MDA-MB231 cancer cells.","method":"Co-immunoprecipitation, Western blot, overexpression, immunofluorescence, migration/colony assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP for complex, multiple functional readouts; single lab","pmids":["25169422"],"is_preprint":false},{"year":2017,"finding":"HN1 promotes breast cancer cell migration, invasion, tumorigenesis and cancer stem cell expansion by upregulating MYC expression and its target genes (CDK4, CCND1, p21, CAV1, SFRP1). MYC knockdown abrogates the effects of HN1 overexpression.","method":"Overexpression, siRNA knockdown, qRT-PCR, Western blot, mammosphere assay, transwell assay, xenograft model, epistasis rescue","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue (MYC KD reverting HN1-OE phenotype) plus multiple orthogonal assays; single lab","pmids":["28490334"],"is_preprint":false},{"year":2019,"finding":"HNRNPA1 regulates the 3′ UTR length of HN1 (JPT1) through alternative polyadenylation (APA): downregulation of HNRNPA1 induces 3′ UTR lengthening of HN1, producing less stable transcripts and less protein, and induces senescence-associated phenotypes that are partially reversed by HN1 overexpression.","method":"APA analysis, siRNA knockdown of HNRNPA1, HN1 overexpression rescue, senescence assays, Western blot","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue (HN1 OE partially reverting HNRNPA1-KD phenotype), APA mapping; single lab","pmids":["31257225"],"is_preprint":false},{"year":2020,"finding":"HN1 interacts with STMN1 (Stathmin 1), prevents STMN1 ubiquitination and proteasomal degradation, and increases STMN1 mRNA expression. HN1 reduces α-tubulin acetylation and promotes EMT in anaplastic thyroid carcinoma (ATC). Loss of STMN1 reduces the malignant potential conferred by HN1; HN1 knockdown combined with STMN1 overexpression restores aggressive ATC cell properties.","method":"Co-immunoprecipitation, Western blot, qRT-PCR, overexpression/knockdown, xenograft model, epistasis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction, ubiquitination assay, epistasis rescue; single lab","pmids":["33359451"],"is_preprint":false},{"year":2021,"finding":"HN1 co-localizes with γ-tubulin foci at centrosomes in prostate cancer cells and physically interacts with γ-tubulin by immunoprecipitation. HN1 depletion increases γ-tubulin foci and disrupts microtubule spindle assembly, implicating HN1 in centrosome clustering.","method":"Immunofluorescence co-localization, co-immunoprecipitation, siRNA knockdown, immunoprecipitation in PC-3 cells","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-IP plus co-localization with functional siRNA KD readout; single lab","pmids":["34382911"],"is_preprint":false},{"year":2022,"finding":"HN1 sustains MYC stability and activity in hepatocellular carcinoma by interacting with GSK3β and preventing GSK3β-mediated phosphorylation and ubiquitin-proteasomal degradation of MYC. Co-immunoprecipitation confirmed HN1–MYC protein interaction. MYC suppression attenuates HN1-driven HCC proliferation and metastasis.","method":"Co-immunoprecipitation, Western blot, luciferase reporter for MYC transcriptional activity, qRT-PCR, in vitro and xenograft models","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction, functional epistasis with MYC suppression; single lab","pmids":["36403281"],"is_preprint":false},{"year":2022,"finding":"HN1 prevents HMGB1 protein from ubiquitination and autophagy-lysosome pathway degradation through interaction with TRIM28. In the nucleus, reduced HMGB1 following HN1 knockdown increases DNA damage and cell death in oxaliplatin-treated HCC cells; in the cytoplasm, HN1 regulates autophagy via HMGB1. HMGB1 overexpression rescues the phenotypes induced by HN1 knockdown.","method":"Co-immunoprecipitation, Western blot, ubiquitination assay, autophagy assays, gain/loss-of-function, rescue experiments, xenograft model","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for HN1–TRIM28 interaction, ubiquitination assay, HMGB1 rescue epistasis; single lab","pmids":["35596723"],"is_preprint":false},{"year":2023,"finding":"HN1 overexpression in prostate cancer cells (post-G2) leads to S-phase accumulation and early mitotic exit. Mechanistically, HN1 interacts with Cyclin B1 and Cdh1 (APC/C co-factor) by co-immunoprecipitation, and promotes Cyclin B1 ubiquitination and degradation by stabilizing Cdh1. Stably HN1-expressing cells show reduced Cdt1 loading onto chromatin, consistent with G1-to-S transition.","method":"Co-immunoprecipitation, Western blot, flow cytometry, immunofluorescence, cellular fractionation, inducible overexpression, ubiquitination assay","journal":"Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for Cyclin B1/Cdh1 interactions, ubiquitination assay, multiple cell cycle readouts; single lab","pmids":["36829467"],"is_preprint":false},{"year":2023,"finding":"HN1 promotes dedifferentiation of anaplastic thyroid cancer cells by inhibiting CTCF expression via epigenetic silencing: HN1 recruits HDAC2 to the CTCF promoter, reducing H3K27 acetylation and suppressing CTCF transcription. ATAC-seq and ChIP-seq showed CTCF regulates chromatin accessibility at thyroid differentiation genes. CTCF overexpression reverses HN1-driven dedifferentiation phenotypes.","method":"ATAC-seq, ChIP-seq, Co-immunoprecipitation (HN1–HDAC2), Western blot, qRT-PCR, overexpression/knockdown epistasis, xenograft and zebrafish models","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — chromatin-level mechanistic evidence (ChIP-seq, ATAC-seq), co-IP of HN1–HDAC2 complex, epistasis rescue; multiple orthogonal methods in one study","pmids":["37993084"],"is_preprint":false},{"year":2022,"finding":"HN1 knockdown in prostate cancer cells sensitizes them to docetaxel- and 2-methoxyestradiol-induced apoptosis (measured by PARP cleavage and Caspase-3 activity). Conversely, HN1 overexpression inhibits drug-induced apoptosis. Simultaneous knockdown of Cyclin B1 and HN1 abolishes the increased apoptotic response caused by HN1 knockdown alone, placing HN1's anti-apoptotic function upstream of Cyclin B1.","method":"siRNA knockdown, cDNA overexpression, PARP cleavage Western blot, Caspase-3 activity assay, epistasis (Cyclin B1 co-KD)","journal":"Annals of clinical and laboratory science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis (double KD rescues phenotype), multiple apoptosis readouts; single lab","pmids":["35414498"],"is_preprint":false},{"year":2024,"finding":"HN1 co-localizes with Aurora A and Eg5 at centrioles and maintains their co-localization with PLK1 and PCM1. HN1 depletion (siRNA/shRNA) disrupts Aurora A and PLK1 co-localizations with Eg5 and PCM1, reduces Aurora A and PLK1 phosphorylation, and increases dysregulated mitotic spindle structures, nuclear and cytokinetic abnormalities, and supernumerary but immature centrosomes. HN1 overexpression suppresses aberrant spindle formation and ensures fidelity of centriole/centrosome duplication.","method":"Immunofluorescence co-localization, siRNA/shRNA knockdown, overexpression, Western blot for Aurora A and PLK1 phosphorylation","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-localization, co-IP, KD with specific mitotic readouts; single lab","pmids":["39291428"],"is_preprint":false},{"year":2024,"finding":"HN1 activates the Akt–SREBP signaling axis to promote lipogenesis in HCC: HN1 overexpression increases SREBP1 and SREBP2 expression and lipid formation, while HN1 silencing decreases them. HN1 silencing downregulates 379 genes enriched in the lipogenic signaling pathway and suppresses HCC xenograft growth.","method":"Gene expression profiling, Western blot, lipid staining, overexpression/knockdown, xenograft model","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with gene expression profiling and in vivo validation; single lab, mechanistic pathway inferred rather than directly reconstituted","pmids":["39251779"],"is_preprint":false},{"year":2024,"finding":"HN1 expression is cell-cycle-phase-dependent in neuroblastoma SH-SY5Y cells, peaking in S-phase and lower in other phases. HN1 overexpression increases the ratio of undifferentiated (S-type) cells and alters cell cycle dynamics, functioning as a dedifferentiation factor. HN1 expression correlates with microtubule stability (nocodazole/taxol treatment experiments).","method":"Flow cytometry (cell cycle phasing), bioinformatics co-expression analysis, nocodazole/taxol treatment, overexpression, in vitro differentiation model","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlation-based microtubule link, limited mechanistic depth in available abstract","pmids":["38629746"],"is_preprint":false},{"year":2025,"finding":"HN1 is required for nucleolar organizer region (NOR) integrity and function, and is a component of the mTOR–RPS6 axis. HN1 depletion reduces mRNA translation in mammalian cancer cells, causes irregular distribution of nucleolar structures, and leads to aggregation of translation machinery components with loss of essential interactions. Immunoprecipitation confirmed HN1 association with components of the mTOR–RPS6 signaling pathway.","method":"Co-immunoprecipitation, immunofluorescence co-localization, Western blot, gain/loss-of-function, mRNA translation assays, nucleolar integrity assays","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for mTOR-RPS6 axis association, multiple orthogonal readouts (NOR integrity, translation); single lab","pmids":["39805577"],"is_preprint":false},{"year":2025,"finding":"HN1 forms a complex with transcription factor CEBPB, preventing CEBPB ubiquitination and degradation, thereby promoting CCL2 transcription in anaplastic thyroid carcinoma cells. HN1-driven CCL2 secretion induces VSIG4+ tumor-associated macrophage differentiation via CCR2/PI3K/AKT pathway activation.","method":"Cytokine array screening, co-culture validation, co-immunoprecipitation (HN1–CEBPB), ubiquitination assay, CCL2-neutralizing antibody, knockdown experiments, in vivo xenograft model","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for HN1–CEBPB complex, ubiquitination assay, antibody blockade epistasis; single lab, recently published","pmids":["42191099"],"is_preprint":false}],"current_model":"JPT1/HN1 is a small, highly conserved protein that functions as a context-dependent regulator of cell cycle progression, microtubule/centrosome integrity, protein stability, and transcriptional control: it physically associates with γ-tubulin and the Aurora A–PLK1–Eg5 axis to maintain centrosome maturation and mitotic fidelity; interacts with Cdh1/APC-C to promote Cyclin B1 ubiquitination and early mitotic exit; stabilizes oncoproteins including MYC and HMGB1 by preventing their GSK3β/ubiquitin-mediated proteasomal or autophagic degradation; associates with the GSK3β/β-catenin destruction complex to promote β-catenin turnover and cell migration; recruits HDAC2 to epigenetically silence CTCF and thereby reduce chromatin accessibility at thyroid differentiation genes; forms a complex with CEBPB to prevent its degradation and drive CCL2-mediated immunosuppressive macrophage polarization; is required for nucleolar integrity and mTOR–RPS6-dependent mRNA translation; and its own expression is post-transcriptionally regulated by HNRNPA1-directed alternative polyadenylation of its 3′ UTR."},"narrative":{"mechanistic_narrative":"JPT1 (HN1) is a small nuclear and cytoplasmic protein that acts as a context-dependent regulator of cell cycle progression, centrosome and microtubule integrity, oncoprotein stability, and transcriptional output, with most evidence drawn from cancer cell models [PMID:15094197, PMID:34382911, PMID:36829467]. At the centrosome, HN1 co-localizes and physically interacts with γ-tubulin and is required for normal centrosome clustering and spindle assembly [PMID:34382911]; it further sustains the Aurora A–PLK1–Eg5 axis at centrioles, with its depletion reducing Aurora A and PLK1 phosphorylation and producing supernumerary immature centrosomes and aberrant mitotic spindles [PMID:39291428]. In cell cycle control, HN1 interacts with Cyclin B1 and the APC/C co-factor Cdh1, stabilizing Cdh1 to promote Cyclin B1 ubiquitination and early mitotic exit, and confers resistance to drug-induced apoptosis upstream of Cyclin B1 [PMID:36829467, PMID:35414498]. A recurrent biochemical theme is HN1-mediated stabilization of partner proteins by blocking their ubiquitin- or autophagy-dependent degradation: it stabilizes MYC by antagonizing GSK3β-mediated phosphorylation/degradation to drive proliferation and stemness [PMID:28490334, PMID:36403281], stabilizes HMGB1 via TRIM28 [PMID:35596723], stabilizes STMN1 to promote EMT [PMID:33359451], and stabilizes the transcription factor CEBPB to drive CCL2-dependent immunosuppressive macrophage polarization [PMID:42191099]. HN1 also associates with the GSK3β/β-catenin destruction complex to promote β-catenin turnover and migration [PMID:25169422], and recruits HDAC2 to epigenetically silence CTCF and thereby drive thyroid cancer dedifferentiation [PMID:37993084]. Beyond these roles, HN1 is required for nucleolar integrity and mTOR–RPS6-dependent mRNA translation [PMID:39805577], and its own expression is post-transcriptionally controlled by HNRNPA1-directed alternative polyadenylation of its 3′ UTR [PMID:31257225].","teleology":[{"year":2004,"claim":"Established the basic identity and subcellular distribution of the HN1/JPT1 gene product, providing the entry point for functional study.","evidence":"GFP fusion expression and Western blot localization in transfected cells","pmids":["15094197"],"confidence":"Medium","gaps":["No functional consequence linked to nuclear localization","Single study, single cell context"]},{"year":2009,"claim":"Showed that HN1 actively maintains a proliferative, undifferentiated state, since its depletion drives differentiation and G1/S arrest.","evidence":"siRNA knockdown with flow cytometry, Western blot, and immunofluorescence in B16.F10 melanoma cells","pmids":["19427096"],"confidence":"Medium","gaps":["Direct molecular partners not identified","Multiple readouts but mechanism upstream of MITF/ERK/p38 changes unresolved"]},{"year":2011,"claim":"Defined HN1 as both an androgen-responsive gene and a feedback regulator of androgen receptor stability and Akt signaling.","evidence":"siRNA, overexpression, kinase-inhibitor co-treatment and qRT-PCR in prostate cancer lines","pmids":["22155408"],"confidence":"Medium","gaps":["Mechanism of AR phosphorylation regulation indirect","No direct HN1–AR interaction shown"]},{"year":2015,"claim":"Connected HN1 to canonical destruction-complex signaling, showing it promotes β-catenin degradation and migration.","evidence":"Reciprocal co-IP, immunofluorescence, migration/colony assays in PC-3 and MDA-MB231","pmids":["25169422"],"confidence":"Medium","gaps":["Direct binding partner within the complex not pinpointed","Single lab"]},{"year":2017,"claim":"Identified MYC upregulation as a key effector of HN1-driven invasion and stemness via epistasis rescue.","evidence":"Overexpression/knockdown, mammosphere/transwell assays, xenografts with MYC-KD reversal","pmids":["28490334"],"confidence":"Medium","gaps":["Whether MYC regulation was transcriptional or post-translational not resolved here","Single tumor type"]},{"year":2019,"claim":"Revealed that HN1 expression itself is post-transcriptionally tuned by HNRNPA1-directed alternative polyadenylation, linking HN1 to senescence control.","evidence":"APA mapping, HNRNPA1 knockdown, HN1-OE rescue, senescence assays","pmids":["31257225"],"confidence":"Medium","gaps":["Only partial rescue by HN1","Generality of APA regulation across tissues untested"]},{"year":2020,"claim":"Generalized HN1's protein-stabilization mechanism by showing it blocks STMN1 ubiquitination to promote EMT and microtubule remodeling.","evidence":"Co-IP, ubiquitination assay, epistasis rescue, xenograft in anaplastic thyroid carcinoma","pmids":["33359451"],"confidence":"Medium","gaps":["E3 ligase antagonized not identified","Mechanism linking STMN1 to tubulin acetylation indirect"]},{"year":2021,"claim":"Placed HN1 directly at the centrosome by demonstrating γ-tubulin interaction and a role in centrosome clustering and spindle assembly.","evidence":"Immunofluorescence co-localization, co-IP, siRNA knockdown in PC-3 cells","pmids":["34382911"],"confidence":"Medium","gaps":["Structural basis of γ-tubulin binding unknown","Whether centrosomal role is direct or scaffolding-dependent unclear"]},{"year":2022,"claim":"Mechanistically resolved HN1–MYC regulation, showing HN1 binds GSK3β to prevent GSK3β-mediated MYC phosphorylation and proteasomal degradation.","evidence":"Co-IP, luciferase reporter, qRT-PCR, xenograft in HCC","pmids":["36403281"],"confidence":"Medium","gaps":["Direct vs indirect HN1–MYC binding not fully separated","Single tumor model"]},{"year":2022,"claim":"Extended HN1's anti-degradation function to HMGB1 via TRIM28, linking HN1 to DNA-damage response and autophagy in chemoresistance.","evidence":"Co-IP, ubiquitination and autophagy assays, HMGB1 rescue, xenograft in HCC","pmids":["35596723"],"confidence":"Medium","gaps":["How HN1 partitions between nuclear and cytoplasmic HMGB1 effects unresolved","TRIM28 directionality not fully dissected"]},{"year":2022,"claim":"Tied HN1's anti-apoptotic activity to its cell-cycle role, placing it upstream of Cyclin B1.","evidence":"siRNA, overexpression, PARP/Caspase-3 readouts, Cyclin B1 co-knockdown epistasis in prostate cancer","pmids":["35414498"],"confidence":"Medium","gaps":["Direct molecular link between HN1 and apoptotic machinery not shown","Restricted to two drugs"]},{"year":2023,"claim":"Defined HN1's mitotic-exit mechanism by showing it interacts with Cyclin B1 and Cdh1 and stabilizes Cdh1 to drive Cyclin B1 ubiquitination.","evidence":"Co-IP, ubiquitination assay, fractionation, inducible overexpression in prostate cancer","pmids":["36829467"],"confidence":"Medium","gaps":["How HN1 stabilizes Cdh1 mechanistically unknown","Effect on full APC/C activity not reconstituted"]},{"year":2023,"claim":"Demonstrated a chromatin-level mechanism whereby HN1 recruits HDAC2 to silence CTCF and reduce accessibility at differentiation genes, driving dedifferentiation.","evidence":"ATAC-seq, ChIP-seq, HN1–HDAC2 co-IP, epistasis rescue, xenograft and zebrafish models","pmids":["37993084"],"confidence":"High","gaps":["How HN1 is targeted to the CTCF promoter unknown","Whether HN1 directly contacts chromatin or DNA unclear"]},{"year":2024,"claim":"Expanded HN1's mitotic role to the Aurora A–PLK1–Eg5 axis, showing it maintains their centriolar co-localization and activating phosphorylation.","evidence":"Immunofluorescence co-localization, siRNA/shRNA, overexpression, phospho-Western blot","pmids":["39291428"],"confidence":"Medium","gaps":["Direct kinase substrate relationships not established","Whether HN1 scaffolds or activates these kinases unresolved"]},{"year":2024,"claim":"Linked HN1 to metabolic reprogramming by showing it activates the Akt–SREBP axis to promote lipogenesis in HCC.","evidence":"Gene expression profiling, lipid staining, gain/loss-of-function, xenograft","pmids":["39251779"],"confidence":"Medium","gaps":["Pathway inferred rather than reconstituted","Direct HN1 target within Akt-SREBP axis unknown"]},{"year":2024,"claim":"Correlated HN1 with cell-cycle-phased expression and microtubule stability, supporting a dedifferentiation function in neuroblastoma.","evidence":"Flow cytometry phasing, co-expression bioinformatics, nocodazole/taxol treatment, overexpression","pmids":["38629746"],"confidence":"Low","gaps":["Microtubule link is correlation-based, not mechanistic","Limited mechanistic depth, single lab"]},{"year":2025,"claim":"Assigned HN1 a role in ribosome/nucleolar biology, showing it is required for nucleolar integrity and mTOR–RPS6-dependent translation.","evidence":"Co-IP with mTOR–RPS6 components, immunofluorescence, translation and NOR integrity assays","pmids":["39805577"],"confidence":"Medium","gaps":["Direct binding partner within mTOR–RPS6 axis not pinpointed","Whether translational role is separable from cell-cycle role unclear"]},{"year":2025,"claim":"Connected HN1 to tumor immune evasion by showing it stabilizes CEBPB to drive CCL2-dependent macrophage polarization.","evidence":"Cytokine array, HN1–CEBPB co-IP, ubiquitination assay, CCL2 blockade, xenograft","pmids":["42191099"],"confidence":"Medium","gaps":["E3 ligase antagonized not identified","Generality beyond anaplastic thyroid carcinoma untested"]},{"year":null,"claim":"It remains unknown what the primary biochemical activity of HN1 is that unifies its diverse roles in protein stabilization, centrosome maintenance, transcriptional silencing, and translation.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No catalytic activity or defining structural domain established","No structural model of HN1 in complex with any partner","Mechanism by which one small protein stabilizes multiple unrelated substrates unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,8,9,10,17]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7,13,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,10,16]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,9,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,9]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[7,13]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10,12,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,8,9,17]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,14]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[16]}],"complexes":["GSK3β/β-catenin destruction complex","mTOR–RPS6 axis"],"partners":["MYC","GSK3B","STMN1","HMGB1","TRIM28","CDH1","HDAC2","CEBPB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UK76","full_name":"Jupiter microtubule associated homolog 1","aliases":["Androgen-regulated protein 2","Hematological and neurological expressed 1 protein"],"length_aa":154,"mass_kda":16.0,"function":"Modulates negatively AKT-mediated GSK3B signaling (PubMed:21323578, PubMed:22155408). Induces CTNNB1 'Ser-33' phosphorylation and degradation through the suppression of the inhibitory 'Ser-9' phosphorylation of GSK3B, which represses the function of the APC:CTNNB1:GSK3B complex and the interaction with CDH1/E-cadherin in adherent junctions (PubMed:25169422). Plays a role in the regulation of cell cycle and cell adhesion (PubMed:25169422, PubMed:25450365). Has an inhibitory role on AR-signaling pathway through the induction of receptor proteasomal degradation (PubMed:22155408)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UK76/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JPT1","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PSMC4","stoichiometry":0.2},{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/JPT1","total_profiled":1310},"omim":[{"mim_id":"619242","title":"JUPITER MICROTUBULE-ASSOCIATED HOMOLOG 1; JPT1","url":"https://www.omim.org/entry/619242"},{"mim_id":"611294","title":"ONE CUT HOMEOBOX 3; ONECUT3","url":"https://www.omim.org/entry/611294"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":394.7}],"url":"https://www.proteinatlas.org/search/JPT1"},"hgnc":{"alias_symbol":["ARM2","HN1A"],"prev_symbol":["HN1"]},"alphafold":{"accession":"Q9UK76","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UK76","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UK76-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UK76-F1-predicted_aligned_error_v6.png","plddt_mean":63.16},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JPT1","jax_strain_url":"https://www.jax.org/strain/search?query=JPT1"},"sequence":{"accession":"Q9UK76","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UK76.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UK76/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UK76"}},"corpus_meta":[{"pmid":"25450365","id":"PMC_25450365","title":"MiR-132 prohibits proliferation, invasion, migration, and metastasis in breast cancer by targeting HN1.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25450365","citation_count":65,"is_preprint":false},{"pmid":"15094197","id":"PMC_15094197","title":"Cloning, expression and subcellular localization of HN1 and HN1L genes, as well as characterization of their orthologs, defining an evolutionarily conserved gene family.","date":"2004","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15094197","citation_count":45,"is_preprint":false},{"pmid":"32077624","id":"PMC_32077624","title":"hsa_circ_0000092 promotes hepatocellular carcinoma progression through up-regulating HN1 expression by binding to microRNA-338-3p.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32077624","citation_count":44,"is_preprint":false},{"pmid":"28490334","id":"PMC_28490334","title":"HN1 contributes to migration, invasion, and tumorigenesis of breast cancer by enhancing MYC activity.","date":"2017","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28490334","citation_count":43,"is_preprint":false},{"pmid":"20175927","id":"PMC_20175927","title":"Establishment and characterization of a novel head and neck squamous cell carcinoma cell line USC-HN1.","date":"2010","source":"Head & neck oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20175927","citation_count":39,"is_preprint":false},{"pmid":"25169422","id":"PMC_25169422","title":"HN1 negatively influences the β-catenin/E-cadherin interaction, and contributes to migration in prostate cells.","date":"2015","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25169422","citation_count":35,"is_preprint":false},{"pmid":"33359451","id":"PMC_33359451","title":"HN1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by interacting with STMN1.","date":"2020","source":"Cancer 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discoidin domain receptor 1 involved in metastasis.","date":"2022","source":"World journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35662982","citation_count":4,"is_preprint":false},{"pmid":"40560191","id":"PMC_40560191","title":"Comprehensive reexamination of the acute toxicity of nitrogen mustards: HN-1, HN-2 and HN-3 as blister agents: application of multi in silico approach.","date":"2025","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/40560191","citation_count":4,"is_preprint":false},{"pmid":"39251779","id":"PMC_39251779","title":"HN1-mediated activation of lipogenesis through Akt-SREBP signaling promotes hepatocellular carcinoma cell proliferation and metastasis.","date":"2024","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39251779","citation_count":3,"is_preprint":false},{"pmid":"36756386","id":"PMC_36756386","title":"Thirdhand Smoke May Promote Lung Adenocarcinoma Development through 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HN1 overexpression promotes ubiquitination-mediated proteasomal degradation of androgen receptor (AR) by reducing AR S213/210 phosphorylation, thereby downregulating AR target genes (KLK3, KLK4, NKX3.1, STAMP2). HN1 knockdown increases Akt(S473) phosphorylation and promotes AR nuclear translocation, an effect blocked by the Akt inhibitor LY294002 but not ERK inhibitor PD98059.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blot, qRT-PCR, co-treatment with kinase inhibitors in prostate cancer cell lines\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (siRNA, OE, pharmacological inhibition, gene expression); single lab\",\n      \"pmids\": [\"22155408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HN1 physically associates with the GSK3β/β-catenin destruction complex and is predominantly cytoplasmic when GSK3β is phosphorylated at S9. Ectopic HN1 expression increases β-catenin degradation, leading to loss of E-cadherin interaction, actin reorganization, colony formation and migration in PC-3 and MDA-MB231 cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, overexpression, immunofluorescence, migration/colony assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP for complex, multiple functional readouts; single lab\",\n      \"pmids\": [\"25169422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HN1 promotes breast cancer cell migration, invasion, tumorigenesis and cancer stem cell expansion by upregulating MYC expression and its target genes (CDK4, CCND1, p21, CAV1, SFRP1). MYC knockdown abrogates the effects of HN1 overexpression.\",\n      \"method\": \"Overexpression, siRNA knockdown, qRT-PCR, Western blot, mammosphere assay, transwell assay, xenograft model, epistasis rescue\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue (MYC KD reverting HN1-OE phenotype) plus multiple orthogonal assays; single lab\",\n      \"pmids\": [\"28490334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HNRNPA1 regulates the 3′ UTR length of HN1 (JPT1) through alternative polyadenylation (APA): downregulation of HNRNPA1 induces 3′ UTR lengthening of HN1, producing less stable transcripts and less protein, and induces senescence-associated phenotypes that are partially reversed by HN1 overexpression.\",\n      \"method\": \"APA analysis, siRNA knockdown of HNRNPA1, HN1 overexpression rescue, senescence assays, Western blot\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue (HN1 OE partially reverting HNRNPA1-KD phenotype), APA mapping; single lab\",\n      \"pmids\": [\"31257225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HN1 interacts with STMN1 (Stathmin 1), prevents STMN1 ubiquitination and proteasomal degradation, and increases STMN1 mRNA expression. HN1 reduces α-tubulin acetylation and promotes EMT in anaplastic thyroid carcinoma (ATC). Loss of STMN1 reduces the malignant potential conferred by HN1; HN1 knockdown combined with STMN1 overexpression restores aggressive ATC cell properties.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, qRT-PCR, overexpression/knockdown, xenograft model, epistasis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction, ubiquitination assay, epistasis rescue; single lab\",\n      \"pmids\": [\"33359451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HN1 co-localizes with γ-tubulin foci at centrosomes in prostate cancer cells and physically interacts with γ-tubulin by immunoprecipitation. HN1 depletion increases γ-tubulin foci and disrupts microtubule spindle assembly, implicating HN1 in centrosome clustering.\",\n      \"method\": \"Immunofluorescence co-localization, co-immunoprecipitation, siRNA knockdown, immunoprecipitation in PC-3 cells\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-IP plus co-localization with functional siRNA KD readout; single lab\",\n      \"pmids\": [\"34382911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HN1 sustains MYC stability and activity in hepatocellular carcinoma by interacting with GSK3β and preventing GSK3β-mediated phosphorylation and ubiquitin-proteasomal degradation of MYC. Co-immunoprecipitation confirmed HN1–MYC protein interaction. MYC suppression attenuates HN1-driven HCC proliferation and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, luciferase reporter for MYC transcriptional activity, qRT-PCR, in vitro and xenograft models\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction, functional epistasis with MYC suppression; single lab\",\n      \"pmids\": [\"36403281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HN1 prevents HMGB1 protein from ubiquitination and autophagy-lysosome pathway degradation through interaction with TRIM28. In the nucleus, reduced HMGB1 following HN1 knockdown increases DNA damage and cell death in oxaliplatin-treated HCC cells; in the cytoplasm, HN1 regulates autophagy via HMGB1. HMGB1 overexpression rescues the phenotypes induced by HN1 knockdown.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, ubiquitination assay, autophagy assays, gain/loss-of-function, rescue experiments, xenograft model\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for HN1–TRIM28 interaction, ubiquitination assay, HMGB1 rescue epistasis; single lab\",\n      \"pmids\": [\"35596723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HN1 overexpression in prostate cancer cells (post-G2) leads to S-phase accumulation and early mitotic exit. Mechanistically, HN1 interacts with Cyclin B1 and Cdh1 (APC/C co-factor) by co-immunoprecipitation, and promotes Cyclin B1 ubiquitination and degradation by stabilizing Cdh1. Stably HN1-expressing cells show reduced Cdt1 loading onto chromatin, consistent with G1-to-S transition.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, flow cytometry, immunofluorescence, cellular fractionation, inducible overexpression, ubiquitination assay\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for Cyclin B1/Cdh1 interactions, ubiquitination assay, multiple cell cycle readouts; single lab\",\n      \"pmids\": [\"36829467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HN1 promotes dedifferentiation of anaplastic thyroid cancer cells by inhibiting CTCF expression via epigenetic silencing: HN1 recruits HDAC2 to the CTCF promoter, reducing H3K27 acetylation and suppressing CTCF transcription. ATAC-seq and ChIP-seq showed CTCF regulates chromatin accessibility at thyroid differentiation genes. CTCF overexpression reverses HN1-driven dedifferentiation phenotypes.\",\n      \"method\": \"ATAC-seq, ChIP-seq, Co-immunoprecipitation (HN1–HDAC2), Western blot, qRT-PCR, overexpression/knockdown epistasis, xenograft and zebrafish models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — chromatin-level mechanistic evidence (ChIP-seq, ATAC-seq), co-IP of HN1–HDAC2 complex, epistasis rescue; multiple orthogonal methods in one study\",\n      \"pmids\": [\"37993084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HN1 knockdown in prostate cancer cells sensitizes them to docetaxel- and 2-methoxyestradiol-induced apoptosis (measured by PARP cleavage and Caspase-3 activity). Conversely, HN1 overexpression inhibits drug-induced apoptosis. Simultaneous knockdown of Cyclin B1 and HN1 abolishes the increased apoptotic response caused by HN1 knockdown alone, placing HN1's anti-apoptotic function upstream of Cyclin B1.\",\n      \"method\": \"siRNA knockdown, cDNA overexpression, PARP cleavage Western blot, Caspase-3 activity assay, epistasis (Cyclin B1 co-KD)\",\n      \"journal\": \"Annals of clinical and laboratory science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis (double KD rescues phenotype), multiple apoptosis readouts; single lab\",\n      \"pmids\": [\"35414498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HN1 co-localizes with Aurora A and Eg5 at centrioles and maintains their co-localization with PLK1 and PCM1. HN1 depletion (siRNA/shRNA) disrupts Aurora A and PLK1 co-localizations with Eg5 and PCM1, reduces Aurora A and PLK1 phosphorylation, and increases dysregulated mitotic spindle structures, nuclear and cytokinetic abnormalities, and supernumerary but immature centrosomes. HN1 overexpression suppresses aberrant spindle formation and ensures fidelity of centriole/centrosome duplication.\",\n      \"method\": \"Immunofluorescence co-localization, siRNA/shRNA knockdown, overexpression, Western blot for Aurora A and PLK1 phosphorylation\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-localization, co-IP, KD with specific mitotic readouts; single lab\",\n      \"pmids\": [\"39291428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HN1 activates the Akt–SREBP signaling axis to promote lipogenesis in HCC: HN1 overexpression increases SREBP1 and SREBP2 expression and lipid formation, while HN1 silencing decreases them. HN1 silencing downregulates 379 genes enriched in the lipogenic signaling pathway and suppresses HCC xenograft growth.\",\n      \"method\": \"Gene expression profiling, Western blot, lipid staining, overexpression/knockdown, xenograft model\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with gene expression profiling and in vivo validation; single lab, mechanistic pathway inferred rather than directly reconstituted\",\n      \"pmids\": [\"39251779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HN1 expression is cell-cycle-phase-dependent in neuroblastoma SH-SY5Y cells, peaking in S-phase and lower in other phases. HN1 overexpression increases the ratio of undifferentiated (S-type) cells and alters cell cycle dynamics, functioning as a dedifferentiation factor. HN1 expression correlates with microtubule stability (nocodazole/taxol treatment experiments).\",\n      \"method\": \"Flow cytometry (cell cycle phasing), bioinformatics co-expression analysis, nocodazole/taxol treatment, overexpression, in vitro differentiation model\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlation-based microtubule link, limited mechanistic depth in available abstract\",\n      \"pmids\": [\"38629746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HN1 is required for nucleolar organizer region (NOR) integrity and function, and is a component of the mTOR–RPS6 axis. HN1 depletion reduces mRNA translation in mammalian cancer cells, causes irregular distribution of nucleolar structures, and leads to aggregation of translation machinery components with loss of essential interactions. Immunoprecipitation confirmed HN1 association with components of the mTOR–RPS6 signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, Western blot, gain/loss-of-function, mRNA translation assays, nucleolar integrity assays\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for mTOR-RPS6 axis association, multiple orthogonal readouts (NOR integrity, translation); single lab\",\n      \"pmids\": [\"39805577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HN1 forms a complex with transcription factor CEBPB, preventing CEBPB ubiquitination and degradation, thereby promoting CCL2 transcription in anaplastic thyroid carcinoma cells. HN1-driven CCL2 secretion induces VSIG4+ tumor-associated macrophage differentiation via CCR2/PI3K/AKT pathway activation.\",\n      \"method\": \"Cytokine array screening, co-culture validation, co-immunoprecipitation (HN1–CEBPB), ubiquitination assay, CCL2-neutralizing antibody, knockdown experiments, in vivo xenograft model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for HN1–CEBPB complex, ubiquitination assay, antibody blockade epistasis; single lab, recently published\",\n      \"pmids\": [\"42191099\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JPT1/HN1 is a small, highly conserved protein that functions as a context-dependent regulator of cell cycle progression, microtubule/centrosome integrity, protein stability, and transcriptional control: it physically associates with γ-tubulin and the Aurora A–PLK1–Eg5 axis to maintain centrosome maturation and mitotic fidelity; interacts with Cdh1/APC-C to promote Cyclin B1 ubiquitination and early mitotic exit; stabilizes oncoproteins including MYC and HMGB1 by preventing their GSK3β/ubiquitin-mediated proteasomal or autophagic degradation; associates with the GSK3β/β-catenin destruction complex to promote β-catenin turnover and cell migration; recruits HDAC2 to epigenetically silence CTCF and thereby reduce chromatin accessibility at thyroid differentiation genes; forms a complex with CEBPB to prevent its degradation and drive CCL2-mediated immunosuppressive macrophage polarization; is required for nucleolar integrity and mTOR–RPS6-dependent mRNA translation; and its own expression is post-transcriptionally regulated by HNRNPA1-directed alternative polyadenylation of its 3′ UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"JPT1 (HN1) is a small nuclear and cytoplasmic protein that acts as a context-dependent regulator of cell cycle progression, centrosome and microtubule integrity, oncoprotein stability, and transcriptional output, with most evidence drawn from cancer cell models [#0, #7, #10]. At the centrosome, HN1 co-localizes and physically interacts with \\u03b3-tubulin and is required for normal centrosome clustering and spindle assembly [#7]; it further sustains the Aurora A\\u2013PLK1\\u2013Eg5 axis at centrioles, with its depletion reducing Aurora A and PLK1 phosphorylation and producing supernumerary immature centrosomes and aberrant mitotic spindles [#13]. In cell cycle control, HN1 interacts with Cyclin B1 and the APC/C co-factor Cdh1, stabilizing Cdh1 to promote Cyclin B1 ubiquitination and early mitotic exit, and confers resistance to drug-induced apoptosis upstream of Cyclin B1 [#10, #12]. A recurrent biochemical theme is HN1-mediated stabilization of partner proteins by blocking their ubiquitin- or autophagy-dependent degradation: it stabilizes MYC by antagonizing GSK3\\u03b2-mediated phosphorylation/degradation to drive proliferation and stemness [#4, #8], stabilizes HMGB1 via TRIM28 [#9], stabilizes STMN1 to promote EMT [#6], and stabilizes the transcription factor CEBPB to drive CCL2-dependent immunosuppressive macrophage polarization [#17]. HN1 also associates with the GSK3\\u03b2/\\u03b2-catenin destruction complex to promote \\u03b2-catenin turnover and migration [#3], and recruits HDAC2 to epigenetically silence CTCF and thereby drive thyroid cancer dedifferentiation [#11]. Beyond these roles, HN1 is required for nucleolar integrity and mTOR\\u2013RPS6-dependent mRNA translation [#16], and its own expression is post-transcriptionally controlled by HNRNPA1-directed alternative polyadenylation of its 3\\u2032 UTR [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the basic identity and subcellular distribution of the HN1/JPT1 gene product, providing the entry point for functional study.\",\n      \"evidence\": \"GFP fusion expression and Western blot localization in transfected cells\",\n      \"pmids\": [\"15094197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence linked to nuclear localization\", \"Single study, single cell context\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that HN1 actively maintains a proliferative, undifferentiated state, since its depletion drives differentiation and G1/S arrest.\",\n      \"evidence\": \"siRNA knockdown with flow cytometry, Western blot, and immunofluorescence in B16.F10 melanoma cells\",\n      \"pmids\": [\"19427096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular partners not identified\", \"Multiple readouts but mechanism upstream of MITF/ERK/p38 changes unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined HN1 as both an androgen-responsive gene and a feedback regulator of androgen receptor stability and Akt signaling.\",\n      \"evidence\": \"siRNA, overexpression, kinase-inhibitor co-treatment and qRT-PCR in prostate cancer lines\",\n      \"pmids\": [\"22155408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of AR phosphorylation regulation indirect\", \"No direct HN1\\u2013AR interaction shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected HN1 to canonical destruction-complex signaling, showing it promotes \\u03b2-catenin degradation and migration.\",\n      \"evidence\": \"Reciprocal co-IP, immunofluorescence, migration/colony assays in PC-3 and MDA-MB231\",\n      \"pmids\": [\"25169422\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partner within the complex not pinpointed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified MYC upregulation as a key effector of HN1-driven invasion and stemness via epistasis rescue.\",\n      \"evidence\": \"Overexpression/knockdown, mammosphere/transwell assays, xenografts with MYC-KD reversal\",\n      \"pmids\": [\"28490334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MYC regulation was transcriptional or post-translational not resolved here\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed that HN1 expression itself is post-transcriptionally tuned by HNRNPA1-directed alternative polyadenylation, linking HN1 to senescence control.\",\n      \"evidence\": \"APA mapping, HNRNPA1 knockdown, HN1-OE rescue, senescence assays\",\n      \"pmids\": [\"31257225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only partial rescue by HN1\", \"Generality of APA regulation across tissues untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Generalized HN1's protein-stabilization mechanism by showing it blocks STMN1 ubiquitination to promote EMT and microtubule remodeling.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, epistasis rescue, xenograft in anaplastic thyroid carcinoma\",\n      \"pmids\": [\"33359451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase antagonized not identified\", \"Mechanism linking STMN1 to tubulin acetylation indirect\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed HN1 directly at the centrosome by demonstrating \\u03b3-tubulin interaction and a role in centrosome clustering and spindle assembly.\",\n      \"evidence\": \"Immunofluorescence co-localization, co-IP, siRNA knockdown in PC-3 cells\",\n      \"pmids\": [\"34382911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of \\u03b3-tubulin binding unknown\", \"Whether centrosomal role is direct or scaffolding-dependent unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mechanistically resolved HN1\\u2013MYC regulation, showing HN1 binds GSK3\\u03b2 to prevent GSK3\\u03b2-mediated MYC phosphorylation and proteasomal degradation.\",\n      \"evidence\": \"Co-IP, luciferase reporter, qRT-PCR, xenograft in HCC\",\n      \"pmids\": [\"36403281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect HN1\\u2013MYC binding not fully separated\", \"Single tumor model\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended HN1's anti-degradation function to HMGB1 via TRIM28, linking HN1 to DNA-damage response and autophagy in chemoresistance.\",\n      \"evidence\": \"Co-IP, ubiquitination and autophagy assays, HMGB1 rescue, xenograft in HCC\",\n      \"pmids\": [\"35596723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HN1 partitions between nuclear and cytoplasmic HMGB1 effects unresolved\", \"TRIM28 directionality not fully dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Tied HN1's anti-apoptotic activity to its cell-cycle role, placing it upstream of Cyclin B1.\",\n      \"evidence\": \"siRNA, overexpression, PARP/Caspase-3 readouts, Cyclin B1 co-knockdown epistasis in prostate cancer\",\n      \"pmids\": [\"35414498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between HN1 and apoptotic machinery not shown\", \"Restricted to two drugs\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined HN1's mitotic-exit mechanism by showing it interacts with Cyclin B1 and Cdh1 and stabilizes Cdh1 to drive Cyclin B1 ubiquitination.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, fractionation, inducible overexpression in prostate cancer\",\n      \"pmids\": [\"36829467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HN1 stabilizes Cdh1 mechanistically unknown\", \"Effect on full APC/C activity not reconstituted\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated a chromatin-level mechanism whereby HN1 recruits HDAC2 to silence CTCF and reduce accessibility at differentiation genes, driving dedifferentiation.\",\n      \"evidence\": \"ATAC-seq, ChIP-seq, HN1\\u2013HDAC2 co-IP, epistasis rescue, xenograft and zebrafish models\",\n      \"pmids\": [\"37993084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HN1 is targeted to the CTCF promoter unknown\", \"Whether HN1 directly contacts chromatin or DNA unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded HN1's mitotic role to the Aurora A\\u2013PLK1\\u2013Eg5 axis, showing it maintains their centriolar co-localization and activating phosphorylation.\",\n      \"evidence\": \"Immunofluorescence co-localization, siRNA/shRNA, overexpression, phospho-Western blot\",\n      \"pmids\": [\"39291428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase substrate relationships not established\", \"Whether HN1 scaffolds or activates these kinases unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked HN1 to metabolic reprogramming by showing it activates the Akt\\u2013SREBP axis to promote lipogenesis in HCC.\",\n      \"evidence\": \"Gene expression profiling, lipid staining, gain/loss-of-function, xenograft\",\n      \"pmids\": [\"39251779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway inferred rather than reconstituted\", \"Direct HN1 target within Akt-SREBP axis unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Correlated HN1 with cell-cycle-phased expression and microtubule stability, supporting a dedifferentiation function in neuroblastoma.\",\n      \"evidence\": \"Flow cytometry phasing, co-expression bioinformatics, nocodazole/taxol treatment, overexpression\",\n      \"pmids\": [\"38629746\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Microtubule link is correlation-based, not mechanistic\", \"Limited mechanistic depth, single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Assigned HN1 a role in ribosome/nucleolar biology, showing it is required for nucleolar integrity and mTOR\\u2013RPS6-dependent translation.\",\n      \"evidence\": \"Co-IP with mTOR\\u2013RPS6 components, immunofluorescence, translation and NOR integrity assays\",\n      \"pmids\": [\"39805577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partner within mTOR\\u2013RPS6 axis not pinpointed\", \"Whether translational role is separable from cell-cycle role unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected HN1 to tumor immune evasion by showing it stabilizes CEBPB to drive CCL2-dependent macrophage polarization.\",\n      \"evidence\": \"Cytokine array, HN1\\u2013CEBPB co-IP, ubiquitination assay, CCL2 blockade, xenograft\",\n      \"pmids\": [\"42191099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase antagonized not identified\", \"Generality beyond anaplastic thyroid carcinoma untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what the primary biochemical activity of HN1 is that unifies its diverse roles in protein stabilization, centrosome maintenance, transcriptional silencing, and translation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No catalytic activity or defining structural domain established\", \"No structural model of HN1 in complex with any partner\", \"Mechanism by which one small protein stabilizes multiple unrelated substrates unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 8, 9, 10, 17]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7, 13, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 10, 16]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 9, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10, 12, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 8, 9, 17]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\n      \"GSK3\\u03b2/\\u03b2-catenin destruction complex\",\n      \"mTOR\\u2013RPS6 axis\"\n    ],\n    \"partners\": [\n      \"MYC\",\n      \"GSK3B\",\n      \"STMN1\",\n      \"HMGB1\",\n      \"TRIM28\",\n      \"CDH1\",\n      \"HDAC2\",\n      \"CEBPB\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}