{"gene":"PROX1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2002,"finding":"Ectopic expression of Prox1 in primary human blood vascular endothelial cells is sufficient to up-regulate lymphatic markers (podoplanin, VEGFR-3) and down-regulate blood vascular markers (laminin, VEGF-C, neuropilin-1, ICAM-1), reprogramming blood vascular endothelium toward a lymphatic phenotype. Prox1-deficient mice lack lymphatic vasculature and fail to acquire lymphatic endothelial cell fate.","method":"Adenoviral gene transfer, transient plasmid transfection, transcriptional profiling, RT-PCR, Western blotting, Prox1 knockout mice","journal":"Developmental dynamics","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function (knockout) and gain-of-function (ectopic expression) with multiple orthogonal readouts; replicated across labs","pmids":["12412020"],"is_preprint":false},{"year":1999,"finding":"Prox1 inactivation in mice causes abnormal cellular proliferation, downregulated expression of cell-cycle inhibitors Cdkn1b (p27KIP1) and Cdkn1c (p57KIP2), misexpression of E-cadherin, and inappropriate apoptosis, resulting in failure of lens cells to polarize and elongate and producing a hollow lens. Prox1 activity is required for progression of terminal fibre differentiation and elongation.","method":"Prox1 knockout mouse, immunostaining, gene expression analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with multiple molecular and cellular phenotypic readouts in vivo","pmids":["10080188"],"is_preprint":false},{"year":2003,"finding":"Prox1 regulates cell cycle exit of retinal progenitor cells; cells lacking Prox1 are less likely to stop dividing, while ectopic Prox1 forces progenitor cells to exit the cell cycle. Prox1 is also necessary and sufficient for horizontal cell fate determination in the vertebrate retina.","method":"Prox1 knockout mice, ectopic Prox1 misexpression in postnatal progenitors, retinal cell fate analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal loss- and gain-of-function with defined cellular phenotypes, multiple orthogonal methods","pmids":["12692551"],"is_preprint":false},{"year":2008,"finding":"Lymphatic endothelial cell identity depends on continuous Prox1 activity for its maintenance. Conditional down-regulation of Prox1 during embryonic, postnatal, or adult stages reprograms LECs into blood vascular endothelial cells, a Prox1-dependent, cell-autonomous process demonstrated by siRNA knockdown.","method":"Conditional Prox1 knockout mice (embryonic/postnatal/adult), siRNA knockdown in cultured LECs, phenotypic analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple temporal conditional knockouts plus in vitro siRNA with phenotypic readouts, cell autonomy established","pmids":["19056883"],"is_preprint":false},{"year":2008,"finding":"PROX1 physically interacts with COUP-TFII to form a stable complex in LECs and other cell types. COUP-TFII acts as a coregulator of Prox1 to control lineage-specific genes including VEGFR-3, FGFR-3, and neuropilin-1, and is required with Prox1 to maintain LEC phenotype.","method":"Co-immunoprecipitation, gene expression analysis in LECs","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal Co-IP showing physical interaction, functional co-regulation shown by knockdown, single lab","pmids":["18815287"],"is_preprint":false},{"year":2011,"finding":"Development of the lymphovenous valve population and maintenance of Prox1 expression in venous ECs requires two functional copies of Prox1, mediated by COUP-TFII/Prox1 complex formation. Reduction in COUP-TFII/Prox1 complex formation in heterozygotes leads to loss of Prox1 expression and absent lymphovenous valves.","method":"Prox1 heterozygous mouse analysis, complex formation assay","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic dosage analysis with molecular mechanism (complex formation), single lab","pmids":["22012621"],"is_preprint":false},{"year":2005,"finding":"Prox1 directly binds to Prox1-response elements in the FGFR-3 promoter to activate FGFR-3 transcription as a direct target gene, establishing FGFR-3 as an initial transcriptional target of Prox1 during lymphatic cell fate specification.","method":"Ectopic Prox1 overexpression in blood vascular ECs, FGFR-3 promoter binding analysis, reporter assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated, gain-of-function with functional readout, single lab","pmids":["16291864"],"is_preprint":false},{"year":2010,"finding":"Prox1 is required for maturation of granule cells in the dentate gyrus during development and for maintenance of intermediate progenitors during adult neurogenesis. Prox1-expressing intermediate progenitors provide a non-cell autonomous feedback mechanism that controls adult neural stem cell self-maintenance; ectopic Prox1 expression induces premature differentiation of neural stem cells.","method":"Prox1 conditional knockout mice, BrdU labeling, immunostaining, ectopic expression","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple cellular phenotypes, non-cell autonomous mechanism identified, gain-of-function confirmation","pmids":["20808958"],"is_preprint":false},{"year":2010,"finding":"miR-181a binds the 3' UTR of Prox1 mRNA, causing translational inhibition and transcript degradation. Increased miR-181a in primary embryonic LECs reduces Prox1 mRNA and protein and reprograms LECs toward blood vascular phenotype; miR-181a antagomir in blood vascular ECs increases Prox1 levels. miR-181a is more highly expressed in blood vascular ECs than LECs.","method":"3' UTR luciferase reporter assay, miR-181a overexpression/antagomir in primary embryonic LECs and BVECs, qRT-PCR, Western blot","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct 3' UTR binding demonstrated by reporter assay, reciprocal gain- and loss-of-function in primary cells with phenotypic readout","pmids":["20558617"],"is_preprint":false},{"year":2010,"finding":"Prox1 interacts with ERRα and PGC-1α, occupies promoters of metabolic genes genome-wide, and inhibits the activity of the ERRα/PGC-1α transcriptional complex. Ablation of Prox1 and ERRα have opposite effects on respiratory capacity of liver cells, revealing a role for Prox1 in control of energy homeostasis.","method":"Co-immunoprecipitation, genome-wide ChIP, reporter assays, Prox1 knockdown in liver cells, respiratory capacity measurements","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, genome-wide ChIP, functional assay, KO phenotype), single lab but rigorous","pmids":["20194433"],"is_preprint":false},{"year":2009,"finding":"Prox1 is SUMOylated at lysine 556 (K556) by SUMO-1. Mutation K556R reduces DNA binding and transcriptional activity of Prox1. SUMOylation controls Prox1's ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells; SUMO-specific protease SENP2 reduces Prox1 sumoylation and Prox1-induced VEGFR3 expression.","method":"In vitro and in vivo sumoylation assays, mutagenesis (K556R), reporter assays, ectopic expression in EA.hy926 cells, SENP2 overexpression","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro and in vivo PTM characterization with site mutagenesis plus functional consequence, single lab","pmids":["19706680"],"is_preprint":false},{"year":2012,"finding":"PROX1 and FOXC2 cooperate to mediate segregation of lymphatic-valve-forming cells and cell mechanosensory responses to shear stress. Mechanistically, PROX1, FOXC2, and flow coordinately control expression of connexin37 and activation of calcineurin/NFAT signaling, both required for assembly and delimitation of lymphatic valve territory.","method":"Conditional knockout mice (PROX1, FOXC2), shear stress in vitro assays, connexin37 and calcineurin loss-of-function, valve morphogenesis analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models, in vitro mechanosensing assay, downstream effector identification with functional rescue","pmids":["22306086"],"is_preprint":false},{"year":2008,"finding":"Cardiac-specific inactivation of Prox1 disrupts expression and localisation of sarcomeric proteins, causes myofibril disarray and growth-retarded hearts. Prox1 directly transcriptionally regulates the genes encoding structural proteins α-actinin, N-RAP, and zyxin, which maintain actin-α-actinin interaction as the fundamental sarcomere association.","method":"Cardiac-specific Prox1 conditional knockout, transcriptomic analysis, direct transcriptional regulation assays","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with identified direct transcriptional targets and mechanistic link to sarcomere integrity","pmids":["19091769"],"is_preprint":false},{"year":2014,"finding":"Prox1 directly regulates Vegfr3 as a dosage-dependent in vivo target, and Vegfr3 in turn maintains Prox1 expression through a feedback loop that is the main sensing mechanism controlling the number of LEC progenitors. Vegfc-mediated activation of Vegfr3 signaling is necessary to maintain Prox1 expression in LEC progenitors.","method":"Multiple mouse genetic models, ChIP, gene expression analysis, Vegfc/Vegfr3 pathway manipulation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mouse models, ChIP for direct target validation, reciprocal feedback loop established with multiple orthogonal approaches","pmids":["25274728"],"is_preprint":false},{"year":2010,"finding":"Prox1 suppresses Notch1 gene expression by direct binding at the Notch1 promoter, counteracting Notch1 signaling in neural progenitor cells. Prox1-mediated suppression of Notch1 relieves its inhibition on neurogenesis, allowing NPCs to exit the cell cycle and differentiate. Loss of Prox1 in the chick neural tube prevents suppression of Notch1 outside the ventricular zone.","method":"ChIP assay, gain-of-function in chick neural tube, loss-of-function in chick neural tube, mouse NPC overexpression, promoter binding assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter binding by ChIP, reciprocal gain- and loss-of-function in two species, defined molecular mechanism","pmids":["21203589"],"is_preprint":false},{"year":2013,"finding":"COUP-TFII homodimers induce a venous EC fate by directly binding to promoters of Notch target genes HEY1 and HEY2, while COUP-TFII/PROX1 heterodimers lack this inhibitory effect. NR2F2/PROX1 heterodimers actively induce LEC-specific gene expression. PROX1 DNA binding also contributes to HEY1 and LEC-specific gene expression.","method":"Heterodimerization assays, promoter binding studies, knockdown experiments in endothelial cells, gene expression analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated, functional consequences of dimer switching shown, single lab","pmids":["23345397"],"is_preprint":false},{"year":2013,"finding":"PROX1 up-regulates HIF-1α transcription and stabilizes HIF-1α protein by recruiting histone deacetylase 1 (HDAC1) to prevent acetylation of HIF-1α, subsequently inducing an epithelial-mesenchymal transition response in HCC cells to promote metastasis.","method":"PROX1 knockdown and overexpression in HCC cells, in vitro migration/invasion assays, in vivo nude mouse metastasis model, co-IP for HDAC1 interaction","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for binding partner, functional KD and OE with cellular phenotype, in vivo validation, single lab","pmids":["23505027"],"is_preprint":false},{"year":2013,"finding":"Prox1 directly interacts with LSD1 (KDM1A) and recruits the LSD1/NuRD complex to the CYP7A1 promoter, co-repressing CYP7A1 transcription via H3K4 demethylation and histone deacetylation. This mechanism is involved in the physiological negative feedback inhibition of CYP7A1 by bile acids.","method":"Immunoprecipitation followed by mass spectrometry, GST pulldown (direct interaction), sequential ChIP, ChIP in siRNA knockdown cells, reporter assays","journal":"PLoS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — GST pulldown for direct interaction, sequential ChIP for co-occupancy, histone modification measurements, bile acid feedback validation, single lab with multiple orthogonal methods","pmids":["23626788"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the SOX18 HMG box bound to a DNA element regulating Prox1 transcription was resolved at 1.75Å. SOX18 directly binds Prox1 promoter DNA; decoy oligonucleotides based on the Prox1-DNA element inhibit SOX18 DNA binding in vitro and suppress SOX18-dependent reporter activity in cells.","method":"X-ray crystallography (1.75Å), in vitro DNA binding assays, decoy oligonucleotide design and testing, luciferase reporter assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation (reporter assay and DNA binding inhibition), single lab","pmids":["26939885"],"is_preprint":false},{"year":2011,"finding":"ERRα, PROX1, and BMAL1 show extensive genomic co-occupancy in the liver. PROX1 is implicated in rhythmic control of metabolic outputs and acts as a corepressor in the ERRα transcriptional network, with genome-wide location analyses revealing transcriptional regulatory loops among these three factors controlling clock and metabolic gene networks.","method":"Genome-wide ChIP-seq (ERRα, PROX1, BMAL1), ERRα-null mouse phenotyping, locomotor activity assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP for co-occupancy, KO phenotype, single lab","pmids":["21731503"],"is_preprint":false},{"year":2017,"finding":"HDAC3 and PROX1 form a corepressor module in vivo (identified by cross-linking mass spectrometry). HDAC3 and PROX1 co-localize extensively on the mouse liver genome and are co-recruited by HNF4α. The HDAC3-PROX1 module controls expression of a gene program regulating lipid homeostasis; hepatic-specific ablation of either component increases triglyceride content in liver.","method":"Cross-linking mass spectrometry (HDAC3 interactome), ChIP-seq, liver-specific conditional knockout of Prox1 and Hdac3","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo cross-linking MS for complex identification, ChIP-seq for genome-wide co-occupancy, multiple conditional KO models with metabolic phenotype","pmids":["28916805"],"is_preprint":false},{"year":2014,"finding":"Prox1 directly binds to the 5' regulatory sequence of the Pdpn (podoplanin) gene in LECs (confirmed by ChIP and DNA pulldown assay) and regulates Pdpn gene expression at the transcriptional level as shown by luciferase reporter assay.","method":"ChIP assay, DNA pulldown assay, luciferase reporter assay","journal":"Microvascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and DNA pulldown for direct binding, reporter assay for functional consequence, single lab","pmids":["24944097"],"is_preprint":false},{"year":2018,"finding":"PROX1 suppresses transcription of MMP14 by binding and suppressing the MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels and siRNA knockdown in human LECs increased MMP14 expression. PROX1 ectopic expression reduced MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells.","method":"Prox1 conditional knockout in vivo, siRNA knockdown in LECs, promoter binding assay, 3D invasion assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO and in vitro KD with consistent MMP14 upregulation, promoter binding established, single lab","pmids":["29934628"],"is_preprint":false},{"year":2018,"finding":"PROX1 forms a complex with β-catenin and the TCF/LEF transcription factor TCF7L1 to enhance Wnt/β-catenin signaling and promote FOXC2 and GATA2 expression in LECs. PROX1 thus directs lymphatic cell fate by acting as a Wnt signaling component.","method":"Co-immunoprecipitation, reporter assays, LEC-specific Wntless knockout mice, in vitro oscillatory shear stress assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for complex formation, in vivo genetic model, functional gene expression readout, single lab","pmids":["30332639"],"is_preprint":false},{"year":2014,"finding":"Prox1 ablation in bipotent hepatoblasts dramatically reduces hepatocyte gene expression, leads to defective hepatocyte morphogenesis, and causes excessive cholangiocyte commitment and biliary hyperplasia, identifying Prox1 as a regulator of cell fate allocation in liver precursors.","method":"Conditional Prox1 knockout in hepatic progenitors, immunostaining, gene expression analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional KO with defined molecular and morphological phenotypes for hepatocyte vs. cholangiocyte fate","pmids":["24449835"],"is_preprint":false},{"year":2015,"finding":"Prox1 activates the NFAT signalling pathway and is necessary and sufficient for the maintenance of slow muscle fibre type gene program. Prox1 is required for myoblast differentiation via bi-directional crosstalk with Notch1. Prox1-positive satellite cells differentiate into muscle fibres (shown by lineage tracing).","method":"Prox1 conditional knockout in satellite cells, Prox1 overexpression, lineage tracing, NFAT reporter assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, gain-of-function, lineage tracing, and pathway reporter assays, multiple orthogonal methods","pmids":["27731315"],"is_preprint":false},{"year":2008,"finding":"Prox1 represses transcriptional activity of Gfi1 independently of Atoh1 in inner ear hair cells (luciferase assay). Prox1 transduction into cochlear outer hair cells caused their degeneration, consistent with Gfi1-deficient phenotype. Prox1 interacts with Atoh1 and Gfi1 and antagonizes the hair cell phenotype.","method":"Adenoviral Prox1 transduction in cochlear explants, luciferase transcriptional activity assay, comparison with Gfi1-deficient mice","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct repression of Gfi1 shown by reporter assay, functional consequence in explants, single lab","pmids":["18652815"],"is_preprint":false},{"year":2014,"finding":"Prox1 suppresses Olig2 expression by directly binding to the proximal promoter and K23 enhancer of the Olig2 gene locus in vivo (shown by ChIP). Prox1 is sufficient and necessary for suppression of Olig2 expression and control of MN versus V2 interneuron identity in ventral spinal cord.","method":"ChIP in mouse neural tube, gain- and loss-of-function in mouse NPCs and chick neural tube, promoter/enhancer reporter assays","journal":"Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP for direct binding, reciprocal gain/loss-of-function in two systems, functional gene regulation at defined cis-elements","pmids":["25411508"],"is_preprint":false},{"year":2019,"finding":"YAP and TAZ negatively regulate Prox1 transcription in LECs through recruitment of the NuRD (nucleosome remodeling and histone deacetylase) complex and endogenous binding of TEAD factors to the PROX1 promoter. LEC-specific YAP/TAZ hyperactivation profoundly downregulates Prox1 and impairs lymphatic specification.","method":"LEC-specific Yap/Taz conditional knockout and hyperactivation mouse models, promoter occupancy assays, NuRD complex recruitment assay","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse models plus mechanistic promoter complex analysis, single lab","pmids":["30582452"],"is_preprint":false},{"year":2022,"finding":"AMPK phosphorylates PROX1 at Ser79, which enhances recruitment of the CUL4-DDB1 ubiquitin ligase to promote PROX1 ubiquitination and proteasomal degradation. PROX1 downregulation by AMPK activates branched-chain amino acid (BCAA) degradation through epigenetic modifications and inhibits mTOR signalling.","method":"AMPK activation/inhibition assays, site-directed mutagenesis (Ser79), co-IP for CUL4-DDB1 interaction, ubiquitination assays, epigenetic modification assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — PTM site identified by mutagenesis, writer (AMPK) and degradation machinery (CUL4-DDB1) identified, downstream metabolic consequences defined, single lab with multiple orthogonal methods","pmids":["36433955"],"is_preprint":false},{"year":2013,"finding":"Transcriptional activation of Prox1 is directly controlled by HIF-1α and HIF-2α binding to a hypoxia-response element (HRE) in the Prox1 promoter/regulatory region, as demonstrated by EMSA and ChIP. HIF-1α/HIF-2α overexpression increases and knockdown decreases Prox1 promoter activity.","method":"EMSA, ChIP, HIF-1α/HIF-2α overexpression and knockdown, Prox1 promoter reporter assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and ChIP for direct HRE binding, functional reporter assay, single lab","pmids":["23395615"],"is_preprint":false},{"year":2015,"finding":"PROX1 promotes HCC cell proliferation and activates the Wnt/β-catenin pathway by upregulating β-catenin transcription via stimulation of the β-catenin promoter and enhancing nuclear translocation of β-catenin in HCC cells.","method":"PROX1 knockdown and overexpression in HCC cells, β-catenin promoter reporter assay, nuclear fractionation, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assay for transcriptional mechanism, nuclear translocation assay, in vivo confirmation, single lab","pmids":["25684142"],"is_preprint":false},{"year":2018,"finding":"PROX1 interacts with the NuRD complex to suppress the Notch pathway in colorectal cancer stem-like cells. PROX1 deletion increases Notch target gene expression and NOTCH1 promoter activity, demonstrating reciprocal regulation.","method":"Co-immunoprecipitation for NuRD complex interaction, PROX1 knockout in organoid cultures, reporter assays, gene expression analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for complex, KO with gene expression readout, single lab","pmids":["30154153"],"is_preprint":false},{"year":2023,"finding":"A PROX1 enhancer element bound by GATA2, FOXC2, NFATC1, and PROX1 itself is required for Prox1 expression in lymphatic endothelial cells. Disruption of the GATA2-binding site within this enhancer by genome editing caused profound lymphatic defects and revealed that lymphatic endothelium has haemogenic capacity ordinarily repressed by Prox1.","method":"Genome editing (5-nt deletion of GATA2-binding site), ChIP (occupancy by GATA2/FOXC2/NFATC1/PROX1), conditional mouse knockout, gene expression analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — precise genome editing of defined cis-element, multiple TF binding validated by ChIP, in vivo phenotype with gene expression analysis","pmids":["36697821"],"is_preprint":false},{"year":2021,"finding":"Mitochondrial complex III activity regulates the critical Prox1-Vegfr3 feedback loop by controlling H3K4me3 and H3K27ac levels at the genomic loci of key LEC fate controllers (Vegfr3, Prox1), linking mitochondrial respiration to epigenetic control of LEC fate specification and maintenance.","method":"Conditional deletion of QPC (mitochondrial complex III subunit) in LECs, H3K4me3/H3K27ac ChIP, gene expression analysis","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with ChIP-based epigenetic mechanism, single lab","pmids":["33931446"],"is_preprint":false},{"year":2020,"finding":"YAP and TAZ are required to maintain PROX1 expression in lymphatic valves and lymphovenous valves in response to VEGF-C signaling. Deletion of Yap and Taz in lymphatic vasculature of mouse embryos did not prevent valve formation but caused their degeneration with loss of PROX1 expression.","method":"Conditional Yap/Taz knockout in lymphatic vasculature, valve morphogenesis analysis, PROX1 expression analysis","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined structural phenotype and molecular readout, single lab","pmids":["33060128"],"is_preprint":false},{"year":2022,"finding":"Autophagy loss in LECs impairs lipid droplet degradation (lipophagy), reducing fatty acid oxidation, mitochondrial ATP production, acetyl-CoA/CoA ratio, and expression of lymphangiogenic PROX1 target genes including VEGFR3. Supplementing acetate (fatty acid precursor) rescues VEGFR3 levels and lymphangiogenesis in LEC-Atg5-/- mice, linking lipophagy to a mitochondrial-PROX1 gene expression circuit.","method":"LEC-specific Atg5 knockout mice, lipid droplet quantification, fatty acid oxidation assays, acetyl-CoA measurement, acetate supplementation rescue","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with metabolic and gene expression analysis, rescue experiment, single lab","pmids":["35589749"],"is_preprint":false},{"year":2001,"finding":"Prox1 and Six3 act antagonistically at the gamma-crystallin (CRYGD/e/f) promoter. A Prox1-responsive element was mapped between -151 and -174 and a Six3-responsive element between -101 and -123. Prox1 stimulates CRYGF promoter activity in cells lacking endogenous Prox1, acting as a transcriptional activator of gamma-crystallin genes.","method":"Cell transfection reporter assays, randomly mutated promoter fragment analysis, cell lines with and without endogenous Prox1","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter reporter mapping with defined response elements, functional antagonism shown, single lab","pmids":["11139622"],"is_preprint":false},{"year":2008,"finding":"Prox1 directly binds to the OL2 element and two additional upstream elements of the chicken betaB1-crystallin basal promoter. At the upstream sites, Prox1 mediates repression rather than activation, demonstrating that Prox1 function as transcriptional activator or repressor at this locus depends on the characteristics of the responsive DNA element and cellular context.","method":"DNase I footprinting, ChIP, transfection reporter assays in multiple lens cell types, transgenic mice","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNA binding by DNase I footprinting and ChIP, functional reporter assays in multiple contexts, single lab","pmids":["18385074"],"is_preprint":false},{"year":2020,"finding":"RNA-binding protein Celf1 post-transcriptionally regulates Prox1 protein levels in lens development via its 3' UTR. Celf1 lens-specific conditional knockout causes abnormal Prox1 protein distribution without changing Prox1 transcript levels. Celf1 protein binds Prox1 transcripts (RNA-immunoprecipitation), and Celf1 negatively controls Prox1 translation via its 3' UTR (reporter assays in KD and OE cells).","method":"Celf1 lens-specific conditional KO, immunostaining, qRT-PCR, RNA-immunoprecipitation, 3' UTR reporter assays in Celf1 KD and OE cells","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP for direct binding, reporter assay for 3' UTR-mediated regulation, conditional KO phenotype, single lab","pmids":["32594240"],"is_preprint":false},{"year":2023,"finding":"PROX1 interacts with KSHV ORF50 (viral initiator of lytic replication) protein and binds to the KSHV genome at the ORF50 promoter region, increasing ORF50 transactivation activity and spontaneous lytic gene expression and infectious virus release from LECs.","method":"Co-immunoprecipitation (PROX1-ORF50 interaction), ChIP on KSHV genome, PROX1 genetic depletion, lytic gene expression and viral production assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for viral protein interaction, ChIP for genome occupancy, functional KD with viral phenotype, single lab","pmids":["32518203"],"is_preprint":false},{"year":2023,"finding":"PROX1 inhibits PDGF-B expression in valvular endothelial cells (VECs) partially via FOXC2, preventing myxomatous degeneration of cardiac valves. Conditional Prox1 deletion from VECs caused FOXC2 downregulation and PDGF-B upregulation; conditional FOXC2 knockdown and PDGF-B overexpression recapitulated the Prox1 KO valve phenotype; pharmacological PDGF-B inhibition (imatinib) partially rescued the defects.","method":"VEC-specific conditional Prox1 knockout, FOXC2 knockdown and PDGF-B overexpression mouse models, echocardiography, histology, pharmacological inhibition","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional mouse models, pharmacological rescue, human tissue validation, pathway mechanism (PROX1→FOXC2→PDGF-B) established","pmids":["37555328"],"is_preprint":false},{"year":2022,"finding":"PROX1 interacts with hnRNPK in breast cancer cells; this interaction inhibits ubiquitination of hnRNPK, which subsequently activates the WNT/β-catenin pathway to promote invasion and metastasis of breast cancer.","method":"Co-immunoprecipitation, ubiquitination assays, WNT pathway reporter, in vitro invasion assays, in vivo lung metastasis model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, ubiquitination assay, pathway reporter, in vivo model, single lab","pmids":["35342346"],"is_preprint":false},{"year":2015,"finding":"ASCL1 complexes with NKX2-1 and PROX1 to co-regulate genes functioning in NOTCH signaling, catecholamine biosynthesis, and cell-cycle processes in ASCL1-high small-cell lung cancer.","method":"Chromatin landscape analysis (super-enhancer mapping), transcriptome analysis, co-occupancy analysis of ASCL1, NKX2-1, PROX1 in SCLC preclinical models","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-occupancy by ChIP without direct biochemical interaction assay for the complex, single lab","pmids":["34466783"],"is_preprint":false},{"year":2009,"finding":"Prox1 (Prospero-related homeobox protein) represses HBV promoters in hepatocytes: for the ENII/Cp promoter, Prox1 serves as a corepressor of LRH-1 and downregulates LRH-1-mediated activation; for the Sp1 promoter, Prox1 partially represses activity by directly interacting with hepatocyte nuclear factor 1 (HNF1).","method":"Reporter-gene analysis of HBV promoters, co-immunoprecipitation for HNF1 interaction, HBV replication assays in hepatocyte cultures","journal":"Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays for promoter-specific mechanism, Co-IP for HNF1 interaction, functional HBV replication assay, single lab","pmids":["19264593"],"is_preprint":false}],"current_model":"PROX1 is a homeodomain transcription factor that acts as a master binary switch controlling lymphatic endothelial cell identity by directly activating lymphatic target genes (VEGFR3, FGFR3, podoplanin) and repressing blood vascular genes, forming obligate complexes with COUP-TFII/NR2F2, β-catenin/TCF7L1, HDAC3, LSD1/NuRD, and ERRα/PGC-1α to regulate metabolic, developmental, and cell-fate gene programs; its activity is post-translationally modulated by SUMO-1 (at K556), AMPK-driven CUL4-DDB1 ubiquitination (at S79), and post-transcriptionally by miR-181a and the RNA-binding protein CELF1, while its own transcription is controlled by HIF-1α/HIF-2α, a GATA2/FOXC2/NFATC1/PROX1 autoregulatory enhancer, and a feedback loop with VEGFR3 signaling."},"narrative":{"mechanistic_narrative":"PROX1 is a homeodomain transcription factor that functions as a master regulator of cell-fate specification across multiple tissues, acting as a binary switch that both activates lineage-defining gene programs and represses alternative-fate genes [PMID:12412020, PMID:19056883]. In the lymphatic system it is necessary and sufficient to reprogram blood vascular endothelium toward lymphatic identity, and continuous PROX1 activity is required to maintain that identity—its loss reprograms lymphatic endothelial cells back to a blood vascular phenotype [PMID:12412020, PMID:19056883]. PROX1 drives this fate by directly activating lymphatic target genes including FGFR-3, VEGFR3, and podoplanin through binding to defined cis-elements in their promoters [PMID:16291864, PMID:25274728, PMID:24944097], with VEGFR3 establishing a feedback loop in which VEGFC/VEGFR3 signaling sustains PROX1 expression to set lymphatic progenitor number [PMID:25274728]. Its DNA-binding specificity and activator-versus-repressor output depend on partner proteins and the responsive element: it heterodimerizes with COUP-TFII/NR2F2 to induce lymphatic genes and block venous Notch-target activation [PMID:18815287, PMID:23345397], cooperates with FOXC2 and Wnt/β-catenin–TCF7L1 to direct valve morphogenesis and lymphatic specification [PMID:22306086, PMID:30332639, PMID:37555328], and assembles its own transcription via a GATA2/FOXC2/NFATC1/PROX1 autoregulatory enhancer [PMID:36697821]. Beyond the vasculature, PROX1 controls cell-cycle exit and fate in lens, retina, dentate gyrus neurons, spinal interneurons, hepatoblasts, and slow muscle fibers, frequently by repressing pro-proliferative or alternative-fate genes such as Notch1 and Olig2 at their promoters [PMID:10080188, PMID:12692551, PMID:20808958, PMID:21203589, PMID:24449835, PMID:27731315, PMID:25411508]. In metabolic tissues PROX1 acts predominantly as a corepressor, partnering with ERRα/PGC-1α, the LSD1/NuRD complex, and HDAC3 to control energy homeostasis, bile-acid feedback, lipid homeostasis, and rhythmic metabolic outputs [PMID:20194433, PMID:23626788, PMID:21731503, PMID:28916805]. PROX1 activity is set post-translationally by SUMOylation at K556, which promotes DNA binding and transcriptional activity [PMID:19706680], and by AMPK-driven phosphorylation at Ser79 that recruits CUL4-DDB1 to trigger ubiquitination and degradation [PMID:36433955]; its levels are further tuned post-transcriptionally by miR-181a and the RNA-binding protein CELF1 acting through its 3' UTR [PMID:20558617, PMID:32594240], and transcriptionally by HIF-1α/HIF-2α, SOX18, and YAP/TAZ [PMID:26939885, PMID:30582452, PMID:23395615, PMID:33060128]. In cancer, PROX1 promotes hepatocellular and breast tumor progression through Wnt/β-catenin activation and HIF-1α stabilization [PMID:23505027, PMID:25684142, PMID:35342346].","teleology":[{"year":1999,"claim":"Established the first in vivo developmental role of Prox1, showing it couples cell-cycle exit to terminal differentiation rather than acting merely as a fate marker.","evidence":"Prox1 knockout mouse with lens phenotyping and cell-cycle inhibitor expression analysis","pmids":["10080188"],"confidence":"High","gaps":["Direct transcriptional targets at the lens not defined","Mechanism of Cdkn1b/Cdkn1c regulation not resolved"]},{"year":2001,"claim":"Defined Prox1 as a sequence-specific transcription factor at the gamma-crystallin promoter, mapping its response element and revealing antagonism with Six3.","evidence":"Reporter assays with mapped Prox1- and Six3-responsive promoter elements","pmids":["11139622"],"confidence":"Medium","gaps":["Direct binding not shown by footprinting/ChIP in this study","Mechanism of Six3 antagonism unresolved"]},{"year":2002,"claim":"Demonstrated that Prox1 is both necessary and sufficient for lymphatic endothelial cell fate, identifying it as a master switch reprogramming blood vascular toward lymphatic identity.","evidence":"Ectopic expression in human BVECs plus Prox1 knockout mice with transcriptional profiling","pmids":["12412020"],"confidence":"High","gaps":["Direct vs. indirect target genes not distinguished","Cofactor requirements not identified"]},{"year":2003,"claim":"Generalized Prox1's fate-switch logic to the retina, showing reciprocal control of progenitor cell-cycle exit and horizontal cell identity.","evidence":"Reciprocal knockout and ectopic misexpression in retinal progenitors","pmids":["12692551"],"confidence":"High","gaps":["Direct target genes in retina not identified","Molecular mechanism of cell-cycle exit not defined"]},{"year":2005,"claim":"Identified the first direct lymphatic target gene, FGFR-3, anchoring Prox1's fate-switch to defined cis-regulatory binding.","evidence":"Promoter binding and reporter assays following ectopic Prox1 in BVECs","pmids":["16291864"],"confidence":"Medium","gaps":["In vivo requirement of FGFR-3 element not tested","Single lab"]},{"year":2008,"claim":"Revealed that Prox1 acts through obligate partnership with COUP-TFII to maintain lymphatic identity, moving the model from a solo switch to a combinatorial code.","evidence":"Reciprocal Co-IP and knockdown co-regulation analysis in LECs","pmids":["18815287"],"confidence":"Medium","gaps":["Structural basis of heterodimer not defined","Genome-wide co-occupancy not yet mapped"]},{"year":2008,"claim":"Extended Prox1's transcriptional logic to context-dependent activation versus repression, showing output depends on the responsive DNA element in lens crystallin genes.","evidence":"DNase I footprinting, ChIP, and reporter assays across lens cell types and transgenic mice","pmids":["18385074"],"confidence":"Medium","gaps":["Cofactors distinguishing activation from repression not identified"]},{"year":2008,"claim":"Showed Prox1 directly transcribes sarcomeric structural genes, establishing a tissue-specific role in cardiac muscle architecture.","evidence":"Cardiac-specific conditional knockout with transcriptomics and direct regulation assays","pmids":["19091769"],"confidence":"High","gaps":["Cofactors for cardiac targets not identified"]},{"year":2008,"claim":"Demonstrated Prox1 represses Gfi1 and antagonizes hair-cell fate, broadening its repressor role in inner ear development.","evidence":"Adenoviral transduction in cochlear explants and luciferase repression assays","pmids":["18652815"],"confidence":"Medium","gaps":["Direct binding to Gfi1 locus not shown","In vivo requirement not tested"]},{"year":2008,"claim":"Showed continuous Prox1 activity is required to maintain LEC identity even in adults, establishing fate maintenance as an active, cell-autonomous process.","evidence":"Temporally staged conditional knockouts and siRNA knockdown in cultured LECs","pmids":["19056883"],"confidence":"High","gaps":["Upstream signals sustaining Prox1 not defined in this study"]},{"year":2009,"claim":"Identified SUMOylation at K556 as a positive post-translational regulator controlling Prox1 DNA binding and lymphatic gene induction.","evidence":"In vitro/in vivo sumoylation assays, K556R mutagenesis, SENP2 reversal, reporter assays","pmids":["19706680"],"confidence":"High","gaps":["SUMO E3 ligase not identified","In vivo physiological importance not tested"]},{"year":2009,"claim":"Defined Prox1 as a promoter-specific corepressor of viral transcription in hepatocytes via LRH-1 and HNF1, illustrating context-dependent repression in the liver.","evidence":"HBV promoter reporter assays, Co-IP for HNF1, and replication assays","pmids":["19264593"],"confidence":"Medium","gaps":["Direct promoter binding not demonstrated","Single lab"]},{"year":2010,"claim":"Placed Prox1 at the center of energy homeostasis as a corepressor of the ERRα/PGC-1α metabolic transcriptional network.","evidence":"Co-IP, genome-wide ChIP, reporter assays, and respiratory-capacity measurements in liver cells","pmids":["20194433"],"confidence":"High","gaps":["Mechanism of ERRα/PGC-1α inhibition not resolved at structural level"]},{"year":2010,"claim":"Identified miR-181a as a direct post-transcriptional repressor of Prox1 that tunes the lymphatic-versus-blood vascular balance.","evidence":"3' UTR luciferase reporter and reciprocal miR-181a gain/loss-of-function in primary endothelial cells","pmids":["20558617"],"confidence":"High","gaps":["Upstream control of miR-181a not defined"]},{"year":2010,"claim":"Extended Prox1's neurogenic role, showing it drives granule-cell maturation and maintains adult neural progenitors through a non-cell-autonomous feedback loop.","evidence":"Conditional knockout, BrdU labeling, and ectopic expression in the dentate gyrus","pmids":["20808958"],"confidence":"High","gaps":["Molecular nature of the feedback signal not identified"]},{"year":2011,"claim":"Mechanistically linked Prox1 gene dosage to lymphovenous valve formation through COUP-TFII/Prox1 complex abundance.","evidence":"Prox1 heterozygous mouse analysis with complex formation assays","pmids":["22012621"],"confidence":"Medium","gaps":["Quantitative threshold of complex required not defined"]},{"year":2011,"claim":"Integrated Prox1 into circadian-metabolic transcriptional loops via genome-wide co-occupancy with ERRα and BMAL1 in liver.","evidence":"ChIP-seq of ERRα/PROX1/BMAL1 and ERRα-null mouse phenotyping","pmids":["21731503"],"confidence":"Medium","gaps":["Direct physical interaction with BMAL1 not shown","Single lab"]},{"year":2012,"claim":"Showed PROX1 cooperates with FOXC2 and fluid shear to translate mechanical signals into lymphatic valve patterning through connexin37 and calcineurin/NFAT.","evidence":"Conditional knockouts, in vitro shear-stress assays, and downstream effector loss-of-function","pmids":["22306086"],"confidence":"High","gaps":["How shear is sensed upstream of the PROX1/FOXC2 module not resolved"]},{"year":2013,"claim":"Revealed that COUP-TFII/PROX1 heterodimer formation, versus COUP-TFII homodimers, switches endothelial output between lymphatic and venous (Notch-target) programs.","evidence":"Heterodimerization and promoter binding studies with knockdown in endothelial cells","pmids":["23345397"],"confidence":"Medium","gaps":["Structural basis of the dimer switch not defined"]},{"year":2013,"claim":"Established HIF-1α/HIF-2α as direct hypoxia-driven activators of Prox1 transcription, linking oxygen sensing to lymphatic fate.","evidence":"EMSA, ChIP, HIF overexpression/knockdown, and Prox1 promoter reporters","pmids":["23395615"],"confidence":"Medium","gaps":["In vivo physiological relevance of the HRE not tested"]},{"year":2013,"claim":"Defined a corepressor mechanism in bile-acid metabolism whereby PROX1 recruits LSD1/NuRD to demethylate and deacetylate the CYP7A1 promoter.","evidence":"IP-MS, GST pulldown, sequential ChIP, and reporter assays","pmids":["23626788"],"confidence":"High","gaps":["Recruitment signal directing PROX1 to CYP7A1 not defined"]},{"year":2013,"claim":"Implicated PROX1 in hepatocellular carcinoma metastasis through HDAC1-dependent HIF-1α stabilization and EMT, identifying an oncogenic role.","evidence":"Knockdown/overexpression in HCC cells, invasion assays, nude mouse metastasis, and HDAC1 Co-IP","pmids":["23505027"],"confidence":"Medium","gaps":["Direct HIF-1α deacetylation by recruited HDAC1 not biochemically resolved"]},{"year":2014,"claim":"Established a PROX1–VEGFR3 feedback loop as the principal sensing mechanism setting LEC progenitor number, with PROX1 directly and dosage-dependently regulating Vegfr3.","evidence":"Multiple mouse genetic models, ChIP, and VEGFC/VEGFR3 pathway manipulation","pmids":["25274728"],"confidence":"High","gaps":["How VEGFR3 signaling feeds back to the Prox1 promoter not fully traced"]},{"year":2014,"claim":"Defined Prox1 as a fate-allocation regulator in liver precursors, promoting hepatocyte over cholangiocyte commitment.","evidence":"Conditional knockout in hepatoblasts with gene expression and morphology analysis","pmids":["24449835"],"confidence":"High","gaps":["Direct hepatocyte target genes not catalogued"]},{"year":2014,"claim":"Confirmed podoplanin as a direct PROX1 transcriptional target in LECs, extending the catalogue of directly bound lymphatic effector genes.","evidence":"ChIP, DNA pulldown, and luciferase reporter assays in LECs","pmids":["24944097"],"confidence":"Medium","gaps":["In vivo enhancer requirement not tested"]},{"year":2014,"claim":"Showed Prox1 directly represses Olig2 at its promoter and enhancer to specify motor-neuron versus V2 interneuron identity in the spinal cord.","evidence":"In vivo ChIP plus reciprocal gain/loss-of-function in mouse and chick neural tube","pmids":["25411508"],"confidence":"High","gaps":["Cofactors at the Olig2 locus not identified"]},{"year":2015,"claim":"Defined Prox1 as a regulator of slow muscle fiber identity through NFAT activation and Notch1 crosstalk.","evidence":"Satellite-cell conditional knockout, gain-of-function, lineage tracing, and NFAT reporters","pmids":["27731315"],"confidence":"High","gaps":["Direct muscle fiber-type target genes not mapped"]},{"year":2015,"claim":"Showed PROX1 promotes HCC proliferation by transactivating the β-catenin promoter and enhancing nuclear β-catenin, defining an oncogenic Wnt-activating mechanism.","evidence":"Knockdown/overexpression, β-catenin promoter reporter, nuclear fractionation, and xenografts","pmids":["25684142"],"confidence":"Medium","gaps":["Direct binding of PROX1 to the β-catenin promoter not shown"]},{"year":2016,"claim":"Resolved the structural and functional basis of SOX18 binding to the Prox1 regulatory DNA element, defining an upstream transcriptional input.","evidence":"1.75Å crystal structure, DNA binding assays, and decoy oligonucleotide reporter inhibition","pmids":["26939885"],"confidence":"High","gaps":["In vivo contribution of this element to Prox1 expression not tested here"]},{"year":2017,"claim":"Identified an in vivo HDAC3–PROX1 corepressor module recruited by HNF4α that controls hepatic lipid homeostasis.","evidence":"Cross-linking MS, ChIP-seq co-occupancy, and conditional knockouts with metabolic phenotyping","pmids":["28916805"],"confidence":"High","gaps":["Stoichiometry and assembly order of the HDAC3-PROX1 module not defined"]},{"year":2018,"claim":"Showed PROX1 partners with β-catenin/TCF7L1 to act as a Wnt signaling component driving FOXC2/GATA2 expression in LECs.","evidence":"Co-IP, reporter assays, LEC-specific Wntless knockout, and shear-stress assays","pmids":["30332639"],"confidence":"Medium","gaps":["Direct vs. cofactor-mediated DNA binding within the complex not resolved"]},{"year":2018,"claim":"Defined PROX1 repression of MMP14 as a brake on invasive/angiogenic behavior, linking it to extracellular matrix remodeling.","evidence":"Conditional knockout, siRNA knockdown, promoter binding, and 3D invasion assays","pmids":["29934628"],"confidence":"Medium","gaps":["Cofactors at the MMP14 promoter not identified"]},{"year":2018,"claim":"Extended PROX1's NuRD-dependent Notch repression to colorectal cancer stem-like cells, showing reciprocal PROX1–Notch regulation.","evidence":"Co-IP, organoid knockout, and NOTCH1 promoter reporter assays","pmids":["30154153"],"confidence":"Medium","gaps":["Direct binding to the NOTCH1 promoter within the NuRD context not fully resolved"]},{"year":2019,"claim":"Identified YAP/TAZ–TEAD with NuRD as a transcriptional repressor of Prox1, defining a Hippo-pathway input to lymphatic specification.","evidence":"LEC-specific Yap/Taz conditional knockout and hyperactivation with promoter occupancy assays","pmids":["30582452"],"confidence":"Medium","gaps":["Reconciliation with the maintenance-promoting YAP/TAZ role at valves not resolved"]},{"year":2020,"claim":"Showed YAP/TAZ are required to maintain PROX1 in lymphatic and lymphovenous valves downstream of VEGF-C, revealing context-dependent Hippo control.","evidence":"Conditional Yap/Taz knockout with valve morphogenesis and PROX1 expression analysis","pmids":["33060128"],"confidence":"Medium","gaps":["Mechanism reconciling positive valve role with negative specification role unresolved"]},{"year":2020,"claim":"Identified CELF1 as a 3' UTR-binding regulator that post-transcriptionally controls Prox1 protein in lens development.","evidence":"Lens-specific Celf1 conditional knockout, RNA-IP, and 3' UTR reporter assays","pmids":["32594240"],"confidence":"Medium","gaps":["Interplay between CELF1 and miR-181a on the same 3' UTR not addressed"]},{"year":2020,"claim":"Revealed that PROX1 is hijacked by KSHV, interacting with ORF50 to promote viral lytic reactivation in LECs.","evidence":"Co-IP, ChIP on the KSHV genome, and genetic depletion with viral production assays","pmids":["32518203"],"confidence":"Medium","gaps":["Whether host gene programs are co-opted not defined"]},{"year":2021,"claim":"Linked mitochondrial complex III activity to epigenetic control of the Prox1–Vegfr3 loop via H3K4me3/H3K27ac at LEC fate loci.","evidence":"LEC-specific complex III subunit deletion with histone-mark ChIP and gene expression","pmids":["33931446"],"confidence":"Medium","gaps":["Metabolite intermediary connecting respiration to histone marks not pinpointed"]},{"year":2022,"claim":"Defined AMPK phosphorylation of PROX1 at Ser79 as a degradation switch recruiting CUL4-DDB1, coupling energy status to PROX1 stability and BCAA/mTOR metabolism.","evidence":"AMPK modulation, Ser79 mutagenesis, CUL4-DDB1 Co-IP, ubiquitination, and metabolic assays","pmids":["36433955"],"confidence":"High","gaps":["Tissue contexts where this degradation operates not fully mapped"]},{"year":2022,"claim":"Connected lipophagy-driven mitochondrial metabolism to PROX1 target gene expression, showing acetyl-CoA availability tunes VEGFR3 and lymphangiogenesis.","evidence":"LEC-specific Atg5 knockout with metabolic profiling and acetate rescue","pmids":["35589749"],"confidence":"Medium","gaps":["Direct epigenetic step on PROX1 targets not pinpointed"]},{"year":2022,"claim":"Identified PROX1–hnRNPK interaction as an oncogenic mechanism stabilizing hnRNPK and activating Wnt/β-catenin in breast cancer metastasis.","evidence":"Co-IP, ubiquitination assays, Wnt reporter, and in vivo metastasis model","pmids":["35342346"],"confidence":"Medium","gaps":["Direct effect of PROX1 on hnRNPK ubiquitination machinery not resolved"]},{"year":2023,"claim":"Defined a PROX1 autoregulatory enhancer bound by GATA2/FOXC2/NFATC1/PROX1 and showed that disrupting its GATA2 site causes lymphatic defects and de-represses hemogenic potential.","evidence":"Precise genome editing of the GATA2 site, ChIP occupancy, and conditional knockout phenotyping","pmids":["36697821"],"confidence":"High","gaps":["Hierarchy among the four enhancer-binding factors not fully ordered"]},{"year":2023,"claim":"Established a PROX1→FOXC2→PDGF-B axis in cardiac valvular endothelium that prevents myxomatous valve degeneration.","evidence":"VEC-specific conditional knockouts, pathway manipulation, echocardiography, and pharmacological rescue with imatinib","pmids":["37555328"],"confidence":"High","gaps":["FOXC2-independent contribution to PDGF-B repression not quantified"]},{"year":null,"claim":"How the diverse PROX1 cofactor repertoire and post-translational/post-transcriptional inputs are integrated to select activator versus repressor output at a given locus in a given tissue remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of PROX1 partner-dependent DNA-element selectivity","Cross-talk between SUMOylation, AMPK-driven degradation, miR-181a, and CELF1 in vivo not integrated","Tissue-specific cofactor hierarchies largely uncatalogued"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,6,9,14,17,20,21,27,37,38]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6,10,14,21,27,38]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[6,14,21,27]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,14,27,31]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6,14,21,27]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,7,24,25,33]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,17,19,20,29,36]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,23,31,42]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[17,20,28,32,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,31,40,42,43]}],"complexes":["PROX1/COUP-TFII(NR2F2) heterodimer","LSD1/NuRD corepressor complex","HDAC3-PROX1 corepressor module","PROX1/β-catenin/TCF7L1 complex"],"partners":["NR2F2","ERRA","PGC1A","KDM1A","HDAC3","CTNNB1","TCF7L1","FOXC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92786","full_name":"Prospero homeobox protein 1","aliases":["Homeobox prospero-like protein PROX1","PROX-1"],"length_aa":737,"mass_kda":83.2,"function":"Transcription factor involved in developmental processes such as cell fate determination, gene transcriptional regulation and progenitor cell regulation in a number of organs. Plays a critical role in embryonic development and functions as a key regulatory protein in neurogenesis and the development of the heart, eye lens, liver, pancreas and the lymphatic system. Involved in the regulation of the circadian rhythm. Represses: transcription of the retinoid-related orphan receptor RORG, transcriptional activator activity of RORA and RORG and the expression of RORA/G-target genes including core clock components: BMAL1, NPAS2 and CRY1 and metabolic genes: AVPR1A and ELOVL3","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q92786/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PROX1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PROX1","total_profiled":1310},"omim":[{"mim_id":"612743","title":"MICRO RNA 181A2; MIR181A2","url":"https://www.omim.org/entry/612743"},{"mim_id":"612742","title":"MICRO RNA 181A1; MIR181A1","url":"https://www.omim.org/entry/612742"},{"mim_id":"609429","title":"FORKHEAD BOX N4; FOXN4","url":"https://www.omim.org/entry/609429"},{"mim_id":"608863","title":"PODOPLANIN; PDPN","url":"https://www.omim.org/entry/608863"},{"mim_id":"601618","title":"SRY-BOX 18; SOX18","url":"https://www.omim.org/entry/601618"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":81.1}],"url":"https://www.proteinatlas.org/search/PROX1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q92786","domains":[{"cath_id":"1.10.10.500","chopping":"581-733","consensus_level":"high","plddt":95.5048,"start":581,"end":733}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92786","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92786-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92786-F1-predicted_aligned_error_v6.png","plddt_mean":60.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PROX1","jax_strain_url":"https://www.jax.org/strain/search?query=PROX1"},"sequence":{"accession":"Q92786","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92786.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92786/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92786"}},"corpus_meta":[{"pmid":"12412020","id":"PMC_12412020","title":"Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate.","date":"2002","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/12412020","citation_count":438,"is_preprint":false},{"pmid":"10080188","id":"PMC_10080188","title":"Prox1 function is crucial for mouse lens-fibre elongation.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10080188","citation_count":359,"is_preprint":false},{"pmid":"22306086","id":"PMC_22306086","title":"Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation.","date":"2012","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/22306086","citation_count":337,"is_preprint":false},{"pmid":"12692551","id":"PMC_12692551","title":"Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian 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human blood vascular endothelial cells is sufficient to up-regulate lymphatic markers (podoplanin, VEGFR-3) and down-regulate blood vascular markers (laminin, VEGF-C, neuropilin-1, ICAM-1), reprogramming blood vascular endothelium toward a lymphatic phenotype. Prox1-deficient mice lack lymphatic vasculature and fail to acquire lymphatic endothelial cell fate.\",\n      \"method\": \"Adenoviral gene transfer, transient plasmid transfection, transcriptional profiling, RT-PCR, Western blotting, Prox1 knockout mice\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function (knockout) and gain-of-function (ectopic expression) with multiple orthogonal readouts; replicated across labs\",\n      \"pmids\": [\"12412020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Prox1 inactivation in mice causes abnormal cellular proliferation, downregulated expression of cell-cycle inhibitors Cdkn1b (p27KIP1) and Cdkn1c (p57KIP2), misexpression of E-cadherin, and inappropriate apoptosis, resulting in failure of lens cells to polarize and elongate and producing a hollow lens. Prox1 activity is required for progression of terminal fibre differentiation and elongation.\",\n      \"method\": \"Prox1 knockout mouse, immunostaining, gene expression analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with multiple molecular and cellular phenotypic readouts in vivo\",\n      \"pmids\": [\"10080188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Prox1 regulates cell cycle exit of retinal progenitor cells; cells lacking Prox1 are less likely to stop dividing, while ectopic Prox1 forces progenitor cells to exit the cell cycle. Prox1 is also necessary and sufficient for horizontal cell fate determination in the vertebrate retina.\",\n      \"method\": \"Prox1 knockout mice, ectopic Prox1 misexpression in postnatal progenitors, retinal cell fate analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal loss- and gain-of-function with defined cellular phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"12692551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Lymphatic endothelial cell identity depends on continuous Prox1 activity for its maintenance. Conditional down-regulation of Prox1 during embryonic, postnatal, or adult stages reprograms LECs into blood vascular endothelial cells, a Prox1-dependent, cell-autonomous process demonstrated by siRNA knockdown.\",\n      \"method\": \"Conditional Prox1 knockout mice (embryonic/postnatal/adult), siRNA knockdown in cultured LECs, phenotypic analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple temporal conditional knockouts plus in vitro siRNA with phenotypic readouts, cell autonomy established\",\n      \"pmids\": [\"19056883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PROX1 physically interacts with COUP-TFII to form a stable complex in LECs and other cell types. COUP-TFII acts as a coregulator of Prox1 to control lineage-specific genes including VEGFR-3, FGFR-3, and neuropilin-1, and is required with Prox1 to maintain LEC phenotype.\",\n      \"method\": \"Co-immunoprecipitation, gene expression analysis in LECs\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal Co-IP showing physical interaction, functional co-regulation shown by knockdown, single lab\",\n      \"pmids\": [\"18815287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Development of the lymphovenous valve population and maintenance of Prox1 expression in venous ECs requires two functional copies of Prox1, mediated by COUP-TFII/Prox1 complex formation. Reduction in COUP-TFII/Prox1 complex formation in heterozygotes leads to loss of Prox1 expression and absent lymphovenous valves.\",\n      \"method\": \"Prox1 heterozygous mouse analysis, complex formation assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dosage analysis with molecular mechanism (complex formation), single lab\",\n      \"pmids\": [\"22012621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Prox1 directly binds to Prox1-response elements in the FGFR-3 promoter to activate FGFR-3 transcription as a direct target gene, establishing FGFR-3 as an initial transcriptional target of Prox1 during lymphatic cell fate specification.\",\n      \"method\": \"Ectopic Prox1 overexpression in blood vascular ECs, FGFR-3 promoter binding analysis, reporter assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated, gain-of-function with functional readout, single lab\",\n      \"pmids\": [\"16291864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Prox1 is required for maturation of granule cells in the dentate gyrus during development and for maintenance of intermediate progenitors during adult neurogenesis. Prox1-expressing intermediate progenitors provide a non-cell autonomous feedback mechanism that controls adult neural stem cell self-maintenance; ectopic Prox1 expression induces premature differentiation of neural stem cells.\",\n      \"method\": \"Prox1 conditional knockout mice, BrdU labeling, immunostaining, ectopic expression\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple cellular phenotypes, non-cell autonomous mechanism identified, gain-of-function confirmation\",\n      \"pmids\": [\"20808958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"miR-181a binds the 3' UTR of Prox1 mRNA, causing translational inhibition and transcript degradation. Increased miR-181a in primary embryonic LECs reduces Prox1 mRNA and protein and reprograms LECs toward blood vascular phenotype; miR-181a antagomir in blood vascular ECs increases Prox1 levels. miR-181a is more highly expressed in blood vascular ECs than LECs.\",\n      \"method\": \"3' UTR luciferase reporter assay, miR-181a overexpression/antagomir in primary embryonic LECs and BVECs, qRT-PCR, Western blot\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct 3' UTR binding demonstrated by reporter assay, reciprocal gain- and loss-of-function in primary cells with phenotypic readout\",\n      \"pmids\": [\"20558617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Prox1 interacts with ERRα and PGC-1α, occupies promoters of metabolic genes genome-wide, and inhibits the activity of the ERRα/PGC-1α transcriptional complex. Ablation of Prox1 and ERRα have opposite effects on respiratory capacity of liver cells, revealing a role for Prox1 in control of energy homeostasis.\",\n      \"method\": \"Co-immunoprecipitation, genome-wide ChIP, reporter assays, Prox1 knockdown in liver cells, respiratory capacity measurements\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, genome-wide ChIP, functional assay, KO phenotype), single lab but rigorous\",\n      \"pmids\": [\"20194433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Prox1 is SUMOylated at lysine 556 (K556) by SUMO-1. Mutation K556R reduces DNA binding and transcriptional activity of Prox1. SUMOylation controls Prox1's ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells; SUMO-specific protease SENP2 reduces Prox1 sumoylation and Prox1-induced VEGFR3 expression.\",\n      \"method\": \"In vitro and in vivo sumoylation assays, mutagenesis (K556R), reporter assays, ectopic expression in EA.hy926 cells, SENP2 overexpression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro and in vivo PTM characterization with site mutagenesis plus functional consequence, single lab\",\n      \"pmids\": [\"19706680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PROX1 and FOXC2 cooperate to mediate segregation of lymphatic-valve-forming cells and cell mechanosensory responses to shear stress. Mechanistically, PROX1, FOXC2, and flow coordinately control expression of connexin37 and activation of calcineurin/NFAT signaling, both required for assembly and delimitation of lymphatic valve territory.\",\n      \"method\": \"Conditional knockout mice (PROX1, FOXC2), shear stress in vitro assays, connexin37 and calcineurin loss-of-function, valve morphogenesis analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models, in vitro mechanosensing assay, downstream effector identification with functional rescue\",\n      \"pmids\": [\"22306086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cardiac-specific inactivation of Prox1 disrupts expression and localisation of sarcomeric proteins, causes myofibril disarray and growth-retarded hearts. Prox1 directly transcriptionally regulates the genes encoding structural proteins α-actinin, N-RAP, and zyxin, which maintain actin-α-actinin interaction as the fundamental sarcomere association.\",\n      \"method\": \"Cardiac-specific Prox1 conditional knockout, transcriptomic analysis, direct transcriptional regulation assays\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with identified direct transcriptional targets and mechanistic link to sarcomere integrity\",\n      \"pmids\": [\"19091769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Prox1 directly regulates Vegfr3 as a dosage-dependent in vivo target, and Vegfr3 in turn maintains Prox1 expression through a feedback loop that is the main sensing mechanism controlling the number of LEC progenitors. Vegfc-mediated activation of Vegfr3 signaling is necessary to maintain Prox1 expression in LEC progenitors.\",\n      \"method\": \"Multiple mouse genetic models, ChIP, gene expression analysis, Vegfc/Vegfr3 pathway manipulation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mouse models, ChIP for direct target validation, reciprocal feedback loop established with multiple orthogonal approaches\",\n      \"pmids\": [\"25274728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Prox1 suppresses Notch1 gene expression by direct binding at the Notch1 promoter, counteracting Notch1 signaling in neural progenitor cells. Prox1-mediated suppression of Notch1 relieves its inhibition on neurogenesis, allowing NPCs to exit the cell cycle and differentiate. Loss of Prox1 in the chick neural tube prevents suppression of Notch1 outside the ventricular zone.\",\n      \"method\": \"ChIP assay, gain-of-function in chick neural tube, loss-of-function in chick neural tube, mouse NPC overexpression, promoter binding assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter binding by ChIP, reciprocal gain- and loss-of-function in two species, defined molecular mechanism\",\n      \"pmids\": [\"21203589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COUP-TFII homodimers induce a venous EC fate by directly binding to promoters of Notch target genes HEY1 and HEY2, while COUP-TFII/PROX1 heterodimers lack this inhibitory effect. NR2F2/PROX1 heterodimers actively induce LEC-specific gene expression. PROX1 DNA binding also contributes to HEY1 and LEC-specific gene expression.\",\n      \"method\": \"Heterodimerization assays, promoter binding studies, knockdown experiments in endothelial cells, gene expression analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated, functional consequences of dimer switching shown, single lab\",\n      \"pmids\": [\"23345397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PROX1 up-regulates HIF-1α transcription and stabilizes HIF-1α protein by recruiting histone deacetylase 1 (HDAC1) to prevent acetylation of HIF-1α, subsequently inducing an epithelial-mesenchymal transition response in HCC cells to promote metastasis.\",\n      \"method\": \"PROX1 knockdown and overexpression in HCC cells, in vitro migration/invasion assays, in vivo nude mouse metastasis model, co-IP for HDAC1 interaction\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for binding partner, functional KD and OE with cellular phenotype, in vivo validation, single lab\",\n      \"pmids\": [\"23505027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Prox1 directly interacts with LSD1 (KDM1A) and recruits the LSD1/NuRD complex to the CYP7A1 promoter, co-repressing CYP7A1 transcription via H3K4 demethylation and histone deacetylation. This mechanism is involved in the physiological negative feedback inhibition of CYP7A1 by bile acids.\",\n      \"method\": \"Immunoprecipitation followed by mass spectrometry, GST pulldown (direct interaction), sequential ChIP, ChIP in siRNA knockdown cells, reporter assays\",\n      \"journal\": \"PLoS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — GST pulldown for direct interaction, sequential ChIP for co-occupancy, histone modification measurements, bile acid feedback validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23626788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the SOX18 HMG box bound to a DNA element regulating Prox1 transcription was resolved at 1.75Å. SOX18 directly binds Prox1 promoter DNA; decoy oligonucleotides based on the Prox1-DNA element inhibit SOX18 DNA binding in vitro and suppress SOX18-dependent reporter activity in cells.\",\n      \"method\": \"X-ray crystallography (1.75Å), in vitro DNA binding assays, decoy oligonucleotide design and testing, luciferase reporter assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation (reporter assay and DNA binding inhibition), single lab\",\n      \"pmids\": [\"26939885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ERRα, PROX1, and BMAL1 show extensive genomic co-occupancy in the liver. PROX1 is implicated in rhythmic control of metabolic outputs and acts as a corepressor in the ERRα transcriptional network, with genome-wide location analyses revealing transcriptional regulatory loops among these three factors controlling clock and metabolic gene networks.\",\n      \"method\": \"Genome-wide ChIP-seq (ERRα, PROX1, BMAL1), ERRα-null mouse phenotyping, locomotor activity assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP for co-occupancy, KO phenotype, single lab\",\n      \"pmids\": [\"21731503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC3 and PROX1 form a corepressor module in vivo (identified by cross-linking mass spectrometry). HDAC3 and PROX1 co-localize extensively on the mouse liver genome and are co-recruited by HNF4α. The HDAC3-PROX1 module controls expression of a gene program regulating lipid homeostasis; hepatic-specific ablation of either component increases triglyceride content in liver.\",\n      \"method\": \"Cross-linking mass spectrometry (HDAC3 interactome), ChIP-seq, liver-specific conditional knockout of Prox1 and Hdac3\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo cross-linking MS for complex identification, ChIP-seq for genome-wide co-occupancy, multiple conditional KO models with metabolic phenotype\",\n      \"pmids\": [\"28916805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Prox1 directly binds to the 5' regulatory sequence of the Pdpn (podoplanin) gene in LECs (confirmed by ChIP and DNA pulldown assay) and regulates Pdpn gene expression at the transcriptional level as shown by luciferase reporter assay.\",\n      \"method\": \"ChIP assay, DNA pulldown assay, luciferase reporter assay\",\n      \"journal\": \"Microvascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and DNA pulldown for direct binding, reporter assay for functional consequence, single lab\",\n      \"pmids\": [\"24944097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PROX1 suppresses transcription of MMP14 by binding and suppressing the MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels and siRNA knockdown in human LECs increased MMP14 expression. PROX1 ectopic expression reduced MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells.\",\n      \"method\": \"Prox1 conditional knockout in vivo, siRNA knockdown in LECs, promoter binding assay, 3D invasion assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO and in vitro KD with consistent MMP14 upregulation, promoter binding established, single lab\",\n      \"pmids\": [\"29934628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PROX1 forms a complex with β-catenin and the TCF/LEF transcription factor TCF7L1 to enhance Wnt/β-catenin signaling and promote FOXC2 and GATA2 expression in LECs. PROX1 thus directs lymphatic cell fate by acting as a Wnt signaling component.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays, LEC-specific Wntless knockout mice, in vitro oscillatory shear stress assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for complex formation, in vivo genetic model, functional gene expression readout, single lab\",\n      \"pmids\": [\"30332639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Prox1 ablation in bipotent hepatoblasts dramatically reduces hepatocyte gene expression, leads to defective hepatocyte morphogenesis, and causes excessive cholangiocyte commitment and biliary hyperplasia, identifying Prox1 as a regulator of cell fate allocation in liver precursors.\",\n      \"method\": \"Conditional Prox1 knockout in hepatic progenitors, immunostaining, gene expression analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional KO with defined molecular and morphological phenotypes for hepatocyte vs. cholangiocyte fate\",\n      \"pmids\": [\"24449835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Prox1 activates the NFAT signalling pathway and is necessary and sufficient for the maintenance of slow muscle fibre type gene program. Prox1 is required for myoblast differentiation via bi-directional crosstalk with Notch1. Prox1-positive satellite cells differentiate into muscle fibres (shown by lineage tracing).\",\n      \"method\": \"Prox1 conditional knockout in satellite cells, Prox1 overexpression, lineage tracing, NFAT reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, gain-of-function, lineage tracing, and pathway reporter assays, multiple orthogonal methods\",\n      \"pmids\": [\"27731315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Prox1 represses transcriptional activity of Gfi1 independently of Atoh1 in inner ear hair cells (luciferase assay). Prox1 transduction into cochlear outer hair cells caused their degeneration, consistent with Gfi1-deficient phenotype. Prox1 interacts with Atoh1 and Gfi1 and antagonizes the hair cell phenotype.\",\n      \"method\": \"Adenoviral Prox1 transduction in cochlear explants, luciferase transcriptional activity assay, comparison with Gfi1-deficient mice\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct repression of Gfi1 shown by reporter assay, functional consequence in explants, single lab\",\n      \"pmids\": [\"18652815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Prox1 suppresses Olig2 expression by directly binding to the proximal promoter and K23 enhancer of the Olig2 gene locus in vivo (shown by ChIP). Prox1 is sufficient and necessary for suppression of Olig2 expression and control of MN versus V2 interneuron identity in ventral spinal cord.\",\n      \"method\": \"ChIP in mouse neural tube, gain- and loss-of-function in mouse NPCs and chick neural tube, promoter/enhancer reporter assays\",\n      \"journal\": \"Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP for direct binding, reciprocal gain/loss-of-function in two systems, functional gene regulation at defined cis-elements\",\n      \"pmids\": [\"25411508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YAP and TAZ negatively regulate Prox1 transcription in LECs through recruitment of the NuRD (nucleosome remodeling and histone deacetylase) complex and endogenous binding of TEAD factors to the PROX1 promoter. LEC-specific YAP/TAZ hyperactivation profoundly downregulates Prox1 and impairs lymphatic specification.\",\n      \"method\": \"LEC-specific Yap/Taz conditional knockout and hyperactivation mouse models, promoter occupancy assays, NuRD complex recruitment assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse models plus mechanistic promoter complex analysis, single lab\",\n      \"pmids\": [\"30582452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AMPK phosphorylates PROX1 at Ser79, which enhances recruitment of the CUL4-DDB1 ubiquitin ligase to promote PROX1 ubiquitination and proteasomal degradation. PROX1 downregulation by AMPK activates branched-chain amino acid (BCAA) degradation through epigenetic modifications and inhibits mTOR signalling.\",\n      \"method\": \"AMPK activation/inhibition assays, site-directed mutagenesis (Ser79), co-IP for CUL4-DDB1 interaction, ubiquitination assays, epigenetic modification assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — PTM site identified by mutagenesis, writer (AMPK) and degradation machinery (CUL4-DDB1) identified, downstream metabolic consequences defined, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36433955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Transcriptional activation of Prox1 is directly controlled by HIF-1α and HIF-2α binding to a hypoxia-response element (HRE) in the Prox1 promoter/regulatory region, as demonstrated by EMSA and ChIP. HIF-1α/HIF-2α overexpression increases and knockdown decreases Prox1 promoter activity.\",\n      \"method\": \"EMSA, ChIP, HIF-1α/HIF-2α overexpression and knockdown, Prox1 promoter reporter assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and ChIP for direct HRE binding, functional reporter assay, single lab\",\n      \"pmids\": [\"23395615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PROX1 promotes HCC cell proliferation and activates the Wnt/β-catenin pathway by upregulating β-catenin transcription via stimulation of the β-catenin promoter and enhancing nuclear translocation of β-catenin in HCC cells.\",\n      \"method\": \"PROX1 knockdown and overexpression in HCC cells, β-catenin promoter reporter assay, nuclear fractionation, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assay for transcriptional mechanism, nuclear translocation assay, in vivo confirmation, single lab\",\n      \"pmids\": [\"25684142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PROX1 interacts with the NuRD complex to suppress the Notch pathway in colorectal cancer stem-like cells. PROX1 deletion increases Notch target gene expression and NOTCH1 promoter activity, demonstrating reciprocal regulation.\",\n      \"method\": \"Co-immunoprecipitation for NuRD complex interaction, PROX1 knockout in organoid cultures, reporter assays, gene expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for complex, KO with gene expression readout, single lab\",\n      \"pmids\": [\"30154153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A PROX1 enhancer element bound by GATA2, FOXC2, NFATC1, and PROX1 itself is required for Prox1 expression in lymphatic endothelial cells. Disruption of the GATA2-binding site within this enhancer by genome editing caused profound lymphatic defects and revealed that lymphatic endothelium has haemogenic capacity ordinarily repressed by Prox1.\",\n      \"method\": \"Genome editing (5-nt deletion of GATA2-binding site), ChIP (occupancy by GATA2/FOXC2/NFATC1/PROX1), conditional mouse knockout, gene expression analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — precise genome editing of defined cis-element, multiple TF binding validated by ChIP, in vivo phenotype with gene expression analysis\",\n      \"pmids\": [\"36697821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mitochondrial complex III activity regulates the critical Prox1-Vegfr3 feedback loop by controlling H3K4me3 and H3K27ac levels at the genomic loci of key LEC fate controllers (Vegfr3, Prox1), linking mitochondrial respiration to epigenetic control of LEC fate specification and maintenance.\",\n      \"method\": \"Conditional deletion of QPC (mitochondrial complex III subunit) in LECs, H3K4me3/H3K27ac ChIP, gene expression analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with ChIP-based epigenetic mechanism, single lab\",\n      \"pmids\": [\"33931446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YAP and TAZ are required to maintain PROX1 expression in lymphatic valves and lymphovenous valves in response to VEGF-C signaling. Deletion of Yap and Taz in lymphatic vasculature of mouse embryos did not prevent valve formation but caused their degeneration with loss of PROX1 expression.\",\n      \"method\": \"Conditional Yap/Taz knockout in lymphatic vasculature, valve morphogenesis analysis, PROX1 expression analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined structural phenotype and molecular readout, single lab\",\n      \"pmids\": [\"33060128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Autophagy loss in LECs impairs lipid droplet degradation (lipophagy), reducing fatty acid oxidation, mitochondrial ATP production, acetyl-CoA/CoA ratio, and expression of lymphangiogenic PROX1 target genes including VEGFR3. Supplementing acetate (fatty acid precursor) rescues VEGFR3 levels and lymphangiogenesis in LEC-Atg5-/- mice, linking lipophagy to a mitochondrial-PROX1 gene expression circuit.\",\n      \"method\": \"LEC-specific Atg5 knockout mice, lipid droplet quantification, fatty acid oxidation assays, acetyl-CoA measurement, acetate supplementation rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with metabolic and gene expression analysis, rescue experiment, single lab\",\n      \"pmids\": [\"35589749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Prox1 and Six3 act antagonistically at the gamma-crystallin (CRYGD/e/f) promoter. A Prox1-responsive element was mapped between -151 and -174 and a Six3-responsive element between -101 and -123. Prox1 stimulates CRYGF promoter activity in cells lacking endogenous Prox1, acting as a transcriptional activator of gamma-crystallin genes.\",\n      \"method\": \"Cell transfection reporter assays, randomly mutated promoter fragment analysis, cell lines with and without endogenous Prox1\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter reporter mapping with defined response elements, functional antagonism shown, single lab\",\n      \"pmids\": [\"11139622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Prox1 directly binds to the OL2 element and two additional upstream elements of the chicken betaB1-crystallin basal promoter. At the upstream sites, Prox1 mediates repression rather than activation, demonstrating that Prox1 function as transcriptional activator or repressor at this locus depends on the characteristics of the responsive DNA element and cellular context.\",\n      \"method\": \"DNase I footprinting, ChIP, transfection reporter assays in multiple lens cell types, transgenic mice\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA binding by DNase I footprinting and ChIP, functional reporter assays in multiple contexts, single lab\",\n      \"pmids\": [\"18385074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RNA-binding protein Celf1 post-transcriptionally regulates Prox1 protein levels in lens development via its 3' UTR. Celf1 lens-specific conditional knockout causes abnormal Prox1 protein distribution without changing Prox1 transcript levels. Celf1 protein binds Prox1 transcripts (RNA-immunoprecipitation), and Celf1 negatively controls Prox1 translation via its 3' UTR (reporter assays in KD and OE cells).\",\n      \"method\": \"Celf1 lens-specific conditional KO, immunostaining, qRT-PCR, RNA-immunoprecipitation, 3' UTR reporter assays in Celf1 KD and OE cells\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP for direct binding, reporter assay for 3' UTR-mediated regulation, conditional KO phenotype, single lab\",\n      \"pmids\": [\"32594240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PROX1 interacts with KSHV ORF50 (viral initiator of lytic replication) protein and binds to the KSHV genome at the ORF50 promoter region, increasing ORF50 transactivation activity and spontaneous lytic gene expression and infectious virus release from LECs.\",\n      \"method\": \"Co-immunoprecipitation (PROX1-ORF50 interaction), ChIP on KSHV genome, PROX1 genetic depletion, lytic gene expression and viral production assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for viral protein interaction, ChIP for genome occupancy, functional KD with viral phenotype, single lab\",\n      \"pmids\": [\"32518203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PROX1 inhibits PDGF-B expression in valvular endothelial cells (VECs) partially via FOXC2, preventing myxomatous degeneration of cardiac valves. Conditional Prox1 deletion from VECs caused FOXC2 downregulation and PDGF-B upregulation; conditional FOXC2 knockdown and PDGF-B overexpression recapitulated the Prox1 KO valve phenotype; pharmacological PDGF-B inhibition (imatinib) partially rescued the defects.\",\n      \"method\": \"VEC-specific conditional Prox1 knockout, FOXC2 knockdown and PDGF-B overexpression mouse models, echocardiography, histology, pharmacological inhibition\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional mouse models, pharmacological rescue, human tissue validation, pathway mechanism (PROX1→FOXC2→PDGF-B) established\",\n      \"pmids\": [\"37555328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PROX1 interacts with hnRNPK in breast cancer cells; this interaction inhibits ubiquitination of hnRNPK, which subsequently activates the WNT/β-catenin pathway to promote invasion and metastasis of breast cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, WNT pathway reporter, in vitro invasion assays, in vivo lung metastasis model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, ubiquitination assay, pathway reporter, in vivo model, single lab\",\n      \"pmids\": [\"35342346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ASCL1 complexes with NKX2-1 and PROX1 to co-regulate genes functioning in NOTCH signaling, catecholamine biosynthesis, and cell-cycle processes in ASCL1-high small-cell lung cancer.\",\n      \"method\": \"Chromatin landscape analysis (super-enhancer mapping), transcriptome analysis, co-occupancy analysis of ASCL1, NKX2-1, PROX1 in SCLC preclinical models\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-occupancy by ChIP without direct biochemical interaction assay for the complex, single lab\",\n      \"pmids\": [\"34466783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Prox1 (Prospero-related homeobox protein) represses HBV promoters in hepatocytes: for the ENII/Cp promoter, Prox1 serves as a corepressor of LRH-1 and downregulates LRH-1-mediated activation; for the Sp1 promoter, Prox1 partially represses activity by directly interacting with hepatocyte nuclear factor 1 (HNF1).\",\n      \"method\": \"Reporter-gene analysis of HBV promoters, co-immunoprecipitation for HNF1 interaction, HBV replication assays in hepatocyte cultures\",\n      \"journal\": \"Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays for promoter-specific mechanism, Co-IP for HNF1 interaction, functional HBV replication assay, single lab\",\n      \"pmids\": [\"19264593\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PROX1 is a homeodomain transcription factor that acts as a master binary switch controlling lymphatic endothelial cell identity by directly activating lymphatic target genes (VEGFR3, FGFR3, podoplanin) and repressing blood vascular genes, forming obligate complexes with COUP-TFII/NR2F2, β-catenin/TCF7L1, HDAC3, LSD1/NuRD, and ERRα/PGC-1α to regulate metabolic, developmental, and cell-fate gene programs; its activity is post-translationally modulated by SUMO-1 (at K556), AMPK-driven CUL4-DDB1 ubiquitination (at S79), and post-transcriptionally by miR-181a and the RNA-binding protein CELF1, while its own transcription is controlled by HIF-1α/HIF-2α, a GATA2/FOXC2/NFATC1/PROX1 autoregulatory enhancer, and a feedback loop with VEGFR3 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PROX1 is a homeodomain transcription factor that functions as a master regulator of cell-fate specification across multiple tissues, acting as a binary switch that both activates lineage-defining gene programs and represses alternative-fate genes [#0, #3]. In the lymphatic system it is necessary and sufficient to reprogram blood vascular endothelium toward lymphatic identity, and continuous PROX1 activity is required to maintain that identity—its loss reprograms lymphatic endothelial cells back to a blood vascular phenotype [#0, #3]. PROX1 drives this fate by directly activating lymphatic target genes including FGFR-3, VEGFR3, and podoplanin through binding to defined cis-elements in their promoters [#6, #13, #21], with VEGFR3 establishing a feedback loop in which VEGFC/VEGFR3 signaling sustains PROX1 expression to set lymphatic progenitor number [#13]. Its DNA-binding specificity and activator-versus-repressor output depend on partner proteins and the responsive element: it heterodimerizes with COUP-TFII/NR2F2 to induce lymphatic genes and block venous Notch-target activation [#4, #15], cooperates with FOXC2 and Wnt/\\u03b2-catenin\\u2013TCF7L1 to direct valve morphogenesis and lymphatic specification [#11, #23, #41], and assembles its own transcription via a GATA2/FOXC2/NFATC1/PROX1 autoregulatory enhancer [#33]. Beyond the vasculature, PROX1 controls cell-cycle exit and fate in lens, retina, dentate gyrus neurons, spinal interneurons, hepatoblasts, and slow muscle fibers, frequently by repressing pro-proliferative or alternative-fate genes such as Notch1 and Olig2 at their promoters [#1, #2, #7, #14, #24, #25, #27]. In metabolic tissues PROX1 acts predominantly as a corepressor, partnering with ERR\\u03b1/PGC-1\\u03b1, the LSD1/NuRD complex, and HDAC3 to control energy homeostasis, bile-acid feedback, lipid homeostasis, and rhythmic metabolic outputs [#9, #17, #19, #20]. PROX1 activity is set post-translationally by SUMOylation at K556, which promotes DNA binding and transcriptional activity [#10], and by AMPK-driven phosphorylation at Ser79 that recruits CUL4-DDB1 to trigger ubiquitination and degradation [#29]; its levels are further tuned post-transcriptionally by miR-181a and the RNA-binding protein CELF1 acting through its 3' UTR [#8, #39], and transcriptionally by HIF-1\\u03b1/HIF-2\\u03b1, SOX18, and YAP/TAZ [#18, #28, #30, #35]. In cancer, PROX1 promotes hepatocellular and breast tumor progression through Wnt/\\u03b2-catenin activation and HIF-1\\u03b1 stabilization [#16, #31, #42].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the first in vivo developmental role of Prox1, showing it couples cell-cycle exit to terminal differentiation rather than acting merely as a fate marker.\",\n      \"evidence\": \"Prox1 knockout mouse with lens phenotyping and cell-cycle inhibitor expression analysis\",\n      \"pmids\": [\"10080188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets at the lens not defined\", \"Mechanism of Cdkn1b/Cdkn1c regulation not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined Prox1 as a sequence-specific transcription factor at the gamma-crystallin promoter, mapping its response element and revealing antagonism with Six3.\",\n      \"evidence\": \"Reporter assays with mapped Prox1- and Six3-responsive promoter elements\",\n      \"pmids\": [\"11139622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding not shown by footprinting/ChIP in this study\", \"Mechanism of Six3 antagonism unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that Prox1 is both necessary and sufficient for lymphatic endothelial cell fate, identifying it as a master switch reprogramming blood vascular toward lymphatic identity.\",\n      \"evidence\": \"Ectopic expression in human BVECs plus Prox1 knockout mice with transcriptional profiling\",\n      \"pmids\": [\"12412020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect target genes not distinguished\", \"Cofactor requirements not identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Generalized Prox1's fate-switch logic to the retina, showing reciprocal control of progenitor cell-cycle exit and horizontal cell identity.\",\n      \"evidence\": \"Reciprocal knockout and ectopic misexpression in retinal progenitors\",\n      \"pmids\": [\"12692551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes in retina not identified\", \"Molecular mechanism of cell-cycle exit not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified the first direct lymphatic target gene, FGFR-3, anchoring Prox1's fate-switch to defined cis-regulatory binding.\",\n      \"evidence\": \"Promoter binding and reporter assays following ectopic Prox1 in BVECs\",\n      \"pmids\": [\"16291864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo requirement of FGFR-3 element not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed that Prox1 acts through obligate partnership with COUP-TFII to maintain lymphatic identity, moving the model from a solo switch to a combinatorial code.\",\n      \"evidence\": \"Reciprocal Co-IP and knockdown co-regulation analysis in LECs\",\n      \"pmids\": [\"18815287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of heterodimer not defined\", \"Genome-wide co-occupancy not yet mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended Prox1's transcriptional logic to context-dependent activation versus repression, showing output depends on the responsive DNA element in lens crystallin genes.\",\n      \"evidence\": \"DNase I footprinting, ChIP, and reporter assays across lens cell types and transgenic mice\",\n      \"pmids\": [\"18385074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cofactors distinguishing activation from repression not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed Prox1 directly transcribes sarcomeric structural genes, establishing a tissue-specific role in cardiac muscle architecture.\",\n      \"evidence\": \"Cardiac-specific conditional knockout with transcriptomics and direct regulation assays\",\n      \"pmids\": [\"19091769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors for cardiac targets not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated Prox1 represses Gfi1 and antagonizes hair-cell fate, broadening its repressor role in inner ear development.\",\n      \"evidence\": \"Adenoviral transduction in cochlear explants and luciferase repression assays\",\n      \"pmids\": [\"18652815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to Gfi1 locus not shown\", \"In vivo requirement not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed continuous Prox1 activity is required to maintain LEC identity even in adults, establishing fate maintenance as an active, cell-autonomous process.\",\n      \"evidence\": \"Temporally staged conditional knockouts and siRNA knockdown in cultured LECs\",\n      \"pmids\": [\"19056883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals sustaining Prox1 not defined in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified SUMOylation at K556 as a positive post-translational regulator controlling Prox1 DNA binding and lymphatic gene induction.\",\n      \"evidence\": \"In vitro/in vivo sumoylation assays, K556R mutagenesis, SENP2 reversal, reporter assays\",\n      \"pmids\": [\"19706680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase not identified\", \"In vivo physiological importance not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined Prox1 as a promoter-specific corepressor of viral transcription in hepatocytes via LRH-1 and HNF1, illustrating context-dependent repression in the liver.\",\n      \"evidence\": \"HBV promoter reporter assays, Co-IP for HNF1, and replication assays\",\n      \"pmids\": [\"19264593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding not demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed Prox1 at the center of energy homeostasis as a corepressor of the ERR\\u03b1/PGC-1\\u03b1 metabolic transcriptional network.\",\n      \"evidence\": \"Co-IP, genome-wide ChIP, reporter assays, and respiratory-capacity measurements in liver cells\",\n      \"pmids\": [\"20194433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ERR\\u03b1/PGC-1\\u03b1 inhibition not resolved at structural level\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified miR-181a as a direct post-transcriptional repressor of Prox1 that tunes the lymphatic-versus-blood vascular balance.\",\n      \"evidence\": \"3' UTR luciferase reporter and reciprocal miR-181a gain/loss-of-function in primary endothelial cells\",\n      \"pmids\": [\"20558617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream control of miR-181a not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended Prox1's neurogenic role, showing it drives granule-cell maturation and maintains adult neural progenitors through a non-cell-autonomous feedback loop.\",\n      \"evidence\": \"Conditional knockout, BrdU labeling, and ectopic expression in the dentate gyrus\",\n      \"pmids\": [\"20808958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of the feedback signal not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mechanistically linked Prox1 gene dosage to lymphovenous valve formation through COUP-TFII/Prox1 complex abundance.\",\n      \"evidence\": \"Prox1 heterozygous mouse analysis with complex formation assays\",\n      \"pmids\": [\"22012621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative threshold of complex required not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Integrated Prox1 into circadian-metabolic transcriptional loops via genome-wide co-occupancy with ERR\\u03b1 and BMAL1 in liver.\",\n      \"evidence\": \"ChIP-seq of ERR\\u03b1/PROX1/BMAL1 and ERR\\u03b1-null mouse phenotyping\",\n      \"pmids\": [\"21731503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction with BMAL1 not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed PROX1 cooperates with FOXC2 and fluid shear to translate mechanical signals into lymphatic valve patterning through connexin37 and calcineurin/NFAT.\",\n      \"evidence\": \"Conditional knockouts, in vitro shear-stress assays, and downstream effector loss-of-function\",\n      \"pmids\": [\"22306086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How shear is sensed upstream of the PROX1/FOXC2 module not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed that COUP-TFII/PROX1 heterodimer formation, versus COUP-TFII homodimers, switches endothelial output between lymphatic and venous (Notch-target) programs.\",\n      \"evidence\": \"Heterodimerization and promoter binding studies with knockdown in endothelial cells\",\n      \"pmids\": [\"23345397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the dimer switch not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established HIF-1\\u03b1/HIF-2\\u03b1 as direct hypoxia-driven activators of Prox1 transcription, linking oxygen sensing to lymphatic fate.\",\n      \"evidence\": \"EMSA, ChIP, HIF overexpression/knockdown, and Prox1 promoter reporters\",\n      \"pmids\": [\"23395615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo physiological relevance of the HRE not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a corepressor mechanism in bile-acid metabolism whereby PROX1 recruits LSD1/NuRD to demethylate and deacetylate the CYP7A1 promoter.\",\n      \"evidence\": \"IP-MS, GST pulldown, sequential ChIP, and reporter assays\",\n      \"pmids\": [\"23626788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment signal directing PROX1 to CYP7A1 not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Implicated PROX1 in hepatocellular carcinoma metastasis through HDAC1-dependent HIF-1\\u03b1 stabilization and EMT, identifying an oncogenic role.\",\n      \"evidence\": \"Knockdown/overexpression in HCC cells, invasion assays, nude mouse metastasis, and HDAC1 Co-IP\",\n      \"pmids\": [\"23505027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HIF-1\\u03b1 deacetylation by recruited HDAC1 not biochemically resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established a PROX1\\u2013VEGFR3 feedback loop as the principal sensing mechanism setting LEC progenitor number, with PROX1 directly and dosage-dependently regulating Vegfr3.\",\n      \"evidence\": \"Multiple mouse genetic models, ChIP, and VEGFC/VEGFR3 pathway manipulation\",\n      \"pmids\": [\"25274728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How VEGFR3 signaling feeds back to the Prox1 promoter not fully traced\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined Prox1 as a fate-allocation regulator in liver precursors, promoting hepatocyte over cholangiocyte commitment.\",\n      \"evidence\": \"Conditional knockout in hepatoblasts with gene expression and morphology analysis\",\n      \"pmids\": [\"24449835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct hepatocyte target genes not catalogued\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Confirmed podoplanin as a direct PROX1 transcriptional target in LECs, extending the catalogue of directly bound lymphatic effector genes.\",\n      \"evidence\": \"ChIP, DNA pulldown, and luciferase reporter assays in LECs\",\n      \"pmids\": [\"24944097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo enhancer requirement not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed Prox1 directly represses Olig2 at its promoter and enhancer to specify motor-neuron versus V2 interneuron identity in the spinal cord.\",\n      \"evidence\": \"In vivo ChIP plus reciprocal gain/loss-of-function in mouse and chick neural tube\",\n      \"pmids\": [\"25411508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors at the Olig2 locus not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined Prox1 as a regulator of slow muscle fiber identity through NFAT activation and Notch1 crosstalk.\",\n      \"evidence\": \"Satellite-cell conditional knockout, gain-of-function, lineage tracing, and NFAT reporters\",\n      \"pmids\": [\"27731315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct muscle fiber-type target genes not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed PROX1 promotes HCC proliferation by transactivating the \\u03b2-catenin promoter and enhancing nuclear \\u03b2-catenin, defining an oncogenic Wnt-activating mechanism.\",\n      \"evidence\": \"Knockdown/overexpression, \\u03b2-catenin promoter reporter, nuclear fractionation, and xenografts\",\n      \"pmids\": [\"25684142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of PROX1 to the \\u03b2-catenin promoter not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the structural and functional basis of SOX18 binding to the Prox1 regulatory DNA element, defining an upstream transcriptional input.\",\n      \"evidence\": \"1.75\\u00c5 crystal structure, DNA binding assays, and decoy oligonucleotide reporter inhibition\",\n      \"pmids\": [\"26939885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of this element to Prox1 expression not tested here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified an in vivo HDAC3\\u2013PROX1 corepressor module recruited by HNF4\\u03b1 that controls hepatic lipid homeostasis.\",\n      \"evidence\": \"Cross-linking MS, ChIP-seq co-occupancy, and conditional knockouts with metabolic phenotyping\",\n      \"pmids\": [\"28916805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the HDAC3-PROX1 module not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed PROX1 partners with \\u03b2-catenin/TCF7L1 to act as a Wnt signaling component driving FOXC2/GATA2 expression in LECs.\",\n      \"evidence\": \"Co-IP, reporter assays, LEC-specific Wntless knockout, and shear-stress assays\",\n      \"pmids\": [\"30332639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. cofactor-mediated DNA binding within the complex not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined PROX1 repression of MMP14 as a brake on invasive/angiogenic behavior, linking it to extracellular matrix remodeling.\",\n      \"evidence\": \"Conditional knockout, siRNA knockdown, promoter binding, and 3D invasion assays\",\n      \"pmids\": [\"29934628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cofactors at the MMP14 promoter not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended PROX1's NuRD-dependent Notch repression to colorectal cancer stem-like cells, showing reciprocal PROX1\\u2013Notch regulation.\",\n      \"evidence\": \"Co-IP, organoid knockout, and NOTCH1 promoter reporter assays\",\n      \"pmids\": [\"30154153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to the NOTCH1 promoter within the NuRD context not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified YAP/TAZ\\u2013TEAD with NuRD as a transcriptional repressor of Prox1, defining a Hippo-pathway input to lymphatic specification.\",\n      \"evidence\": \"LEC-specific Yap/Taz conditional knockout and hyperactivation with promoter occupancy assays\",\n      \"pmids\": [\"30582452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with the maintenance-promoting YAP/TAZ role at valves not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed YAP/TAZ are required to maintain PROX1 in lymphatic and lymphovenous valves downstream of VEGF-C, revealing context-dependent Hippo control.\",\n      \"evidence\": \"Conditional Yap/Taz knockout with valve morphogenesis and PROX1 expression analysis\",\n      \"pmids\": [\"33060128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism reconciling positive valve role with negative specification role unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified CELF1 as a 3' UTR-binding regulator that post-transcriptionally controls Prox1 protein in lens development.\",\n      \"evidence\": \"Lens-specific Celf1 conditional knockout, RNA-IP, and 3' UTR reporter assays\",\n      \"pmids\": [\"32594240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between CELF1 and miR-181a on the same 3' UTR not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed that PROX1 is hijacked by KSHV, interacting with ORF50 to promote viral lytic reactivation in LECs.\",\n      \"evidence\": \"Co-IP, ChIP on the KSHV genome, and genetic depletion with viral production assays\",\n      \"pmids\": [\"32518203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether host gene programs are co-opted not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked mitochondrial complex III activity to epigenetic control of the Prox1\\u2013Vegfr3 loop via H3K4me3/H3K27ac at LEC fate loci.\",\n      \"evidence\": \"LEC-specific complex III subunit deletion with histone-mark ChIP and gene expression\",\n      \"pmids\": [\"33931446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Metabolite intermediary connecting respiration to histone marks not pinpointed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined AMPK phosphorylation of PROX1 at Ser79 as a degradation switch recruiting CUL4-DDB1, coupling energy status to PROX1 stability and BCAA/mTOR metabolism.\",\n      \"evidence\": \"AMPK modulation, Ser79 mutagenesis, CUL4-DDB1 Co-IP, ubiquitination, and metabolic assays\",\n      \"pmids\": [\"36433955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue contexts where this degradation operates not fully mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected lipophagy-driven mitochondrial metabolism to PROX1 target gene expression, showing acetyl-CoA availability tunes VEGFR3 and lymphangiogenesis.\",\n      \"evidence\": \"LEC-specific Atg5 knockout with metabolic profiling and acetate rescue\",\n      \"pmids\": [\"35589749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct epigenetic step on PROX1 targets not pinpointed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified PROX1\\u2013hnRNPK interaction as an oncogenic mechanism stabilizing hnRNPK and activating Wnt/\\u03b2-catenin in breast cancer metastasis.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, Wnt reporter, and in vivo metastasis model\",\n      \"pmids\": [\"35342346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect of PROX1 on hnRNPK ubiquitination machinery not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a PROX1 autoregulatory enhancer bound by GATA2/FOXC2/NFATC1/PROX1 and showed that disrupting its GATA2 site causes lymphatic defects and de-represses hemogenic potential.\",\n      \"evidence\": \"Precise genome editing of the GATA2 site, ChIP occupancy, and conditional knockout phenotyping\",\n      \"pmids\": [\"36697821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among the four enhancer-binding factors not fully ordered\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a PROX1\\u2192FOXC2\\u2192PDGF-B axis in cardiac valvular endothelium that prevents myxomatous valve degeneration.\",\n      \"evidence\": \"VEC-specific conditional knockouts, pathway manipulation, echocardiography, and pharmacological rescue with imatinib\",\n      \"pmids\": [\"37555328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FOXC2-independent contribution to PDGF-B repression not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse PROX1 cofactor repertoire and post-translational/post-transcriptional inputs are integrated to select activator versus repressor output at a given locus in a given tissue remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of PROX1 partner-dependent DNA-element selectivity\", \"Cross-talk between SUMOylation, AMPK-driven degradation, miR-181a, and CELF1 in vivo not integrated\", \"Tissue-specific cofactor hierarchies largely uncatalogued\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 6, 9, 14, 17, 20, 21, 27, 37, 38]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6, 10, 14, 21, 27, 38]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [6, 14, 21, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 14, 27, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 14, 21, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 7, 24, 25, 33]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 17, 19, 20, 29, 36]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 23, 31, 42]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [17, 20, 28, 32, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 31, 40, 42, 43]}\n    ],\n    \"complexes\": [\n      \"PROX1/COUP-TFII(NR2F2) heterodimer\",\n      \"LSD1/NuRD corepressor complex\",\n      \"HDAC3-PROX1 corepressor module\",\n      \"PROX1/\\u03b2-catenin/TCF7L1 complex\"\n    ],\n    \"partners\": [\n      \"NR2F2\",\n      \"ERRA\",\n      \"PGC1A\",\n      \"KDM1A\",\n      \"HDAC3\",\n      \"CTNNB1\",\n      \"TCF7L1\",\n      \"FOXC2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}