{"gene":"PTOV1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2001,"finding":"PTOV1 protein consists of two novel homologous domains (PTOV blocks) arranged in tandem, and localizes predominantly to the perinuclear region in cultured cells, as shown by immunocytochemistry and expression of chimeric GFP-PTOV1 proteins.","method":"GFP fusion protein imaging, immunocytochemistry","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with GFP fusion, replicated by immunocytochemistry, single lab","pmids":["11313889"],"is_preprint":false},{"year":2003,"finding":"PTOV1 shuttles between cytoplasm and nucleus in a cell cycle-dependent manner: it localizes to the cytoplasm in quiescent cells, translocates to the nucleus at the onset of S phase after serum stimulation, and exits the nucleus at the end of mitosis. Overexpression of PTOV1 forces entry into S phase and increases cyclin D1 protein levels.","method":"Immunofluorescence, GFP live imaging, flow cytometry, Western blot","journal":"The American Journal of Pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (live imaging, flow cytometry, cyclin D1 Western blot), single lab","pmids":["12598323"],"is_preprint":false},{"year":2005,"finding":"PTOV1 physically interacts with flotillin-1, co-purifying with it in detergent-insoluble lipid raft fractions. PTOV1 enables nuclear translocation of flotillin-1: depletion of PTOV1 significantly inhibited nuclear localization of flotillin-1, whereas depletion of flotillin-1 did not affect nuclear localization of PTOV1. Both proteins are required for cell proliferation, and their proliferative effect requires nuclear localization.","method":"Co-immunoprecipitation, subcellular fractionation, immunocytochemistry, siRNA knockdown, overexpression with proliferation assays","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, fractionation, siRNA rescue, multiple orthogonal methods in one rigorous study","pmids":["15713644"],"is_preprint":false},{"year":2006,"finding":"PTOV1 gene expression is induced by testosterone in androgen receptor-positive human vascular smooth muscle cells (VSMCs), and siRNA-mediated knockdown of PTOV1 suppresses testosterone-induced VSMC proliferation, placing PTOV1 downstream of androgen receptor signaling in VSMCs.","method":"Microarray, quantitative RT-PCR, siRNA knockdown with proliferation assay","journal":"The Journal of Pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional siRNA knockdown with defined proliferation readout, corroborated by expression analysis, single lab","pmids":["16639697"],"is_preprint":false},{"year":2010,"finding":"PTOV1 antagonizes MED25 in retinoic acid receptor (RAR) transcriptional activation through competitive binding to CBP and opposing regulation of CBP recruitment to RA-responsive gene promoters, modulating RA sensitivity in cancer cells.","method":"Co-immunoprecipitation, reporter (luciferase) assay, chromatin immunoprecipitation (ChIP)","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, and reporter assay provide multiple orthogonal methods; single lab","pmids":["21110951"],"is_preprint":false},{"year":2011,"finding":"PTOV1 physically interacts with ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) in mouse oocytes, as identified by pull-down screening of UCH-L1-binding proteins from mouse ovaries; PTOV1 distribution in oocytes changes from cytoplasm/nucleus in prepubescent mice to nucleus/plasma membrane in adults, and estradiol treatment induces the adult-specific distribution pattern.","method":"Protein pull-down/binding screen, immunohistochemistry, estradiol treatment","journal":"Histochemistry and Cell Biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pull-down interaction, localization by IHC, single lab, no functional rescue","pmids":["21678139"],"is_preprint":false},{"year":2013,"finding":"Zyxin translocates to the nucleus in response to retinoic acid (RA) and forms a ternary complex with PTOV1 and the RAR coactivator CBP, thereby promoting dissociation of CBP from RAR at RA-responsive promoters and repressing RAR transcriptional activity, contributing to RA resistance.","method":"Co-immunoprecipitation, ChIP, reporter assay, nuclear translocation imaging","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and reporter assay in a single lab study; mechanistically extends prior MED25/PTOV1/CBP finding","pmids":["23321499"],"is_preprint":false},{"year":2014,"finding":"PTOV1 counteracts Notch signaling by associating with the HEY1 and HES1 promoters together with components of the Notch repressor complex under inactive Notch conditions, thereby repressing these Notch target genes. Active Notch1 provokes dismissal of PTOV1 from these promoters. In Drosophila, human PTOV1 exacerbated Notch deletion mutant phenotypes and suppressed constitutively active Notch effects, confirming epistatic antagonism. PTOV1 is required for in vitro invasiveness and anchorage-independent growth of PC-3 cells, and for their in vivo metastatic spread.","method":"ChIP, co-immunoprecipitation, pull-down, luciferase reporter assay, Drosophila genetic epistasis, SCID-Beige mouse xenograft, lentiviral knockdown/overexpression","journal":"Molecular Cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, Co-IP, reporter, Drosophila epistasis, in vivo xenograft), mechanistically replicated across systems","pmids":["24684754"],"is_preprint":false},{"year":2019,"finding":"PTOV1 contains an AT-hook-like DNA-binding motif within its PTOV-A domain that directly binds to the promoters of ALDH1A1 and CCNG2. Mutation of this motif significantly decreased PTOV1-promoted expression of these genes. PTOV1 also associates with mitotic chromosomes in high-grade carcinomas.","method":"Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), mutagenesis, immunohistochemistry","journal":"Cancer Letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — EMSA (in vitro DNA binding), ChIP, and active-site mutagenesis in a single study; provides direct biochemical evidence for DNA-binding activity","pmids":["30922918"],"is_preprint":false},{"year":2019,"finding":"PTOV1 physically interacts with PIN1 in breast cancer cells (MDA-MB-231), validated by co-immunoprecipitation. Overexpression of PIN1 increases PTOV1 expression. Knockdown of PTOV1 inhibits cyclin D1, c-Myc, and β-catenin expression and induces apoptosis markers (increased BAX, LC3, Beclin-1; decreased Bcl-2, Bcl-xL).","method":"Co-immunoprecipitation, siRNA knockdown, Western blot, flow cytometry","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction validated, multiple downstream readouts by Western blot, single lab","pmids":["31083670"],"is_preprint":false},{"year":2019,"finding":"Depletion of PTOV1 in NSCLC cells attenuates cancer stem cell traits by impairing DKK1/β-catenin signaling, leading to increased sensitivity to cisplatin and docetaxel.","method":"siRNA knockdown, flow cytometry, colony formation, tumor sphere formation, xenograft model, Western blot","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with defined pathway readout (DKK1/β-catenin), in vivo xenograft corroboration, single lab","pmids":["31387622"],"is_preprint":false},{"year":2021,"finding":"SGK2 phosphorylates PTOV1 at serine 36, which is required for 14-3-3 binding to PTOV1. 14-3-3 sequesters PTOV1 in the cytosol, stabilizing it by preventing its interaction with the E3 ubiquitin ligase HUWE1. Disruption of PTOV1-14-3-3 interaction causes PTOV1 accumulation in the nucleus and proteasome-dependent degradation of PTOV1 via HUWE1. Cytosolic 14-3-3-bound PTOV1 promotes expression of cJun to drive cell-cycle progression.","method":"Co-immunoprecipitation, phospho-mutagenesis, proteasome inhibitor rescue, subcellular fractionation, Western blot, overexpression/knockdown","journal":"Molecular Cancer Research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — phospho-mutagenesis at defined residue, Co-IP, proteasome inhibitor rescue, multiple orthogonal methods in single study establishing the SGK2-14-3-3-HUWE1 regulatory axis","pmids":["34654719"],"is_preprint":false},{"year":2021,"finding":"PTOV1 overexpression increases NF-κB pathway activity, as shown by increased nuclear translocation of p65 and phosphorylation of IKKα/β. Pharmacological inhibition of NF-κB in PTOV1-overexpressing ovarian cancer cells restored cisplatin-induced apoptosis, placing PTOV1 upstream of NF-κB in chemoresistance.","method":"Overexpression/knockdown, Western blot for NF-κB pathway markers, nuclear fractionation, NF-κB inhibitor rescue, apoptosis assay, xenograft model","journal":"Molecular Therapy Oncolytics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway inhibitor epistasis rescue, Western blot for phospho-IKK and nuclear p65, single lab","pmids":["33738336"],"is_preprint":false},{"year":2024,"finding":"PTOV1 facilitates colorectal cancer cell proliferation through activation of the AKT1 signaling pathway: PTOV1 overexpression increases AKT1 phosphorylation and reduces cell cycle inhibitors P21 and P27, while pharmacological inhibition of AKT1 phosphorylation with MK2206 reverses PTOV1-induced proliferation.","method":"siRNA knockdown, overexpression, Western blot for p-AKT1/P21/P27, AKT1 inhibitor (MK2206) rescue, CCK-8/colony formation assays","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inhibitor-based epistasis rescue and Western blot pathway markers, single lab","pmids":["39229496"],"is_preprint":false},{"year":2025,"finding":"PTOV1 destabilizes p53 by activating autophagy and recruiting p53 to the cargo receptor SQSTM1 for autophagic degradation. PTOV1 physically interacts with p53 (identified by IP-mass spectrometry and Co-IP). Overexpression of p53 or knockdown of SQSTM1 reverses PTOV1-driven pro-tumor phenotypes in colorectal cancer.","method":"Immunoprecipitation-mass spectrometry, co-immunoprecipitation, immunofluorescence, Western blot, transmission electron microscopy (autophagy), p53 overexpression/SQSTM1 knockdown rescue, in vivo mouse model","journal":"Journal of Translational Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with MS identification of interaction, TEM for autophagy, rescue experiments, single lab","pmids":["39905441"],"is_preprint":false},{"year":2025,"finding":"PTOV1 physically interacts with ZNF449, and this complex synergistically promotes transcription of MYC. The interaction was demonstrated by Co-IP and GST pull-down. A TAT-PTOV1(125-283 aa) peptide disrupting the PTOV1/ZNF449 interaction inhibited colorectal cancer development in a xenograft model.","method":"Co-immunoprecipitation, GST pull-down, luciferase reporter assay (implied by 'promoted transcription of MYC'), xenograft mouse model, peptide disruption","journal":"Communications Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down confirming direct interaction, in vivo peptide disruption rescue, single lab","pmids":["40133702"],"is_preprint":false}],"current_model":"PTOV1 is a cell cycle-regulated adaptor/transcription-translation regulator that shuttles between the cytoplasm and nucleus (peaking in S phase), where it directly binds DNA via an AT-hook-like motif in its PTOV-A domain to activate target gene promoters (e.g., ALDH1A1, CCNG2), represses Notch target genes (HES1, HEY1) by associating with their promoter repressor complexes, competes with MED25 for CBP binding to antagonize RAR-mediated transcription, and cooperates with ZNF449 to drive MYC transcription; its cytoplasmic stability and localization are controlled by an SGK2-phosphorylation-dependent interaction with 14-3-3 that sequesters PTOV1 from nuclear accumulation and protects it from HUWE1-mediated proteasomal degradation, while nuclear PTOV1 promotes cell-cycle progression via cJun; additional mechanisms include activation of the NF-κB and AKT1/PI3K pathways, promotion of SQSTM1-directed autophagic degradation of p53, interaction with flotillin-1 (enabling its nuclear import), and interaction with PIN1."},"narrative":{"mechanistic_narrative":"PTOV1 is a cell cycle-regulated adaptor and transcriptional regulator that promotes proliferation by coupling nucleocytoplasmic shuttling to control of growth-related gene expression [PMID:12598323, PMID:30922918]. Built from two tandem homologous PTOV domains, it shuttles between the cytoplasm and nucleus in a cell cycle-dependent manner, accumulating in the nucleus at the onset of S phase and forcing entry into S phase with elevated cyclin D1 [PMID:11313889, PMID:12598323]. In the nucleus, PTOV1 acts directly on chromatin: an AT-hook-like motif within its PTOV-A domain binds the promoters of ALDH1A1 and CCNG2 to drive their expression, and it associates with mitotic chromosomes [PMID:30922918]. Its transcriptional output is bidirectional — it represses Notch target genes HES1 and HEY1 by joining the Notch repressor complex at their promoters until active Notch evicts it [PMID:24684754], antagonizes retinoic acid receptor signaling by competing for CBP together with MED25 and zyxin [PMID:21110951, PMID:23321499], and cooperates with ZNF449 to activate MYC transcription [PMID:40133702]. PTOV1 abundance and localization are governed by an SGK2-phosphorylation-dependent switch: phosphorylation at serine 36 enables 14-3-3 binding, which sequesters PTOV1 in the cytosol and shields it from HUWE1-mediated proteasomal degradation, while disruption of this interaction drives nuclear accumulation and turnover; cytosolic 14-3-3-bound PTOV1 induces cJun to drive cell-cycle progression [PMID:34654719]. In cancer, PTOV1 drives invasion, stemness and chemoresistance through Notch antagonism, β-catenin/DKK1 signaling, NF-κB and AKT1 activation, and SQSTM1-directed autophagic degradation of p53 [PMID:24684754, PMID:31387622, PMID:33738336, PMID:39229496, PMID:39905441].","teleology":[{"year":2001,"claim":"Established PTOV1 as a novel protein with a distinctive two-domain architecture and defined its baseline subcellular distribution, providing the structural starting point for all later mechanistic work.","evidence":"GFP fusion imaging and immunocytochemistry in cultured cells","pmids":["11313889"],"confidence":"Medium","gaps":["No function assigned to the PTOV domains","Perinuclear localization not linked to a molecular activity"]},{"year":2003,"claim":"Showed that PTOV1 localization is cell-cycle gated and functionally drives proliferation, reframing it from a localized protein to an S-phase-coupled growth regulator.","evidence":"Immunofluorescence, GFP live imaging, flow cytometry and cyclin D1 Western blot after serum stimulation","pmids":["12598323"],"confidence":"Medium","gaps":["Mechanism connecting nuclear entry to S-phase induction unresolved","Direct transcriptional targets unidentified"]},{"year":2005,"claim":"Identified flotillin-1 as a physical partner and positioned PTOV1 as a determinant of partner nuclear import, the first direct interaction underpinning its proliferative role.","evidence":"Reciprocal Co-IP, lipid-raft fractionation, siRNA depletion and proliferation assays","pmids":["15713644"],"confidence":"High","gaps":["Molecular import machinery used by PTOV1 unknown","Relationship to its own shuttling not defined"]},{"year":2006,"claim":"Placed PTOV1 downstream of androgen receptor signaling, linking its expression to a hormonal proliferative stimulus in vascular smooth muscle.","evidence":"Microarray, qRT-PCR and siRNA knockdown with proliferation readout in AR-positive VSMCs","pmids":["16639697"],"confidence":"Medium","gaps":["Direct AR-responsive elements at the PTOV1 locus not mapped","Relevance beyond VSMCs untested"]},{"year":2013,"claim":"Defined PTOV1 as a transcriptional antagonist of retinoic acid signaling by competing for the coactivator CBP, the first specific transcriptional mechanism for the protein.","evidence":"Co-IP, ChIP, reporter assays and nuclear translocation imaging implicating MED25 and zyxin in CBP competition","pmids":["21110951","23321499"],"confidence":"Medium","gaps":["Whether PTOV1 contacts CBP directly or via partners unresolved","Genome-wide RAR targets affected not defined"]},{"year":2014,"claim":"Established PTOV1 as a sequence-context chromatin-associated repressor of Notch targets and a driver of invasion and metastasis, demonstrating bidirectional transcriptional control with in vivo consequence.","evidence":"ChIP, Co-IP, reporter assays, Drosophila genetic epistasis and SCID-Beige xenografts","pmids":["24684754"],"confidence":"High","gaps":["How PTOV1 is recruited to Notch repressor complexes not defined","Whether DNA binding underlies promoter association unknown at this stage"]},{"year":2019,"claim":"Provided direct biochemical evidence that PTOV1 is a DNA-binding protein through an AT-hook-like motif in its PTOV-A domain, converting prior promoter-association data into an intrinsic activity.","evidence":"EMSA, ChIP and motif mutagenesis at ALDH1A1/CCNG2 promoters plus mitotic chromosome IHC","pmids":["30922918"],"confidence":"High","gaps":["Genome-wide DNA-binding landscape unmapped","Sequence specificity of the AT-hook motif not fully defined"]},{"year":2019,"claim":"Extended PTOV1's proliferative network through PIN1 interaction and downstream control of cyclin D1, c-Myc and β-catenin with apoptotic consequences upon depletion.","evidence":"Co-IP, siRNA knockdown, Western blot and flow cytometry in breast cancer cells","pmids":["31083670"],"confidence":"Medium","gaps":["Whether PIN1 isomerizes PTOV1 directly untested","Mechanism linking PTOV1 to the listed effectors indirect"]},{"year":2021,"claim":"Resolved how PTOV1 stability and localization are controlled, defining an SGK2-Ser36-phosphorylation/14-3-3/HUWE1 axis that gates cytosolic sequestration versus nuclear accumulation and degradation.","evidence":"Phospho-mutagenesis, Co-IP, proteasome-inhibitor rescue and subcellular fractionation","pmids":["34654719"],"confidence":"High","gaps":["Signals upstream of SGK2 activation toward PTOV1 unknown","Whether nuclear PTOV1 is the active transcriptional pool not directly shown here"]},{"year":2021,"claim":"Linked PTOV1 to NF-κB activation as a mechanism of chemoresistance, broadening its pro-survival signaling reach.","evidence":"Overexpression/knockdown, phospho-IKK and nuclear p65 Western blots, NF-κB inhibitor rescue and xenografts in ovarian cancer","pmids":["33738336"],"confidence":"Medium","gaps":["Direct molecular step connecting PTOV1 to IKK unknown","Whether effect is transcriptional or post-translational unresolved"]},{"year":2024,"claim":"Connected PTOV1 to AKT1 pathway activation and cell-cycle inhibitor suppression in colorectal cancer, adding a kinase-signaling arm to its proliferative function.","evidence":"Knockdown/overexpression, p-AKT1/P21/P27 Western blots and MK2206 rescue with proliferation assays","pmids":["39229496"],"confidence":"Medium","gaps":["Mechanism of AKT1 activation by PTOV1 not defined","Direct versus indirect coupling untested"]},{"year":2025,"claim":"Revealed a post-translational route by which PTOV1 destabilizes p53 — recruitment to SQSTM1 for autophagic degradation — and a ZNF449 partnership driving MYC, deepening its pro-tumor mechanism and identifying a druggable interaction interface.","evidence":"IP-MS, Co-IP, GST pull-down, TEM autophagy imaging, rescue with p53 overexpression/SQSTM1 knockdown, reporter assays and TAT-peptide disruption xenografts","pmids":["39905441","40133702"],"confidence":"Medium","gaps":["How PTOV1 triggers autophagy initiation unresolved","Whether ZNF449/MYC activation requires PTOV1 DNA binding untested"]},{"year":null,"claim":"How PTOV1's intrinsic AT-hook DNA binding, its many partner interactions, and its NF-κB/AKT1 signaling outputs are integrated into a single coherent regulatory program remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the PTOV domains or DNA-bound complex","Genome-wide direct target set unmapped","Whether signaling effects are downstream of its transcriptional activity or independent is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,6,7,8,15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,11]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,7,8,15]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,13]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[14]}],"complexes":[],"partners":["FLOT1","MED25","ZYX","CBP","PIN1","ZNF449","TP53","YWHA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86YD1","full_name":"Prostate tumor-overexpressed gene 1 protein","aliases":["Activator interaction domain-containing protein 2"],"length_aa":416,"mass_kda":46.9,"function":"May activate transcription. Required for nuclear translocation of FLOT1. Promotes cell proliferation","subcellular_location":"Cytoplasm; Nucleus; Cell membrane; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q86YD1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTOV1","classification":"Not Classified","n_dependent_lines":82,"n_total_lines":1208,"dependency_fraction":0.06788079470198675},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PTOV1","total_profiled":1310},"omim":[{"mim_id":"610197","title":"MEDIATOR COMPLEX SUBUNIT 25; MED25","url":"https://www.omim.org/entry/610197"},{"mim_id":"610195","title":"PTOV1 EXTENDED AT-HOOK-CONTAINING ADAPTOR PROTEIN; PTOV1","url":"https://www.omim.org/entry/610195"},{"mim_id":"606998","title":"FLOTILLIN 1; FLOT1","url":"https://www.omim.org/entry/606998"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTOV1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q86YD1","domains":[{"cath_id":"2.40.290.30","chopping":"90-235","consensus_level":"high","plddt":75.0303,"start":90,"end":235},{"cath_id":"2.40.290.30","chopping":"253-402","consensus_level":"high","plddt":79.0607,"start":253,"end":402}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86YD1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86YD1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86YD1-F1-predicted_aligned_error_v6.png","plddt_mean":67.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTOV1","jax_strain_url":"https://www.jax.org/strain/search?query=PTOV1"},"sequence":{"accession":"Q86YD1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86YD1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86YD1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86YD1"}},"corpus_meta":[{"pmid":"15713644","id":"PMC_15713644","title":"PTOV1 enables the nuclear translocation and mitogenic activity of flotillin-1, a major protein of lipid rafts.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15713644","citation_count":86,"is_preprint":false},{"pmid":"11313889","id":"PMC_11313889","title":"PTOV1, a novel protein overexpressed in prostate cancer containing a new class of protein homology blocks.","date":"2001","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11313889","citation_count":60,"is_preprint":false},{"pmid":"12598323","id":"PMC_12598323","title":"PTOV-1, a novel protein overexpressed in prostate cancer, shuttles between the cytoplasm and the nucleus and promotes entry into the S phase of the cell division cycle.","date":"2003","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12598323","citation_count":48,"is_preprint":false},{"pmid":"18451224","id":"PMC_18451224","title":"PTOV1 expression predicts prostate cancer in men with isolated high-grade prostatic intraepithelial neoplasia in needle biopsy.","date":"2008","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/18451224","citation_count":46,"is_preprint":false},{"pmid":"24684754","id":"PMC_24684754","title":"Prostate tumor OVerexpressed-1 (PTOV1) down-regulates HES1 and HEY1 notch targets genes and promotes prostate cancer progression.","date":"2014","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24684754","citation_count":32,"is_preprint":false},{"pmid":"21181414","id":"PMC_21181414","title":"PTOV1 is overexpressed in human high-grade malignant tumors.","date":"2010","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21181414","citation_count":23,"is_preprint":false},{"pmid":"21110951","id":"PMC_21110951","title":"PTOV1 antagonizes MED25 in RAR transcriptional activation.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21110951","citation_count":23,"is_preprint":false},{"pmid":"31387622","id":"PMC_31387622","title":"Depleting PTOV1 sensitizes non-small cell lung cancer cells to chemotherapy through attenuating cancer stem cell traits.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31387622","citation_count":21,"is_preprint":false},{"pmid":"23321499","id":"PMC_23321499","title":"Zyxin cooperates with PTOV1 to confer retinoic acid resistance by repressing RAR activity.","date":"2013","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/23321499","citation_count":18,"is_preprint":false},{"pmid":"16639697","id":"PMC_16639697","title":"PTOV1: a novel testosterone-induced atherogenic gene in human aorta.","date":"2006","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16639697","citation_count":17,"is_preprint":false},{"pmid":"28938627","id":"PMC_28938627","title":"Prostate Tumor Overexpressed-1 (PTOV1) promotes docetaxel-resistance and survival of castration resistant prostate cancer cells.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28938627","citation_count":15,"is_preprint":false},{"pmid":"31083670","id":"PMC_31083670","title":"Knockdown of PTOV1 and PIN1 exhibit common phenotypic anti-cancer effects in MDA-MB-231 cells.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31083670","citation_count":14,"is_preprint":false},{"pmid":"28228215","id":"PMC_28228215","title":"hnRNPK-regulated PTOV1-AS1 modulates heme oxygenase-1 expression via miR-1207-5p.","date":"2017","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/28228215","citation_count":14,"is_preprint":false},{"pmid":"23132460","id":"PMC_23132460","title":"Immunohistochemical expression of prostate tumour overexpressed 1 (PTOV1) in atypical adenomatous hyperplasia (AAH) of the prostate: additional evidence linking (AAH) to adenocarcinoma.","date":"2012","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/23132460","citation_count":10,"is_preprint":false},{"pmid":"33738336","id":"PMC_33738336","title":"PTOV1 promotes cisplatin-induced chemotherapy resistance by activating the nuclear factor kappa B pathway in ovarian cancer.","date":"2021","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/33738336","citation_count":9,"is_preprint":false},{"pmid":"28651486","id":"PMC_28651486","title":"Overexpressed PTOV1 associates with tumorigenesis and progression of esophageal squamous cell carcinoma.","date":"2017","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28651486","citation_count":8,"is_preprint":false},{"pmid":"34654719","id":"PMC_34654719","title":"SGK2, 14-3-3, and HUWE1 Cooperate to Control the Localization, Stability, and Function of the Oncoprotein PTOV1.","date":"2021","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/34654719","citation_count":7,"is_preprint":false},{"pmid":"37352125","id":"PMC_37352125","title":"Upregulation of lncRNA PTOV1-AS1 in hepatocellular carcinoma contributes to disease progression and sorafenib resistance through regulating miR-505.","date":"2023","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/37352125","citation_count":7,"is_preprint":false},{"pmid":"21678139","id":"PMC_21678139","title":"PTOV1 is associated with UCH-L1 and in response to estrogen stimuli during the mouse oocyte development.","date":"2011","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21678139","citation_count":7,"is_preprint":false},{"pmid":"39229496","id":"PMC_39229496","title":"PTOV1 facilitates colorectal cancer cell proliferation through activating AKT1 signaling pathway.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39229496","citation_count":6,"is_preprint":false},{"pmid":"36960218","id":"PMC_36960218","title":"LncRNA PTOV1-AS2 Promotes Colon Cancer Progression through the miR-145-5p/FSCN1 Axis.","date":"2023","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36960218","citation_count":6,"is_preprint":false},{"pmid":"38194947","id":"PMC_38194947","title":"PTOV1-AS1 desensitizes colorectal cancer cells to 5-FU through depressing miR-149-5p to activate the positive feedback loop with Wnt/β-catenin pathway.","date":"2024","source":"Phytotherapy research : PTR","url":"https://pubmed.ncbi.nlm.nih.gov/38194947","citation_count":5,"is_preprint":false},{"pmid":"27804940","id":"PMC_27804940","title":"[Estimation of the diagnostic potential of APOD, PTOV1, and EPHA4 for prostatic neoplasms].","date":"2016","source":"Arkhiv patologii","url":"https://pubmed.ncbi.nlm.nih.gov/27804940","citation_count":5,"is_preprint":false},{"pmid":"30922918","id":"PMC_30922918","title":"A novel DNA-binding motif in prostate tumor overexpressed-1 (PTOV1) required for the expression of ALDH1A1 and CCNG2 in cancer cells.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30922918","citation_count":4,"is_preprint":false},{"pmid":"39905441","id":"PMC_39905441","title":"PTOV1 exerts pro-oncogenic role in colorectal cancer by modulating SQSTM1-mediated autophagic degradation of p53.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39905441","citation_count":1,"is_preprint":false},{"pmid":"39678549","id":"PMC_39678549","title":"Association of PTOV1 and Cyfra21-1 with neoadjuvant chemosensitivity in patients with lung adenocarcinoma.","date":"2024","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/39678549","citation_count":1,"is_preprint":false},{"pmid":"40133702","id":"PMC_40133702","title":"PTOV1 interacts with ZNF449 to promote colorectal cancer development.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/40133702","citation_count":0,"is_preprint":false},{"pmid":"41329068","id":"PMC_41329068","title":"Salidroside Alleviates Lung Ischemia-Reperfusion Injury by Inhibiting Ferroptosis Through the MAFK/lncRNA PTOV1-AS2/miR-525-5p/ACE2 Axis.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41329068","citation_count":0,"is_preprint":false},{"pmid":"42108773","id":"PMC_42108773","title":"Exploring the Role of Novel N (4) Substituted 5,7-Dibromoisatin Thiosemicarbazones in Modulating PTOV1 Activity for Therapeutic Relevance in Breast Cancer.","date":"2026","source":"Drug development research","url":"https://pubmed.ncbi.nlm.nih.gov/42108773","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18161,"output_tokens":4195,"usd":0.058704,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12149,"output_tokens":4044,"usd":0.080922,"stage2_stop_reason":"end_turn"},"total_usd":0.139626,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"PTOV1 protein consists of two novel homologous domains (PTOV blocks) arranged in tandem, and localizes predominantly to the perinuclear region in cultured cells, as shown by immunocytochemistry and expression of chimeric GFP-PTOV1 proteins.\",\n      \"method\": \"GFP fusion protein imaging, immunocytochemistry\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with GFP fusion, replicated by immunocytochemistry, single lab\",\n      \"pmids\": [\"11313889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PTOV1 shuttles between cytoplasm and nucleus in a cell cycle-dependent manner: it localizes to the cytoplasm in quiescent cells, translocates to the nucleus at the onset of S phase after serum stimulation, and exits the nucleus at the end of mitosis. Overexpression of PTOV1 forces entry into S phase and increases cyclin D1 protein levels.\",\n      \"method\": \"Immunofluorescence, GFP live imaging, flow cytometry, Western blot\",\n      \"journal\": \"The American Journal of Pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (live imaging, flow cytometry, cyclin D1 Western blot), single lab\",\n      \"pmids\": [\"12598323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PTOV1 physically interacts with flotillin-1, co-purifying with it in detergent-insoluble lipid raft fractions. PTOV1 enables nuclear translocation of flotillin-1: depletion of PTOV1 significantly inhibited nuclear localization of flotillin-1, whereas depletion of flotillin-1 did not affect nuclear localization of PTOV1. Both proteins are required for cell proliferation, and their proliferative effect requires nuclear localization.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, immunocytochemistry, siRNA knockdown, overexpression with proliferation assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, fractionation, siRNA rescue, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"15713644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PTOV1 gene expression is induced by testosterone in androgen receptor-positive human vascular smooth muscle cells (VSMCs), and siRNA-mediated knockdown of PTOV1 suppresses testosterone-induced VSMC proliferation, placing PTOV1 downstream of androgen receptor signaling in VSMCs.\",\n      \"method\": \"Microarray, quantitative RT-PCR, siRNA knockdown with proliferation assay\",\n      \"journal\": \"The Journal of Pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional siRNA knockdown with defined proliferation readout, corroborated by expression analysis, single lab\",\n      \"pmids\": [\"16639697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PTOV1 antagonizes MED25 in retinoic acid receptor (RAR) transcriptional activation through competitive binding to CBP and opposing regulation of CBP recruitment to RA-responsive gene promoters, modulating RA sensitivity in cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, reporter (luciferase) assay, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, and reporter assay provide multiple orthogonal methods; single lab\",\n      \"pmids\": [\"21110951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTOV1 physically interacts with ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) in mouse oocytes, as identified by pull-down screening of UCH-L1-binding proteins from mouse ovaries; PTOV1 distribution in oocytes changes from cytoplasm/nucleus in prepubescent mice to nucleus/plasma membrane in adults, and estradiol treatment induces the adult-specific distribution pattern.\",\n      \"method\": \"Protein pull-down/binding screen, immunohistochemistry, estradiol treatment\",\n      \"journal\": \"Histochemistry and Cell Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pull-down interaction, localization by IHC, single lab, no functional rescue\",\n      \"pmids\": [\"21678139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Zyxin translocates to the nucleus in response to retinoic acid (RA) and forms a ternary complex with PTOV1 and the RAR coactivator CBP, thereby promoting dissociation of CBP from RAR at RA-responsive promoters and repressing RAR transcriptional activity, contributing to RA resistance.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, reporter assay, nuclear translocation imaging\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and reporter assay in a single lab study; mechanistically extends prior MED25/PTOV1/CBP finding\",\n      \"pmids\": [\"23321499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTOV1 counteracts Notch signaling by associating with the HEY1 and HES1 promoters together with components of the Notch repressor complex under inactive Notch conditions, thereby repressing these Notch target genes. Active Notch1 provokes dismissal of PTOV1 from these promoters. In Drosophila, human PTOV1 exacerbated Notch deletion mutant phenotypes and suppressed constitutively active Notch effects, confirming epistatic antagonism. PTOV1 is required for in vitro invasiveness and anchorage-independent growth of PC-3 cells, and for their in vivo metastatic spread.\",\n      \"method\": \"ChIP, co-immunoprecipitation, pull-down, luciferase reporter assay, Drosophila genetic epistasis, SCID-Beige mouse xenograft, lentiviral knockdown/overexpression\",\n      \"journal\": \"Molecular Cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, Co-IP, reporter, Drosophila epistasis, in vivo xenograft), mechanistically replicated across systems\",\n      \"pmids\": [\"24684754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTOV1 contains an AT-hook-like DNA-binding motif within its PTOV-A domain that directly binds to the promoters of ALDH1A1 and CCNG2. Mutation of this motif significantly decreased PTOV1-promoted expression of these genes. PTOV1 also associates with mitotic chromosomes in high-grade carcinomas.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), mutagenesis, immunohistochemistry\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — EMSA (in vitro DNA binding), ChIP, and active-site mutagenesis in a single study; provides direct biochemical evidence for DNA-binding activity\",\n      \"pmids\": [\"30922918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTOV1 physically interacts with PIN1 in breast cancer cells (MDA-MB-231), validated by co-immunoprecipitation. Overexpression of PIN1 increases PTOV1 expression. Knockdown of PTOV1 inhibits cyclin D1, c-Myc, and β-catenin expression and induces apoptosis markers (increased BAX, LC3, Beclin-1; decreased Bcl-2, Bcl-xL).\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Western blot, flow cytometry\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction validated, multiple downstream readouts by Western blot, single lab\",\n      \"pmids\": [\"31083670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Depletion of PTOV1 in NSCLC cells attenuates cancer stem cell traits by impairing DKK1/β-catenin signaling, leading to increased sensitivity to cisplatin and docetaxel.\",\n      \"method\": \"siRNA knockdown, flow cytometry, colony formation, tumor sphere formation, xenograft model, Western blot\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with defined pathway readout (DKK1/β-catenin), in vivo xenograft corroboration, single lab\",\n      \"pmids\": [\"31387622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SGK2 phosphorylates PTOV1 at serine 36, which is required for 14-3-3 binding to PTOV1. 14-3-3 sequesters PTOV1 in the cytosol, stabilizing it by preventing its interaction with the E3 ubiquitin ligase HUWE1. Disruption of PTOV1-14-3-3 interaction causes PTOV1 accumulation in the nucleus and proteasome-dependent degradation of PTOV1 via HUWE1. Cytosolic 14-3-3-bound PTOV1 promotes expression of cJun to drive cell-cycle progression.\",\n      \"method\": \"Co-immunoprecipitation, phospho-mutagenesis, proteasome inhibitor rescue, subcellular fractionation, Western blot, overexpression/knockdown\",\n      \"journal\": \"Molecular Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — phospho-mutagenesis at defined residue, Co-IP, proteasome inhibitor rescue, multiple orthogonal methods in single study establishing the SGK2-14-3-3-HUWE1 regulatory axis\",\n      \"pmids\": [\"34654719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTOV1 overexpression increases NF-κB pathway activity, as shown by increased nuclear translocation of p65 and phosphorylation of IKKα/β. Pharmacological inhibition of NF-κB in PTOV1-overexpressing ovarian cancer cells restored cisplatin-induced apoptosis, placing PTOV1 upstream of NF-κB in chemoresistance.\",\n      \"method\": \"Overexpression/knockdown, Western blot for NF-κB pathway markers, nuclear fractionation, NF-κB inhibitor rescue, apoptosis assay, xenograft model\",\n      \"journal\": \"Molecular Therapy Oncolytics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway inhibitor epistasis rescue, Western blot for phospho-IKK and nuclear p65, single lab\",\n      \"pmids\": [\"33738336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTOV1 facilitates colorectal cancer cell proliferation through activation of the AKT1 signaling pathway: PTOV1 overexpression increases AKT1 phosphorylation and reduces cell cycle inhibitors P21 and P27, while pharmacological inhibition of AKT1 phosphorylation with MK2206 reverses PTOV1-induced proliferation.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blot for p-AKT1/P21/P27, AKT1 inhibitor (MK2206) rescue, CCK-8/colony formation assays\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inhibitor-based epistasis rescue and Western blot pathway markers, single lab\",\n      \"pmids\": [\"39229496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTOV1 destabilizes p53 by activating autophagy and recruiting p53 to the cargo receptor SQSTM1 for autophagic degradation. PTOV1 physically interacts with p53 (identified by IP-mass spectrometry and Co-IP). Overexpression of p53 or knockdown of SQSTM1 reverses PTOV1-driven pro-tumor phenotypes in colorectal cancer.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, co-immunoprecipitation, immunofluorescence, Western blot, transmission electron microscopy (autophagy), p53 overexpression/SQSTM1 knockdown rescue, in vivo mouse model\",\n      \"journal\": \"Journal of Translational Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with MS identification of interaction, TEM for autophagy, rescue experiments, single lab\",\n      \"pmids\": [\"39905441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTOV1 physically interacts with ZNF449, and this complex synergistically promotes transcription of MYC. The interaction was demonstrated by Co-IP and GST pull-down. A TAT-PTOV1(125-283 aa) peptide disrupting the PTOV1/ZNF449 interaction inhibited colorectal cancer development in a xenograft model.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, luciferase reporter assay (implied by 'promoted transcription of MYC'), xenograft mouse model, peptide disruption\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down confirming direct interaction, in vivo peptide disruption rescue, single lab\",\n      \"pmids\": [\"40133702\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTOV1 is a cell cycle-regulated adaptor/transcription-translation regulator that shuttles between the cytoplasm and nucleus (peaking in S phase), where it directly binds DNA via an AT-hook-like motif in its PTOV-A domain to activate target gene promoters (e.g., ALDH1A1, CCNG2), represses Notch target genes (HES1, HEY1) by associating with their promoter repressor complexes, competes with MED25 for CBP binding to antagonize RAR-mediated transcription, and cooperates with ZNF449 to drive MYC transcription; its cytoplasmic stability and localization are controlled by an SGK2-phosphorylation-dependent interaction with 14-3-3 that sequesters PTOV1 from nuclear accumulation and protects it from HUWE1-mediated proteasomal degradation, while nuclear PTOV1 promotes cell-cycle progression via cJun; additional mechanisms include activation of the NF-κB and AKT1/PI3K pathways, promotion of SQSTM1-directed autophagic degradation of p53, interaction with flotillin-1 (enabling its nuclear import), and interaction with PIN1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTOV1 is a cell cycle-regulated adaptor and transcriptional regulator that promotes proliferation by coupling nucleocytoplasmic shuttling to control of growth-related gene expression [#1, #8]. Built from two tandem homologous PTOV domains, it shuttles between the cytoplasm and nucleus in a cell cycle-dependent manner, accumulating in the nucleus at the onset of S phase and forcing entry into S phase with elevated cyclin D1 [#0, #1]. In the nucleus, PTOV1 acts directly on chromatin: an AT-hook-like motif within its PTOV-A domain binds the promoters of ALDH1A1 and CCNG2 to drive their expression, and it associates with mitotic chromosomes [#8]. Its transcriptional output is bidirectional — it represses Notch target genes HES1 and HEY1 by joining the Notch repressor complex at their promoters until active Notch evicts it [#7], antagonizes retinoic acid receptor signaling by competing for CBP together with MED25 and zyxin [#4, #6], and cooperates with ZNF449 to activate MYC transcription [#15]. PTOV1 abundance and localization are governed by an SGK2-phosphorylation-dependent switch: phosphorylation at serine 36 enables 14-3-3 binding, which sequesters PTOV1 in the cytosol and shields it from HUWE1-mediated proteasomal degradation, while disruption of this interaction drives nuclear accumulation and turnover; cytosolic 14-3-3-bound PTOV1 induces cJun to drive cell-cycle progression [#11]. In cancer, PTOV1 drives invasion, stemness and chemoresistance through Notch antagonism, β-catenin/DKK1 signaling, NF-κB and AKT1 activation, and SQSTM1-directed autophagic degradation of p53 [#7, #10, #12, #13, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established PTOV1 as a novel protein with a distinctive two-domain architecture and defined its baseline subcellular distribution, providing the structural starting point for all later mechanistic work.\",\n      \"evidence\": \"GFP fusion imaging and immunocytochemistry in cultured cells\",\n      \"pmids\": [\"11313889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No function assigned to the PTOV domains\", \"Perinuclear localization not linked to a molecular activity\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed that PTOV1 localization is cell-cycle gated and functionally drives proliferation, reframing it from a localized protein to an S-phase-coupled growth regulator.\",\n      \"evidence\": \"Immunofluorescence, GFP live imaging, flow cytometry and cyclin D1 Western blot after serum stimulation\",\n      \"pmids\": [\"12598323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting nuclear entry to S-phase induction unresolved\", \"Direct transcriptional targets unidentified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified flotillin-1 as a physical partner and positioned PTOV1 as a determinant of partner nuclear import, the first direct interaction underpinning its proliferative role.\",\n      \"evidence\": \"Reciprocal Co-IP, lipid-raft fractionation, siRNA depletion and proliferation assays\",\n      \"pmids\": [\"15713644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular import machinery used by PTOV1 unknown\", \"Relationship to its own shuttling not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed PTOV1 downstream of androgen receptor signaling, linking its expression to a hormonal proliferative stimulus in vascular smooth muscle.\",\n      \"evidence\": \"Microarray, qRT-PCR and siRNA knockdown with proliferation readout in AR-positive VSMCs\",\n      \"pmids\": [\"16639697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AR-responsive elements at the PTOV1 locus not mapped\", \"Relevance beyond VSMCs untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined PTOV1 as a transcriptional antagonist of retinoic acid signaling by competing for the coactivator CBP, the first specific transcriptional mechanism for the protein.\",\n      \"evidence\": \"Co-IP, ChIP, reporter assays and nuclear translocation imaging implicating MED25 and zyxin in CBP competition\",\n      \"pmids\": [\"21110951\", \"23321499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PTOV1 contacts CBP directly or via partners unresolved\", \"Genome-wide RAR targets affected not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established PTOV1 as a sequence-context chromatin-associated repressor of Notch targets and a driver of invasion and metastasis, demonstrating bidirectional transcriptional control with in vivo consequence.\",\n      \"evidence\": \"ChIP, Co-IP, reporter assays, Drosophila genetic epistasis and SCID-Beige xenografts\",\n      \"pmids\": [\"24684754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PTOV1 is recruited to Notch repressor complexes not defined\", \"Whether DNA binding underlies promoter association unknown at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided direct biochemical evidence that PTOV1 is a DNA-binding protein through an AT-hook-like motif in its PTOV-A domain, converting prior promoter-association data into an intrinsic activity.\",\n      \"evidence\": \"EMSA, ChIP and motif mutagenesis at ALDH1A1/CCNG2 promoters plus mitotic chromosome IHC\",\n      \"pmids\": [\"30922918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide DNA-binding landscape unmapped\", \"Sequence specificity of the AT-hook motif not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended PTOV1's proliferative network through PIN1 interaction and downstream control of cyclin D1, c-Myc and β-catenin with apoptotic consequences upon depletion.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, Western blot and flow cytometry in breast cancer cells\",\n      \"pmids\": [\"31083670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PIN1 isomerizes PTOV1 directly untested\", \"Mechanism linking PTOV1 to the listed effectors indirect\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved how PTOV1 stability and localization are controlled, defining an SGK2-Ser36-phosphorylation/14-3-3/HUWE1 axis that gates cytosolic sequestration versus nuclear accumulation and degradation.\",\n      \"evidence\": \"Phospho-mutagenesis, Co-IP, proteasome-inhibitor rescue and subcellular fractionation\",\n      \"pmids\": [\"34654719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals upstream of SGK2 activation toward PTOV1 unknown\", \"Whether nuclear PTOV1 is the active transcriptional pool not directly shown here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked PTOV1 to NF-κB activation as a mechanism of chemoresistance, broadening its pro-survival signaling reach.\",\n      \"evidence\": \"Overexpression/knockdown, phospho-IKK and nuclear p65 Western blots, NF-κB inhibitor rescue and xenografts in ovarian cancer\",\n      \"pmids\": [\"33738336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular step connecting PTOV1 to IKK unknown\", \"Whether effect is transcriptional or post-translational unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected PTOV1 to AKT1 pathway activation and cell-cycle inhibitor suppression in colorectal cancer, adding a kinase-signaling arm to its proliferative function.\",\n      \"evidence\": \"Knockdown/overexpression, p-AKT1/P21/P27 Western blots and MK2206 rescue with proliferation assays\",\n      \"pmids\": [\"39229496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of AKT1 activation by PTOV1 not defined\", \"Direct versus indirect coupling untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a post-translational route by which PTOV1 destabilizes p53 — recruitment to SQSTM1 for autophagic degradation — and a ZNF449 partnership driving MYC, deepening its pro-tumor mechanism and identifying a druggable interaction interface.\",\n      \"evidence\": \"IP-MS, Co-IP, GST pull-down, TEM autophagy imaging, rescue with p53 overexpression/SQSTM1 knockdown, reporter assays and TAT-peptide disruption xenografts\",\n      \"pmids\": [\"39905441\", \"40133702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PTOV1 triggers autophagy initiation unresolved\", \"Whether ZNF449/MYC activation requires PTOV1 DNA binding untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTOV1's intrinsic AT-hook DNA binding, its many partner interactions, and its NF-κB/AKT1 signaling outputs are integrated into a single coherent regulatory program remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the PTOV domains or DNA-bound complex\", \"Genome-wide direct target set unmapped\", \"Whether signaling effects are downstream of its transcriptional activity or independent is unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 6, 7, 8, 15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 7, 8, 15]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FLOT1\", \"MED25\", \"ZYX\", \"CBP\", \"PIN1\", \"ZNF449\", \"TP53\", \"YWHA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}