{"gene":"PTTG1IP","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2007,"finding":"PTTG1IP (PBF) and PTTG repress sodium iodide symporter (NIS) mRNA expression and inhibit iodide uptake, acting at least in part through fibroblast growth factor-2, and specifically inhibiting NIS promoter activity via the human upstream enhancer element (hNUE) through a complex PAX8-USF1 response element; PTTG repression is contingent on the USF1 site.","method":"Promoter-reporter assays (NIS promoter constructs in FRTL-5 and human primary thyroid cells), transfection/overexpression, siRNA knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple reporter assays with defined promoter elements and primary human cells, single lab","pmids":["17297475"],"is_preprint":false},{"year":2011,"finding":"Transgenic thyroid-specific overexpression of PBF/PTTG1IP causes thyroid gland enlargement, hyperplastic and macrofollicular lesions, upregulates Akt, TSHR, and cyclin D1, and potently inhibits NIS expression and iodide uptake; PBF depletion in primary thyroid cultures rescues radioiodine uptake.","method":"Transgenic mouse model (bovine thyroglobulin promoter-driven PBF), primary thyroid cell culture, siRNA knockdown, iodide uptake assays, IHC, western blot","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — in vivo transgenic model with defined cellular phenotypes and rescue experiment","pmids":["21844185"],"is_preprint":false},{"year":2013,"finding":"PBF/PTTG1IP is a tyrosine phosphoprotein that specifically binds Src kinase; Src phosphorylates PBF at residue Y174. Phosphorylation at Y174 promotes internalization of PBF from the plasma membrane (PM), and abrogation of Y174 results in PM retention and markedly reduced ability to bind and internalize NIS. The Src inhibitor PP1 inhibits PBF phosphorylation and stimulates iodide uptake in thyroid carcinoma and primary thyroid cells.","method":"Mass spectrometry, GST pulldown, co-immunoprecipitation, site-directed mutagenesis (Y174A), cell surface biotinylation, iodide uptake assay, pharmacological inhibition (PP1)","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (MS, GST pulldown, Co-IP, mutagenesis, functional rescue) in a single study","pmids":["23678037"],"is_preprint":false},{"year":2012,"finding":"PBF/PTTG1IP binds MCT8 (monocarboxylate transporter 8) in vitro and causes a marked shift in MCT8 subcellular localization away from the plasma membrane, resulting in reduced MCT8 at the plasma membrane. In vivo, PBF-Tg mice show enhanced thyroidal thyroid hormone accumulation and reduced TH secretion upon TSH stimulation, phenocopying Mct8-knockout mice.","method":"Co-immunoprecipitation, cell surface biotinylation assay, confocal colocalization, transgenic mouse model (PBF-Tg), mRNA and protein expression analysis","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding and localization assays corroborated by in vivo mouse model with functional TH secretion phenotype","pmids":["22535767"],"is_preprint":false},{"year":2014,"finding":"PBF/PTTG1IP binds specifically to p53 in thyroid cells, represses p53-dependent transactivation, and decreases p53 stability by enhancing ubiquitination dependent on Mdm2 E3 ligase activity. PBF transgenic mouse thyroids show increased genomic instability and repression of ~40% of DNA repair genes.","method":"Co-immunoprecipitation, proximity ligation assay, ubiquitination assay, p53-responsive promoter-reporter assays, fluorescent ISSR-PCR for genomic instability, transgenic mouse model","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods plus in vivo transgenic confirmation","pmids":["24506068"],"is_preprint":false},{"year":2016,"finding":"PBF/PTTG1IP physically interacts and co-localizes with cortactin (CTTN) at the cell periphery and leading edge of migrating cancer cells, and PBF-induced cellular invasion and migration in thyroid and breast cancer cells is entirely abrogated in the absence of CTTN. Mutation of PBF at Y174A or pharmacological intervention modulates the PBF:CTTN interaction and attenuates invasive properties.","method":"Co-immunoprecipitation, proximity ligation assay, confocal colocalization, 2D Boyden chamber invasion assay, 3D organotypic assay, siRNA knockdown, site-directed mutagenesis (Y174A)","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 1-2 — physical interaction confirmed by multiple methods plus functional dependency established by knockout and mutagenesis","pmids":["27603901"],"is_preprint":false},{"year":2017,"finding":"PBF/PTTG1IP missense mutations C51R and R140W reduce protein stability, alter subcellular localization (C51R retained in ER; R140W in Golgi), abolish induction of cellular migration and invasion, and prevent colony formation and anchorage-independent growth, whereas both mutants retain the ability to repress radioiodide uptake.","method":"Anisomycin protein half-life assay, immunofluorescence/confocal localization, proliferation assay, Boyden chamber invasion assay, colony formation assay, soft agar assay, iodide uptake assay","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays with defined mutations, single lab","pmids":["28676500"],"is_preprint":false},{"year":2018,"finding":"Androgen receptor (AR) directly binds a novel androgen response element in the PBF/PTTG1IP gene promoter upon androgen stimulation, upregulating PBF expression; RNAi knockdown of PBF significantly reduces androgen-induced LNCaP cell growth and invasion.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, RNA interference, proliferation and invasion assays","journal":"Neoplasma","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms direct AR binding at PBF promoter; functional RNAi data, single lab","pmids":["30569723"],"is_preprint":false},{"year":2022,"finding":"The transcription factor Sp4 binds the PTTG1IP gene promoter at Sp4 response elements within a -212 to +7 bp region and positively regulates PTTG1IP transcription and expression.","method":"Luciferase reporter assay (promoter deletion analysis), electrophoretic mobility shift assay (EMSA), Sp4 overexpression in HeLa cells","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — EMSA confirms direct binding, reporter assay confirms functional effect, single lab","pmids":["36383136"],"is_preprint":false},{"year":2024,"finding":"PTTG1IP is a small N-glycosylated single-spanning transmembrane protein whose N-glycosylation (at two arginine residues) is required for its sorting into extracellular vesicles (EVs); chimeric PTTG1IP fusion proteins enable highly efficient loading of therapeutic cargoes (Cre protein, Cas9-sgRNA) into EVs for functional delivery to recipient cells.","method":"Bioinformatics (N-glycosylation prediction), mutagenesis of glycosylation sites, EV isolation and cargo loading assays, functional delivery assays (Cre reporter, Cas9-sgRNA reporter) in cell culture and mouse xenograft","journal":"Extracellular vesicle","confidence":"Medium","confidence_rationale":"Tier 1-2 — mutagenesis of N-glycosylation sites with functional EV-loading readout, corroborated in vivo","pmids":["39712388"],"is_preprint":false},{"year":2025,"finding":"PTTG1IP forms an endogenous complex with cortactin (CTTN) in thyroid cancer cells, co-localizing by immunofluorescence, and occupies the promoters of DDR genes BRCA1, BRCA2, RAD51, RAD51AP1, and ATM as determined by ChIP-qPCR; PTTG1IP depletion increases radiation-induced DNA damage and cell death.","method":"Co-immunoprecipitation, immunofluorescence, ChIP-qPCR, shRNA knockdown, cell viability assay, TUNEL apoptosis assay, γH2AX immunofluorescence after irradiation","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, functional knockdown), single lab, no independent replication","pmids":["41074439"],"is_preprint":false},{"year":2008,"finding":"A fusion protein (F-PBF(β-TrCP)) constructed by replacing the WD40-repeat of F-box protein β-TrCP with PTTG1IP (PBF) degrades both exogenous PTTG1-EGFP and endogenous PTTG1 protein via the ubiquitin-proteasome system, demonstrating that PBF physically recruits PTTG1 into an SCF E3 ligase complex.","method":"Fusion protein construction, co-expression in COS-7 and HeLa cells, western blot for PTTG1 protein levels, proliferation and colony assays","journal":"Journal of biotechnology","confidence":"Low","confidence_rationale":"Tier 3 — engineered fusion protein context; indirect demonstration of PBF-PTTG1 binding capability, single lab","pmids":["18977400"],"is_preprint":false},{"year":2011,"finding":"PBF/PTTG1IP is reported to induce translocation of PTTG1 (securin) from the cytoplasm to the nucleus, and possesses independent transforming ability, transforming NIH 3T3 fibroblasts and inducing tumors in nude mice in vivo.","method":"NIH 3T3 transformation assay, nude mouse tumor formation assay (referenced in review)","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo transformation assays described in review context referencing prior experimental work","pmids":["21450804"],"is_preprint":false}],"current_model":"PTTG1IP/PBF is a multifunctional glycoprotein proto-oncogene that acts as a scaffold protein: it physically interacts with PTTG1/securin to promote its nuclear translocation, binds and internalizes NIS and MCT8 away from the plasma membrane (regulated by Src-mediated phosphorylation at Y174), interacts with cortactin at the cell leading edge to drive cancer cell invasion, binds p53 and promotes its Mdm2-dependent ubiquitination and degradation, occupies DNA damage repair gene promoters, and is sorted into extracellular vesicles via N-glycosylation, with its expression transcriptionally regulated by Sp4 and androgen receptor."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing that PTTG1IP functionally represses NIS expression answered whether PBF had a direct role in thyroid iodide handling beyond its known PTTG1 interaction.","evidence":"NIS promoter-reporter assays with defined PAX8-USF1 elements in FRTL-5 and primary human thyroid cells","pmids":["17297475"],"confidence":"Medium","gaps":["Mechanism of PBF-mediated NIS promoter repression not fully delineated","Whether PBF directly contacts NIS protein at this stage unresolved"]},{"year":2008,"claim":"An engineered SCF-PBF fusion that degraded PTTG1 via the proteasome demonstrated that PBF can physically recruit PTTG1, clarifying the molecular basis of PBF-PTTG1 interaction.","evidence":"Fusion protein (F-PBF-β-TrCP) co-expression in COS-7/HeLa cells with western blot for PTTG1 degradation","pmids":["18977400"],"confidence":"Low","gaps":["Engineered fusion context does not prove endogenous complex formation","Stoichiometry and endogenous relevance not established","No reciprocal validation of endogenous interaction"]},{"year":2011,"claim":"In vivo transgenic overexpression proved PBF is a bona fide proto-oncogene that drives thyroid hyperplasia and suppresses NIS, moving beyond cell-based assays to organismal phenotypes; independently, PBF was shown to promote PTTG1 nuclear translocation and transform NIH 3T3 cells.","evidence":"Thyroid-specific PBF transgenic mouse model with IHC, iodide uptake, and primary culture rescue (siRNA); NIH 3T3 transformation and nude mouse assays","pmids":["21844185","21450804"],"confidence":"High","gaps":["Whether transformation is PTTG1-dependent or independent not resolved","Mechanism of Akt/cyclin D1 upregulation downstream of PBF unclear"]},{"year":2012,"claim":"Discovery that PBF binds and internalizes MCT8 away from the plasma membrane extended its transporter-regulatory function beyond NIS to thyroid hormone efflux, explaining in vivo thyroid hormone accumulation in PBF-Tg mice.","evidence":"Co-immunoprecipitation, cell surface biotinylation, confocal microscopy, and PBF-Tg mouse TH secretion assays","pmids":["22535767"],"confidence":"High","gaps":["Direct binding domain on MCT8 not mapped","Whether Y174 phosphorylation also regulates MCT8 internalization untested"]},{"year":2013,"claim":"Identification of Src as the kinase phosphorylating PBF at Y174, and demonstration that this modification controls PBF plasma membrane dynamics and NIS internalization, provided the first signaling-level regulatory mechanism for PBF function.","evidence":"Mass spectrometry, GST pulldown, Co-IP, Y174A mutagenesis, cell surface biotinylation, PP1 inhibitor rescue of iodide uptake","pmids":["23678037"],"confidence":"High","gaps":["Other potential phosphorylation sites not systematically surveyed","Structural basis of Src-PBF recognition unknown"]},{"year":2014,"claim":"Demonstrating that PBF binds p53 and promotes its Mdm2-dependent ubiquitination, while PBF-Tg thyroids show repression of DNA repair genes and genomic instability, revealed a second oncogenic axis independent of transporter regulation.","evidence":"Co-IP, proximity ligation assay, ubiquitination assay, p53 reporter assays, ISSR-PCR genomic instability, transgenic mouse model","pmids":["24506068"],"confidence":"High","gaps":["Whether PBF directly enhances Mdm2-p53 interaction or acts allosterically unresolved","Causal relationship between DDR gene repression and genomic instability not mechanistically dissected"]},{"year":2016,"claim":"Identification of cortactin as a PBF-interacting partner at the leading edge that is required for PBF-driven invasion established the molecular mechanism linking PBF to cell motility.","evidence":"Co-IP, proximity ligation assay, confocal colocalization, 2D/3D invasion assays, CTTN siRNA rescue, Y174A mutagenesis","pmids":["27603901"],"confidence":"High","gaps":["Whether PBF directly activates cortactin branched-actin nucleation or acts as a scaffold not determined","Contribution of PBF-cortactin axis versus PBF-p53 axis to tumor progression in vivo unknown"]},{"year":2017,"claim":"Cancer-associated missense mutations (C51R, R140W) that disrupt protein stability and localization but retain NIS-repressive function showed that PBF's oncogenic activities (invasion, colony formation) and transporter-repressive functions are mechanistically separable.","evidence":"Protein half-life assays, confocal localization, Boyden chamber invasion, colony formation, soft agar, and iodide uptake assays with site-directed mutants","pmids":["28676500"],"confidence":"Medium","gaps":["Whether these mutations affect cortactin or p53 binding not tested","No patient cohort to assess clinical prevalence of these variants"]},{"year":2018,"claim":"Discovery that androgen receptor directly binds the PTTG1IP promoter and drives its expression linked PBF upregulation to androgen signaling, providing a transcriptional mechanism for PBF overexpression in prostate cancer.","evidence":"ChIP at PBF promoter ARE, luciferase reporter, RNAi knockdown of PBF reducing androgen-driven proliferation/invasion in LNCaP cells","pmids":["30569723"],"confidence":"Medium","gaps":["Whether AR regulation of PBF is relevant in thyroid or breast contexts untested","Epigenetic regulation of PTTG1IP locus not explored"]},{"year":2022,"claim":"Identification of Sp4 as a direct transcriptional activator of PTTG1IP via promoter-proximal Sp4 response elements added a second transcription factor to PBF's regulatory circuitry.","evidence":"EMSA confirming direct Sp4 binding, promoter deletion/reporter analysis in HeLa cells","pmids":["36383136"],"confidence":"Medium","gaps":["Physiological context in which Sp4 regulates PBF not established","Interplay between Sp4 and AR at the PTTG1IP promoter unknown"]},{"year":2024,"claim":"Demonstration that N-glycosylation is required for PTTG1IP sorting into extracellular vesicles revealed a new trafficking fate and functional context for the protein beyond plasma membrane and intracellular compartments.","evidence":"Mutagenesis of N-glycosylation sites, EV isolation, functional cargo delivery assays in vitro and in mouse xenograft","pmids":["39712388"],"confidence":"Medium","gaps":["Endogenous cargo carried by PTTG1IP-positive EVs not identified","Whether EV-sorted PBF retains oncogenic signaling in recipient cells unknown"]},{"year":2025,"claim":"ChIP-qPCR showing PBF occupies promoters of BRCA1, BRCA2, RAD51, RAD51AP1, and ATM, combined with the observation that PBF depletion sensitizes cells to radiation-induced DNA damage, provided direct evidence for PBF's role in DNA damage repair gene regulation.","evidence":"Co-IP confirming endogenous PBF-cortactin complex, ChIP-qPCR at DDR promoters, shRNA knockdown with γH2AX and TUNEL assays after irradiation","pmids":["41074439"],"confidence":"Medium","gaps":["Whether PBF activates or represses DDR gene transcription at these promoters not clarified (contrasts with earlier repression data)","Mechanism by which a transmembrane protein occupies gene promoters not explained","Not independently replicated"]},{"year":null,"claim":"The mechanism by which a single-pass transmembrane glycoprotein accesses nuclear gene promoters and coordinates its dual membrane-trafficking and transcriptional functions remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PTTG1IP exists","Nuclear versus membrane pool partitioning mechanism unknown","Whether PBF's diverse functions (NIS/MCT8 internalization, p53 destabilization, cortactin-mediated invasion, DDR gene regulation, EV sorting) operate in the same or distinct cellular contexts is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,10,12]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,5,12]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,3,9]}],"complexes":[],"partners":["NIS","MCT8","CTTN","PTTG1","TP53","SRC","MDM2"],"other_free_text":[]},"mechanistic_narrative":"PTTG1IP (PBF) is a single-spanning transmembrane glycoprotein proto-oncogene that functions as a multifunctional scaffold controlling plasma membrane transporter availability, p53 stability, DNA damage repair gene expression, and cell invasion. It binds and internalizes the sodium iodide symporter (NIS) and monocarboxylate transporter 8 (MCT8) away from the plasma membrane in a process regulated by Src-mediated phosphorylation at Y174, thereby suppressing iodide uptake and thyroid hormone secretion [PMID:23678037, PMID:22535767, PMID:21844185]. PTTG1IP interacts with cortactin at the cell leading edge to drive cancer cell invasion, binds p53 to promote its Mdm2-dependent ubiquitination and degradation causing genomic instability, and occupies promoters of DNA damage repair genes including BRCA1, BRCA2, and RAD51 [PMID:27603901, PMID:24506068, PMID:41074439]. Its N-glycosylation is required for sorting into extracellular vesicles, and it promotes PTTG1/securin nuclear translocation and possesses independent transforming activity in fibroblasts and nude mice [PMID:39712388, PMID:21450804]."},"prefetch_data":{"uniprot":{"accession":"P53801","full_name":"Pituitary tumor-transforming gene 1 protein-interacting protein","aliases":["Pituitary tumor-transforming gene protein-binding factor","PBF","PTTG-binding factor"],"length_aa":180,"mass_kda":20.3,"function":"May facilitate PTTG1 nuclear translocation","subcellular_location":"Membrane; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P53801/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTTG1IP","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"VAMP8","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"LAMP1","stoichiometry":0.2},{"gene":"NAPA","stoichiometry":0.2},{"gene":"RAB11A","stoichiometry":0.2},{"gene":"RAB7A","stoichiometry":0.2},{"gene":"STX12","stoichiometry":0.2},{"gene":"STX6","stoichiometry":0.2},{"gene":"STX7","stoichiometry":0.2},{"gene":"STX8","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PTTG1IP","total_profiled":1310},"omim":[{"mim_id":"603784","title":"PPTG1-INTERACTING PROTEIN; PTTG1IP","url":"https://www.omim.org/entry/603784"},{"mim_id":"190685","title":"DOWN SYNDROME","url":"https://www.omim.org/entry/190685"}],"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/PTTG1IP"},"hgnc":{"alias_symbol":["PBF","PTTG1IP1"],"prev_symbol":["C21orf3","C21orf1"]},"alphafold":{"accession":"P53801","domains":[{"cath_id":"3.30.1680","chopping":"39-94","consensus_level":"medium","plddt":86.8827,"start":39,"end":94}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P53801","model_url":"https://alphafold.ebi.ac.uk/files/AF-P53801-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P53801-F1-predicted_aligned_error_v6.png","plddt_mean":77.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTTG1IP","jax_strain_url":"https://www.jax.org/strain/search?query=PTTG1IP"},"sequence":{"accession":"P53801","fasta_url":"https://rest.uniprot.org/uniprotkb/P53801.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P53801/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P53801"}},"corpus_meta":[{"pmid":"27621432","id":"PMC_27621432","title":"Maize endosperm-specific transcription factors O2 and PBF network the regulation of protein and starch synthesis.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27621432","citation_count":145,"is_preprint":false},{"pmid":"10948264","id":"PMC_10948264","title":"PBF-2 is a novel single-stranded DNA binding factor implicated in PR-10a gene activation in potato.","date":"2000","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/10948264","citation_count":110,"is_preprint":false},{"pmid":"2209543","id":"PMC_2209543","title":"Purified presequence binding factor (PBF) forms an import-competent complex with a purified mitochondrial precursor protein.","date":"1990","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/2209543","citation_count":94,"is_preprint":false},{"pmid":"12242377","id":"PMC_12242377","title":"The Activation of the Potato PR-10a Gene Requires the Phosphorylation of the Nuclear Factor PBF-1.","date":"1995","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/12242377","citation_count":77,"is_preprint":false},{"pmid":"18379885","id":"PMC_18379885","title":"The maize Dof protein PBF activates transcription of gamma-zein during maize seed development.","date":"2008","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18379885","citation_count":51,"is_preprint":false},{"pmid":"17297475","id":"PMC_17297475","title":"PTTG and PBF repress the human sodium iodide symporter.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17297475","citation_count":43,"is_preprint":false},{"pmid":"21844185","id":"PMC_21844185","title":"Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21844185","citation_count":40,"is_preprint":false},{"pmid":"25674221","id":"PMC_25674221","title":"MicroRNA-584 functions as a tumor suppressor and targets PTTG1IP in glioma.","date":"2014","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25674221","citation_count":39,"is_preprint":false},{"pmid":"23678037","id":"PMC_23678037","title":"Manipulation of PBF/PTTG1IP phosphorylation status; a potential new therapeutic strategy for improving radioiodine uptake in thyroid and other tumors.","date":"2013","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23678037","citation_count":39,"is_preprint":false},{"pmid":"24506068","id":"PMC_24506068","title":"The PTTG1-binding factor (PBF/PTTG1IP) regulates p53 activity in thyroid cells.","date":"2014","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24506068","citation_count":30,"is_preprint":false},{"pmid":"29078751","id":"PMC_29078751","title":"PTTG1-interacting protein (PTTG1IP/PBF) predicts breast cancer survival.","date":"2017","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29078751","citation_count":26,"is_preprint":false},{"pmid":"9858759","id":"PMC_9858759","title":"Characterization of the maize prolamin box-binding factor-1 (PBF-1) and its role in the developmental regulation of the zein multigene family.","date":"1998","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9858759","citation_count":26,"is_preprint":false},{"pmid":"15564534","id":"PMC_15564534","title":"The maize O2 and PBF proteins act additively to promote transcription from storage protein gene promoters in rice endosperm cells.","date":"2004","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15564534","citation_count":23,"is_preprint":false},{"pmid":"34100377","id":"PMC_34100377","title":"circ-PTTG1IP/miR-671-5p/TLR4 axis regulates proliferation, migration, invasion and inflammatory response of fibroblast-like synoviocytes in rheumatoid arthritis.","date":"2021","source":"General physiology and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/34100377","citation_count":22,"is_preprint":false},{"pmid":"21450804","id":"PMC_21450804","title":"Expression and function of the novel proto-oncogene PBF in thyroid cancer: a new target for augmenting radioiodine uptake.","date":"2011","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/21450804","citation_count":21,"is_preprint":false},{"pmid":"17531190","id":"PMC_17531190","title":"Papillomavirus binding factor (PBF)-mediated inhibition of cell growth is regulated by 14-3-3beta.","date":"2007","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/17531190","citation_count":21,"is_preprint":false},{"pmid":"22535767","id":"PMC_22535767","title":"PTTG-binding factor (PBF) is a novel regulator of the thyroid hormone transporter MCT8.","date":"2012","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22535767","citation_count":19,"is_preprint":false},{"pmid":"22404099","id":"PMC_22404099","title":"Functional variable number of tandem repeats variation in the promoter of proto-oncogene PTTG1IP is associated with risk of estrogen receptor-positive breast cancer.","date":"2012","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/22404099","citation_count":14,"is_preprint":false},{"pmid":"27709636","id":"PMC_27709636","title":"PTTG1IP and MAML3, novel genomewide association study genes for severity of hyperresponsiveness in adult asthma.","date":"2016","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/27709636","citation_count":13,"is_preprint":false},{"pmid":"27603901","id":"PMC_27603901","title":"Pro-invasive Effect of Proto-oncogene PBF Is Modulated by an Interaction with Cortactin.","date":"2016","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/27603901","citation_count":12,"is_preprint":false},{"pmid":"31423188","id":"PMC_31423188","title":"Hypermethylation of the PTTG1IP promoter leads to low expression in early-stage non-small cell lung cancer.","date":"2019","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31423188","citation_count":9,"is_preprint":false},{"pmid":"37550824","id":"PMC_37550824","title":"Super Antibacterial Capacity and Cell Envelope-Disruptive Mechanism of Ultrasonically Grafted N-Halamine PBAT/PBF Films against Escherichia coli.","date":"2023","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/37550824","citation_count":9,"is_preprint":false},{"pmid":"18977400","id":"PMC_18977400","title":"Antitumor effect of F-PBF(beta-TrCP)-induced targeted PTTG1 degradation in HeLa cells.","date":"2008","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/18977400","citation_count":9,"is_preprint":false},{"pmid":"28676500","id":"PMC_28676500","title":"Functional consequences of the first reported mutations of the proto-oncogene PTTG1IP/PBF.","date":"2017","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28676500","citation_count":8,"is_preprint":false},{"pmid":"38230375","id":"PMC_38230375","title":"Advancing Fluoride-Ion Batteries with a Pb-PbF2 Counter Electrode and a Diluted Liquid Electrolyte.","date":"2023","source":"ACS energy letters","url":"https://pubmed.ncbi.nlm.nih.gov/38230375","citation_count":8,"is_preprint":false},{"pmid":"26237280","id":"PMC_26237280","title":"Regulation of Ace2-dependent genes requires components of the PBF complex in Schizosaccharomyces pombe.","date":"2015","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/26237280","citation_count":8,"is_preprint":false},{"pmid":"19883062","id":"PMC_19883062","title":"Enantioselective syntheses of alpha-Fmoc-Pbf-[2-(13)C]-L-arginine and Fmoc-[1,3-(13)C2]-L-proline and Incorporation into the neurotensin receptor 1 ligand, NT(8-13).","date":"2009","source":"The Journal of organic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19883062","citation_count":6,"is_preprint":false},{"pmid":"39712388","id":"PMC_39712388","title":"An extracellular vesicle delivery platform based on the PTTG1IP protein.","date":"2024","source":"Extracellular vesicle","url":"https://pubmed.ncbi.nlm.nih.gov/39712388","citation_count":4,"is_preprint":false},{"pmid":"11807255","id":"PMC_11807255","title":"Crystallization and preliminary X-ray crystallographic analysis of p24, a component of the potato nuclear factor PBF-2.","date":"2002","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/11807255","citation_count":4,"is_preprint":false},{"pmid":"23460987","id":"PMC_23460987","title":"Universal perceptron and DNA-like learning algorithm for binary neural networks: LSBF and PBF implementations.","date":"2009","source":"IEEE transactions on neural networks","url":"https://pubmed.ncbi.nlm.nih.gov/23460987","citation_count":4,"is_preprint":false},{"pmid":"30569723","id":"PMC_30569723","title":"Pituitary tumor transforming gene binding factor (PBF) is required for androgen-induced prostate cancer proliferation and invasion.","date":"2018","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/30569723","citation_count":3,"is_preprint":false},{"pmid":"31637306","id":"PMC_31637306","title":"PBF, a Proto-oncogene in Esophageal Carcinoma.","date":"2019","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/31637306","citation_count":3,"is_preprint":false},{"pmid":"38181569","id":"PMC_38181569","title":"Numerical design of open-porous titanium scaffolds for Powder Bed Fusion using Laser Beam (PBF-LB).","date":"2023","source":"Journal of the mechanical behavior of biomedical materials","url":"https://pubmed.ncbi.nlm.nih.gov/38181569","citation_count":2,"is_preprint":false},{"pmid":"25471943","id":"PMC_25471943","title":"Papillomavirus binding factor (PBF) is an intrinsically disordered protein with potential participation in osteosarcoma genesis, in silico evidence.","date":"2014","source":"Theoretical biology & medical modelling","url":"https://pubmed.ncbi.nlm.nih.gov/25471943","citation_count":2,"is_preprint":false},{"pmid":"40849421","id":"PMC_40849421","title":"Utilizing PBF-LB/M AlSI10Mg alloy post-processed via KOBO-extrusion and subsequent cold drawing to obtain high-strength wire.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40849421","citation_count":2,"is_preprint":false},{"pmid":"41335275","id":"PMC_41335275","title":"Phase 1 dose escalation trial of the selective adenosine A2B antagonist PBF-1129 in patients with metastatic non-small cell lung cancer.","date":"2025","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/41335275","citation_count":1,"is_preprint":false},{"pmid":"40243578","id":"PMC_40243578","title":"Evaluating Surface Properties and Cellular Responses to Surface-Treated Different Triple Periodic Minimal Surface L-PBF Ti6Al4V Lattices for Biomedical Devices.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40243578","citation_count":1,"is_preprint":false},{"pmid":"38204107","id":"PMC_38204107","title":"Nanoscale and Tensile-Like Properties by an Instrumented Indentation Test on PBF-LB SS 316L Steel.","date":"2024","source":"Materials (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38204107","citation_count":1,"is_preprint":false},{"pmid":"41074439","id":"PMC_41074439","title":"PTTG1IP Orchestrates Epithelial-Mesenchymal Transition and DNA Damage Response in Thyroid Cancer Progression.","date":"2025","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/41074439","citation_count":0,"is_preprint":false},{"pmid":"36383136","id":"PMC_36383136","title":"Sp4 Regulates PTTG1IP Gene Transcription and Expression.","date":"2022","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/36383136","citation_count":0,"is_preprint":false},{"pmid":"39978508","id":"PMC_39978508","title":"Molecular mechanisms of recombinant proteins PTTG1IP, ADAM12, PAPSS1, and MYO1B and their effects on wound repair induced by tendon exposure: Analysis of key genes.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39978508","citation_count":0,"is_preprint":false},{"pmid":"41893202","id":"PMC_41893202","title":"Cytocompatibility Assessment of L-PBF-Manufactured Zinc-Silver-Copper Alloys for Customized Biodegradable Medical Implants.","date":"2026","source":"Journal of functional biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/41893202","citation_count":0,"is_preprint":false},{"pmid":"40355047","id":"PMC_40355047","title":"Potential participants and regulatory factors in ginsenoside biosynthesis of Panax ginseng C.A. Meyer: The role of endophytic fungus PBF-08.","date":"2025","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/40355047","citation_count":0,"is_preprint":false},{"pmid":"7334781","id":"PMC_7334781","title":"Serum protein bound fucose (PBF) in untreated leprosy patients.","date":"1981","source":"Leprosy in India","url":"https://pubmed.ncbi.nlm.nih.gov/7334781","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.21.25331940","title":"How decentralized facility financing improved supply chains and product availability in primary healthcare centers, a randomized trial in Nigeria","date":"2025-07-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.21.25331940","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.08.681256","title":"Pulmonary Vascular Endothelial Dysfunction is Induced by Non-Pulsatile Pulmonary Blood Flow in an Ovine Classic Glenn Model","date":"2025-10-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.08.681256","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.26.690630","title":"Azimuthal Segment Imaging in cryo-STEM Tomography","date":"2025-11-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.26.690630","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23961,"output_tokens":3383,"usd":0.061314},"stage2":{"model":"claude-opus-4-6","input_tokens":6757,"output_tokens":3194,"usd":0.170453},"total_usd":0.231767,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"PTTG1IP (PBF) and PTTG repress sodium iodide symporter (NIS) mRNA expression and inhibit iodide uptake, acting at least in part through fibroblast growth factor-2, and specifically inhibiting NIS promoter activity via the human upstream enhancer element (hNUE) through a complex PAX8-USF1 response element; PTTG repression is contingent on the USF1 site.\",\n      \"method\": \"Promoter-reporter assays (NIS promoter constructs in FRTL-5 and human primary thyroid cells), transfection/overexpression, siRNA knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple reporter assays with defined promoter elements and primary human cells, single lab\",\n      \"pmids\": [\"17297475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Transgenic thyroid-specific overexpression of PBF/PTTG1IP causes thyroid gland enlargement, hyperplastic and macrofollicular lesions, upregulates Akt, TSHR, and cyclin D1, and potently inhibits NIS expression and iodide uptake; PBF depletion in primary thyroid cultures rescues radioiodine uptake.\",\n      \"method\": \"Transgenic mouse model (bovine thyroglobulin promoter-driven PBF), primary thyroid cell culture, siRNA knockdown, iodide uptake assays, IHC, western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic model with defined cellular phenotypes and rescue experiment\",\n      \"pmids\": [\"21844185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PBF/PTTG1IP is a tyrosine phosphoprotein that specifically binds Src kinase; Src phosphorylates PBF at residue Y174. Phosphorylation at Y174 promotes internalization of PBF from the plasma membrane (PM), and abrogation of Y174 results in PM retention and markedly reduced ability to bind and internalize NIS. The Src inhibitor PP1 inhibits PBF phosphorylation and stimulates iodide uptake in thyroid carcinoma and primary thyroid cells.\",\n      \"method\": \"Mass spectrometry, GST pulldown, co-immunoprecipitation, site-directed mutagenesis (Y174A), cell surface biotinylation, iodide uptake assay, pharmacological inhibition (PP1)\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (MS, GST pulldown, Co-IP, mutagenesis, functional rescue) in a single study\",\n      \"pmids\": [\"23678037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PBF/PTTG1IP binds MCT8 (monocarboxylate transporter 8) in vitro and causes a marked shift in MCT8 subcellular localization away from the plasma membrane, resulting in reduced MCT8 at the plasma membrane. In vivo, PBF-Tg mice show enhanced thyroidal thyroid hormone accumulation and reduced TH secretion upon TSH stimulation, phenocopying Mct8-knockout mice.\",\n      \"method\": \"Co-immunoprecipitation, cell surface biotinylation assay, confocal colocalization, transgenic mouse model (PBF-Tg), mRNA and protein expression analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding and localization assays corroborated by in vivo mouse model with functional TH secretion phenotype\",\n      \"pmids\": [\"22535767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PBF/PTTG1IP binds specifically to p53 in thyroid cells, represses p53-dependent transactivation, and decreases p53 stability by enhancing ubiquitination dependent on Mdm2 E3 ligase activity. PBF transgenic mouse thyroids show increased genomic instability and repression of ~40% of DNA repair genes.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, ubiquitination assay, p53-responsive promoter-reporter assays, fluorescent ISSR-PCR for genomic instability, transgenic mouse model\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods plus in vivo transgenic confirmation\",\n      \"pmids\": [\"24506068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PBF/PTTG1IP physically interacts and co-localizes with cortactin (CTTN) at the cell periphery and leading edge of migrating cancer cells, and PBF-induced cellular invasion and migration in thyroid and breast cancer cells is entirely abrogated in the absence of CTTN. Mutation of PBF at Y174A or pharmacological intervention modulates the PBF:CTTN interaction and attenuates invasive properties.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, confocal colocalization, 2D Boyden chamber invasion assay, 3D organotypic assay, siRNA knockdown, site-directed mutagenesis (Y174A)\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — physical interaction confirmed by multiple methods plus functional dependency established by knockout and mutagenesis\",\n      \"pmids\": [\"27603901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PBF/PTTG1IP missense mutations C51R and R140W reduce protein stability, alter subcellular localization (C51R retained in ER; R140W in Golgi), abolish induction of cellular migration and invasion, and prevent colony formation and anchorage-independent growth, whereas both mutants retain the ability to repress radioiodide uptake.\",\n      \"method\": \"Anisomycin protein half-life assay, immunofluorescence/confocal localization, proliferation assay, Boyden chamber invasion assay, colony formation assay, soft agar assay, iodide uptake assay\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with defined mutations, single lab\",\n      \"pmids\": [\"28676500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Androgen receptor (AR) directly binds a novel androgen response element in the PBF/PTTG1IP gene promoter upon androgen stimulation, upregulating PBF expression; RNAi knockdown of PBF significantly reduces androgen-induced LNCaP cell growth and invasion.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, RNA interference, proliferation and invasion assays\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct AR binding at PBF promoter; functional RNAi data, single lab\",\n      \"pmids\": [\"30569723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The transcription factor Sp4 binds the PTTG1IP gene promoter at Sp4 response elements within a -212 to +7 bp region and positively regulates PTTG1IP transcription and expression.\",\n      \"method\": \"Luciferase reporter assay (promoter deletion analysis), electrophoretic mobility shift assay (EMSA), Sp4 overexpression in HeLa cells\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA confirms direct binding, reporter assay confirms functional effect, single lab\",\n      \"pmids\": [\"36383136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTTG1IP is a small N-glycosylated single-spanning transmembrane protein whose N-glycosylation (at two arginine residues) is required for its sorting into extracellular vesicles (EVs); chimeric PTTG1IP fusion proteins enable highly efficient loading of therapeutic cargoes (Cre protein, Cas9-sgRNA) into EVs for functional delivery to recipient cells.\",\n      \"method\": \"Bioinformatics (N-glycosylation prediction), mutagenesis of glycosylation sites, EV isolation and cargo loading assays, functional delivery assays (Cre reporter, Cas9-sgRNA reporter) in cell culture and mouse xenograft\",\n      \"journal\": \"Extracellular vesicle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of N-glycosylation sites with functional EV-loading readout, corroborated in vivo\",\n      \"pmids\": [\"39712388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTTG1IP forms an endogenous complex with cortactin (CTTN) in thyroid cancer cells, co-localizing by immunofluorescence, and occupies the promoters of DDR genes BRCA1, BRCA2, RAD51, RAD51AP1, and ATM as determined by ChIP-qPCR; PTTG1IP depletion increases radiation-induced DNA damage and cell death.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, ChIP-qPCR, shRNA knockdown, cell viability assay, TUNEL apoptosis assay, γH2AX immunofluorescence after irradiation\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, functional knockdown), single lab, no independent replication\",\n      \"pmids\": [\"41074439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A fusion protein (F-PBF(β-TrCP)) constructed by replacing the WD40-repeat of F-box protein β-TrCP with PTTG1IP (PBF) degrades both exogenous PTTG1-EGFP and endogenous PTTG1 protein via the ubiquitin-proteasome system, demonstrating that PBF physically recruits PTTG1 into an SCF E3 ligase complex.\",\n      \"method\": \"Fusion protein construction, co-expression in COS-7 and HeLa cells, western blot for PTTG1 protein levels, proliferation and colony assays\",\n      \"journal\": \"Journal of biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — engineered fusion protein context; indirect demonstration of PBF-PTTG1 binding capability, single lab\",\n      \"pmids\": [\"18977400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PBF/PTTG1IP is reported to induce translocation of PTTG1 (securin) from the cytoplasm to the nucleus, and possesses independent transforming ability, transforming NIH 3T3 fibroblasts and inducing tumors in nude mice in vivo.\",\n      \"method\": \"NIH 3T3 transformation assay, nude mouse tumor formation assay (referenced in review)\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo transformation assays described in review context referencing prior experimental work\",\n      \"pmids\": [\"21450804\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTTG1IP/PBF is a multifunctional glycoprotein proto-oncogene that acts as a scaffold protein: it physically interacts with PTTG1/securin to promote its nuclear translocation, binds and internalizes NIS and MCT8 away from the plasma membrane (regulated by Src-mediated phosphorylation at Y174), interacts with cortactin at the cell leading edge to drive cancer cell invasion, binds p53 and promotes its Mdm2-dependent ubiquitination and degradation, occupies DNA damage repair gene promoters, and is sorted into extracellular vesicles via N-glycosylation, with its expression transcriptionally regulated by Sp4 and androgen receptor.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PTTG1IP (PBF) is a single-spanning transmembrane glycoprotein proto-oncogene that functions as a multifunctional scaffold controlling plasma membrane transporter availability, p53 stability, DNA damage repair gene expression, and cell invasion. It binds and internalizes the sodium iodide symporter (NIS) and monocarboxylate transporter 8 (MCT8) away from the plasma membrane in a process regulated by Src-mediated phosphorylation at Y174, thereby suppressing iodide uptake and thyroid hormone secretion [PMID:23678037, PMID:22535767, PMID:21844185]. PTTG1IP interacts with cortactin at the cell leading edge to drive cancer cell invasion, binds p53 to promote its Mdm2-dependent ubiquitination and degradation causing genomic instability, and occupies promoters of DNA damage repair genes including BRCA1, BRCA2, and RAD51 [PMID:27603901, PMID:24506068, PMID:41074439]. Its N-glycosylation is required for sorting into extracellular vesicles, and it promotes PTTG1/securin nuclear translocation and possesses independent transforming activity in fibroblasts and nude mice [PMID:39712388, PMID:21450804].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that PTTG1IP functionally represses NIS expression answered whether PBF had a direct role in thyroid iodide handling beyond its known PTTG1 interaction.\",\n      \"evidence\": \"NIS promoter-reporter assays with defined PAX8-USF1 elements in FRTL-5 and primary human thyroid cells\",\n      \"pmids\": [\"17297475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PBF-mediated NIS promoter repression not fully delineated\", \"Whether PBF directly contacts NIS protein at this stage unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"An engineered SCF-PBF fusion that degraded PTTG1 via the proteasome demonstrated that PBF can physically recruit PTTG1, clarifying the molecular basis of PBF-PTTG1 interaction.\",\n      \"evidence\": \"Fusion protein (F-PBF-β-TrCP) co-expression in COS-7/HeLa cells with western blot for PTTG1 degradation\",\n      \"pmids\": [\"18977400\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Engineered fusion context does not prove endogenous complex formation\", \"Stoichiometry and endogenous relevance not established\", \"No reciprocal validation of endogenous interaction\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"In vivo transgenic overexpression proved PBF is a bona fide proto-oncogene that drives thyroid hyperplasia and suppresses NIS, moving beyond cell-based assays to organismal phenotypes; independently, PBF was shown to promote PTTG1 nuclear translocation and transform NIH 3T3 cells.\",\n      \"evidence\": \"Thyroid-specific PBF transgenic mouse model with IHC, iodide uptake, and primary culture rescue (siRNA); NIH 3T3 transformation and nude mouse assays\",\n      \"pmids\": [\"21844185\", \"21450804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether transformation is PTTG1-dependent or independent not resolved\", \"Mechanism of Akt/cyclin D1 upregulation downstream of PBF unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that PBF binds and internalizes MCT8 away from the plasma membrane extended its transporter-regulatory function beyond NIS to thyroid hormone efflux, explaining in vivo thyroid hormone accumulation in PBF-Tg mice.\",\n      \"evidence\": \"Co-immunoprecipitation, cell surface biotinylation, confocal microscopy, and PBF-Tg mouse TH secretion assays\",\n      \"pmids\": [\"22535767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding domain on MCT8 not mapped\", \"Whether Y174 phosphorylation also regulates MCT8 internalization untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of Src as the kinase phosphorylating PBF at Y174, and demonstration that this modification controls PBF plasma membrane dynamics and NIS internalization, provided the first signaling-level regulatory mechanism for PBF function.\",\n      \"evidence\": \"Mass spectrometry, GST pulldown, Co-IP, Y174A mutagenesis, cell surface biotinylation, PP1 inhibitor rescue of iodide uptake\",\n      \"pmids\": [\"23678037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other potential phosphorylation sites not systematically surveyed\", \"Structural basis of Src-PBF recognition unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that PBF binds p53 and promotes its Mdm2-dependent ubiquitination, while PBF-Tg thyroids show repression of DNA repair genes and genomic instability, revealed a second oncogenic axis independent of transporter regulation.\",\n      \"evidence\": \"Co-IP, proximity ligation assay, ubiquitination assay, p53 reporter assays, ISSR-PCR genomic instability, transgenic mouse model\",\n      \"pmids\": [\"24506068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PBF directly enhances Mdm2-p53 interaction or acts allosterically unresolved\", \"Causal relationship between DDR gene repression and genomic instability not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of cortactin as a PBF-interacting partner at the leading edge that is required for PBF-driven invasion established the molecular mechanism linking PBF to cell motility.\",\n      \"evidence\": \"Co-IP, proximity ligation assay, confocal colocalization, 2D/3D invasion assays, CTTN siRNA rescue, Y174A mutagenesis\",\n      \"pmids\": [\"27603901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PBF directly activates cortactin branched-actin nucleation or acts as a scaffold not determined\", \"Contribution of PBF-cortactin axis versus PBF-p53 axis to tumor progression in vivo unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Cancer-associated missense mutations (C51R, R140W) that disrupt protein stability and localization but retain NIS-repressive function showed that PBF's oncogenic activities (invasion, colony formation) and transporter-repressive functions are mechanistically separable.\",\n      \"evidence\": \"Protein half-life assays, confocal localization, Boyden chamber invasion, colony formation, soft agar, and iodide uptake assays with site-directed mutants\",\n      \"pmids\": [\"28676500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these mutations affect cortactin or p53 binding not tested\", \"No patient cohort to assess clinical prevalence of these variants\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that androgen receptor directly binds the PTTG1IP promoter and drives its expression linked PBF upregulation to androgen signaling, providing a transcriptional mechanism for PBF overexpression in prostate cancer.\",\n      \"evidence\": \"ChIP at PBF promoter ARE, luciferase reporter, RNAi knockdown of PBF reducing androgen-driven proliferation/invasion in LNCaP cells\",\n      \"pmids\": [\"30569723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AR regulation of PBF is relevant in thyroid or breast contexts untested\", \"Epigenetic regulation of PTTG1IP locus not explored\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of Sp4 as a direct transcriptional activator of PTTG1IP via promoter-proximal Sp4 response elements added a second transcription factor to PBF's regulatory circuitry.\",\n      \"evidence\": \"EMSA confirming direct Sp4 binding, promoter deletion/reporter analysis in HeLa cells\",\n      \"pmids\": [\"36383136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context in which Sp4 regulates PBF not established\", \"Interplay between Sp4 and AR at the PTTG1IP promoter unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that N-glycosylation is required for PTTG1IP sorting into extracellular vesicles revealed a new trafficking fate and functional context for the protein beyond plasma membrane and intracellular compartments.\",\n      \"evidence\": \"Mutagenesis of N-glycosylation sites, EV isolation, functional cargo delivery assays in vitro and in mouse xenograft\",\n      \"pmids\": [\"39712388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous cargo carried by PTTG1IP-positive EVs not identified\", \"Whether EV-sorted PBF retains oncogenic signaling in recipient cells unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ChIP-qPCR showing PBF occupies promoters of BRCA1, BRCA2, RAD51, RAD51AP1, and ATM, combined with the observation that PBF depletion sensitizes cells to radiation-induced DNA damage, provided direct evidence for PBF's role in DNA damage repair gene regulation.\",\n      \"evidence\": \"Co-IP confirming endogenous PBF-cortactin complex, ChIP-qPCR at DDR promoters, shRNA knockdown with γH2AX and TUNEL assays after irradiation\",\n      \"pmids\": [\"41074439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PBF activates or represses DDR gene transcription at these promoters not clarified (contrasts with earlier repression data)\", \"Mechanism by which a transmembrane protein occupies gene promoters not explained\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which a single-pass transmembrane glycoprotein accesses nuclear gene promoters and coordinates its dual membrane-trafficking and transcriptional functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PTTG1IP exists\", \"Nuclear versus membrane pool partitioning mechanism unknown\", \"Whether PBF's diverse functions (NIS/MCT8 internalization, p53 destabilization, cortactin-mediated invasion, DDR gene regulation, EV sorting) operate in the same or distinct cellular contexts is unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 10, 12]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 5, 12]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 3, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NIS\", \"MCT8\", \"CTTN\", \"PTTG1\", \"TP53\", \"SRC\", \"MDM2\"],\n    \"other_free_text\": []\n  }\n}\n```"}