Affinage

PAX8

Paired box protein Pax-8 · UniProt Q06710

Length
450 aa
Mass
48.2 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAX8 is a paired-domain transcription factor that drives lineage-specific transcriptional programs in the thyroid and nephric systems and is co-opted as a lineage-survival oncogene in renal and ovarian cancers (PMID:1723950, PMID:11069301, PMID:35676472). It binds DNA through cooperative action of its PAI and RED paired-domain subdomains, with the RED subdomain required for correct DNA recognition by PAI, and transactivates through a serine/threonine/proline-rich C-terminal domain that is regulated by adjacent inhibitory sequences and is present only in the transcriptionally active spliced isoforms (PMID:8413205, PMID:8617244, PMID:9882622). In thyroid follicular cells PAX8 is a direct activator of the thyroid differentiation program, switching on endogenous thyroglobulin, thyroperoxidase, and the sodium/iodide symporter, cooperating with TTF-1 at the thyroglobulin promoter, and its loss triggers p53/TP53INP1-dependent apoptosis; PAX8 also controls thyroid follicular apical-basal polarity and lumen formation through cadherin-16 (PMID:11069301, PMID:23868062, PMID:27780871). Together with Pax2, PAX8 specifies the nephric lineage by driving the mesenchymal-to-epithelial transition and activating Lim1/c-Ret, and in the adult kidney it maintains urine-concentrating function by activating urea transporters and aquaporins via recruitment of a histone methyltransferase complex (PMID:12435636, PMID:32381599). Its activity is tuned by redox-sensitive Ref-1 enhancement of DNA binding, retinoblastoma protein coactivation, cAMP/TSH-driven expression, TGF-β1-mediated suppression, PIASy-dependent sumoylation at K309 controlling stability and nuclear-body targeting, and Skp2-mediated ubiquitination at K275 antagonized by Aurora A phosphorylation at S209/T277 (PMID:9813166, PMID:16007137, PMID:8652674, PMID:11145590, PMID:18974227, PMID:31391550). In cancer, PAX8 occupies active enhancers genome-wide and recruits histone acetylation and chromatin-looping activity to target promoters, and serves as the platform onto which HIF2A is recruited in VHL-deficient clear cell renal carcinoma to drive CCND1 and MYC expression; in ovarian carcinoma it partners with PRDM3, SOX17 and TAZ to control adhesion/ECM, angiogenesis (via SERPINE1 suppression) and cell-cycle programs (PMID:31431624, PMID:35676472, PMID:33903593, PMID:35380877, PMID:33830648). Congenital hypothyroidism is caused by dominant-negative paired-domain missense mutations (G41V, D94N) that impair PAX8 DNA binding and target-gene activation (PMID:28060725).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1990 High

    Establishing where Pax8 acts: identifying its expression in developing thyroid, mesonephros/metanephros, and neural tube defined the tissues whose development it might control and predicted a sequence-specific transcription factor role.

    Evidence cDNA isolation, ORF analysis and in situ hybridization in mouse embryos

    PMID:1723950

    Open questions at the time
    • Direct target genes not identified
    • No demonstration of transcriptional activity at this stage
  2. 1993 High

    Resolving which gene products are transcriptionally active: alternative splicing of exons 7/8 produces isoforms that all bind DNA but differ in transactivation, showing the C-terminus dictates activator function.

    Evidence Isoform cloning, transfection transactivation assays, RNase protection in mouse tissues

    PMID:8413205

    Open questions at the time
    • Physiological consequence of isoform switching in vivo not established
    • Regulators of splice choice unknown
  3. 1996 High

    Defining the activation machinery and its upstream control: a transactivation domain bounded by an inhibitory element was delineated, and TSH/cAMP signalling was shown to upregulate Pax8 expression.

    Evidence GAL4-fusion domain swaps and mutagenesis; forskolin treatment of primary thyrocytes with immunoblotting

    PMID:8617244 PMID:8652674

    Open questions at the time
    • Identity of the inhibitory module's binding partners unknown
    • cAMP control of activity (vs expression) not resolved
  4. 1998 Medium

    Mapping how PAX8 reads DNA and is biochemically tuned: PAI/RED subdomain cooperativity defined the recognition mechanism, and Ref-1 was shown to redox-stimulate paired-domain DNA binding.

    Evidence Isolated subdomain binding assays with C-site mutants; in vitro DNA binding and reporter assays with Ref-1

    PMID:9813166 PMID:9882622

    Open questions at the time
    • No co-crystal structure of the PAX8 paired domain on DNA
    • Ref-1 redox control validated in single lab without in vivo perturbation
  5. 1998 High

    Identifying direct target genes: PAX8 was shown to bind and activate the WT1, thyroperoxidase, and N-CAM promoters via defined sites, establishing it as a direct transcriptional activator across multiple lineages.

    Evidence Gel-shift binding, promoter-reporter assays and site-directed mutagenesis of binding sites

    PMID:8071351 PMID:9388203 PMID:9512459

    Open questions at the time
    • Cofactor requirements at these promoters not defined
    • Mostly promoter-reporter rather than endogenous-locus evidence
  6. 2002 High

    Defining its developmental requirement: Pax2/Pax8 double-null embryos fail nephric specification, the mesenchymal-to-epithelial transition, and Lim1/c-Ret activation, establishing PAX8 as essential and redundant with Pax2 for the nephric lineage.

    Evidence Double-knockout mouse genetics with target-gene in situ hybridization and chick gain-of-function

    PMID:10491256 PMID:12435636

    Open questions at the time
    • Direct nephric target genes of PAX8 itself not separated from Pax2
    • Cofactor (Xlim-1) interaction biochemistry undefined
  7. 2000 High

    Connecting PAX8 to disease and to endogenous program control: it directly activates endogenous thyroid differentiation genes upon re-expression in dedifferentiated cells, and a PAX8-PPARgamma1 fusion was found in follicular thyroid carcinoma.

    Evidence Retroviral re-expression with RT-PCR of endogenous genes; RT-PCR/western and dominant-negative transactivation assay of the fusion

    PMID:10958784 PMID:11069301

    Open questions at the time
    • Mechanism of fusion-driven transformation beyond PPARgamma dominant negativity unclear
    • TTF-1 cooperation structurally undefined
  8. 2005 High

    Identifying protein coregulators: pRb was shown to act as a PAX8 transcriptional coactivator at thyroid promoters, linking PAX8 to cell-cycle regulators.

    Evidence Co-immunoprecipitation, reporter assays, pRb RNAi and E1A inhibition

    PMID:16007137

    Open questions at the time
    • Structural basis of PAX8-pRb interaction unknown
    • Single lab
  9. 2008 High

    Establishing post-translational and oncogenic control: PAX8 is sumoylated at K309 by PIASy controlling stability/nuclear-body targeting, and it directly activates telomerase (hTERT/hTR) in glioma.

    Evidence Sumoylation assays with K309R mutagenesis and PIASy co-transfection; EMSA, ChIP, telomerase activity and siRNA

    PMID:18632625 PMID:18974227

    Open questions at the time
    • Functional consequence of nuclear-body targeting for transcription not resolved
    • Telomerase regulation shown in single lab/cell type
  10. 2013 Medium

    Defining PAX8 as a survival factor: its loss triggers p53/TP53INP1-dependent apoptosis and G1/S arrest/senescence while activating E2F1 and stabilizing RB, framing PAX8 as a pro-proliferative/survival transcription factor.

    Evidence shRNA/siRNA knockdown, reporter and ChIP assays, apoptosis and cell-cycle analysis

    PMID:21602887 PMID:23868062

    Open questions at the time
    • Direct vs indirect TP53INP1 regulation not fully resolved
    • Single-lab mechanism for each pathway
  11. 2016 Medium

    Defining a morphogenetic role: PAX8 controls thyroid follicular apical-basal polarity and lumen formation through cadherin-16, connecting it to epithelial architecture beyond gene activation.

    Evidence 3D culture, RNAi of Pax8 and Cdh16, microarray and immunostaining

    PMID:27780871

    Open questions at the time
    • Direct ChIP evidence for Cdh16 regulation limited
    • Single lab/model
  12. 2019 High

    Establishing the genome-wide enhancer mechanism and ovarian cancer functions: PAX8 occupies active enhancers, recruits histone acetylation and chromatin looping, and drives ITGB3-dependent adhesion, FGF18/super-enhancer-controlled migration, and mutant-p53 signalling.

    Evidence ChIP-seq, 3C/Hi-C, H3K27ac analysis, knockdown phenotypes and reporter assays across RCC and ovarian models

    PMID:29379162 PMID:31050342 PMID:31431624 PMID:31832016

    Open questions at the time
    • Cofactors at most enhancers not identified
    • Causal chain from cistrome to phenotype incomplete for some targets
  13. 2019 High

    Resolving PAX8 stability control in cancer: Skp2 ubiquitinates PAX8 at K275 via the Prd domain, Aurora A phosphorylation at S209/T277 blocks this, and HBx stabilizes PAX8 by inhibiting Skp2; METTL3-mediated m6A controls PAX8 expression in thyroid cancer.

    Evidence Co-IP, ubiquitination/kinase assays with residue mutagenesis; METTL3 knockout mouse and m6A assays

    PMID:31391550 PMID:38993572

    Open questions at the time
    • Cell-cycle coupling of Aurora A phosphorylation not defined
    • m6A axis (idx 33) is Medium-confidence and single lab
  14. 2022 High

    Defining PAX8 as a lineage-survival oncogene platform: in VHL-deficient ccRCC HIF2A is recruited to PAX8-bound enhancers to drive CCND1 and MYC, and in ovarian carcinoma PAX8 partners with PRDM3, SOX17 and TAZ to control adhesion/ECM, angiogenesis via SERPINE1, and cell-cycle programs.

    Evidence ChIP-seq, CRISPR perturbation, allele-specific reporters, reciprocal Co-IP, in vivo angiogenesis and xenograft assays

    PMID:33830648 PMID:33903593 PMID:35124696 PMID:35380877 PMID:35676472

    Open questions at the time
    • Determinants of partner choice across tissues unknown
    • Structural basis of PAX8-partner complexes undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PAX8 selects among its many partners (HIF2A, PRDM3, SOX17, TAZ, pRb) and target programs across thyroid, kidney, and tumor contexts, and the structural basis of paired-domain target selection, remains unresolved.
  • No structural model of PAX8 in complex with cofactors on DNA
  • Context-specific cistrome determinants not defined
  • Integration of post-translational marks with partner recruitment unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 4 GO:0140097 catalytic activity, acting on DNA 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 2
Partners
HIF2APIASYPRDM3RB1SKP2SOX17TAZTTF-1
Complex memberships
PAX8-PRDM3 complexPAX8-SOX17 chromatin remodeling complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 The t(2;3)(q13;p25) chromosomal translocation in follicular thyroid carcinoma creates a PAX8-PPARgamma1 fusion protein that fuses the DNA-binding domains of PAX8 to domains A–F of PPARgamma1; this fusion protein acts as a dominant-negative inhibitor of thiazolidinedione-induced transactivation by wild-type PPARgamma1. RT-PCR and protein detection of fusion transcript/protein in tumor samples; dominant-negative transactivation assay in transfected cells Science High 10958784
1990 Murine Pax8 is expressed in the developing thyroid gland (beginning at E10.5), mesonephros and metanephros (mesenchymal condensations that form nephrons), and transiently in the neural tube; the encoded protein contains a paired domain near its amino terminus and an octapeptide conserved region, consistent with a sequence-specific transcription factor role in kidney epithelium induction and thyroid development. cDNA isolation, open reading frame analysis, in situ hybridization, interspecies backcross mapping Development High 1723950
2002 Pax2 and Pax8 together are required for specification of the nephric lineage: mouse embryos double-null for Pax2 and Pax8 fail to form the pronephros or any later nephric structure, do not undergo mesenchymal-to-epithelial transition for nephric duct formation, fail to activate kidney-specific Lim1 and c-Ret expression, and lose intermediate mesoderm by apoptosis. Retroviral misexpression of Pax2 alone was sufficient to induce ectopic nephric structures in chick embryos. Double-knockout mouse genetics, in situ hybridization for target genes (Lim1, c-Ret), retroviral misexpression in chick embryos Genes & development High 12435636
1993 Pax-8 produces at least four alternatively spliced mRNA isoforms (a–d) arising from inclusion/exclusion of exons 7 and/or 8. All isoforms retain the paired domain as their DNA-binding motif and recognize DNA in the same manner as Pax-2 and BSAP. However, only isoforms a and b (which encode a serine/threonine/tyrosine-rich C-terminus) strongly stimulate transcription from a paired-domain recognition sequence promoter, whereas isoforms c and d (with a proline-rich C-terminus) do not. Alternative splicing is temporally and spatially regulated during mouse development. PCR cloning of isoforms, exon-intron structure analysis, transfection transactivation assays, RNase protection analysis in mouse embryo and adult tissues Molecular and cellular biology High 8413205
1996 The C-terminal serine/threonine/proline-rich region of Pax-8 (and the closely related Pax-2 and Pax-5/BSAP) contains a potent transactivation domain whose activity is negatively regulated by adjacent sequences at the extreme C-terminus; this activating/inhibitory module functions as an independent regulatory unit and is conserved across Pax-2, Pax-8, zebrafish Pax-b, and sea urchin Pax-258. In vitro mutagenesis, transient transfection transactivation assays, GAL4-fusion domain-swap experiments The EMBO journal High 8617244
1998 The redox-regulatory protein Ref-1 stimulates the DNA-binding activity of the Pax-8 paired domain in vitro, and in co-transfection experiments Ref-1 increases Pax-8-mediated activation of the thyroglobulin promoter. Levels of Ref-1 in thyroid cell nuclear extracts correlate with amounts of reduced (active) Pax-8, suggesting redox-dependent control of Pax-8 DNA-binding activity in vivo. In vitro DNA-binding assay, co-transfection with reporter assay, immunoreactivity analysis of nuclear extracts Biochemical and biophysical research communications Medium 9813166
1999 The Pax-8 paired domain interacts with the C site of the thyroglobulin promoter through co-operation between its PAI (N-terminal) and RED (C-terminal) subdomains, each of which binds as a monomer with lower affinity than the full-length protein. The presence of the RED subdomain is necessary for correct DNA recognition by the PAI subdomain, establishing a chronological order in DNA binding. Binding assays with isolated PAI and RED subdomains, mutant C-site variants, in vitro DNA-binding and co-transfection experiments The Biochemical journal High 9882622
1997 PAX8 binds a single functional site located 250 bp upstream of the minimal WT1 promoter and activates WT1 transcription; endogenous PAX8 is required for this activation, and mutation of the PAX8-binding site abolishes both PAX8 binding and promoter up-regulation. Gel-shift binding assays, promoter-reporter transfection assays, enhancer-position/orientation independence tests The Journal of biological chemistry High 9388203
1998 PAX8 binds a cis element in the enhancer of the human thyroperoxidase gene and activates its transcriptional activity; mutation of the PAX8-binding site in the enhancer abolishes PAX8-mediated activation. In vitro binding assays, co-transfection reporter assays, site-directed mutagenesis of the PAX8 binding site The Biochemical journal High 9512459
1994 Pax-8 binds two TGCTCC motifs (PBS-1 and PBS-2) in the N-CAM promoter and activates N-CAM transcription ~13-fold in co-transfection experiments; mutation of both sites eliminates Pax-8 activation, and transfection of Pax-8 into N2A neuroblastoma cells increases endogenous N-CAM transcription ~5-fold. Co-transfection reporter assays, gel-shift with GST-fusion protein and COS-7 cell extracts, mutagenesis of binding sites, endogenous gene activation assay The Journal of biological chemistry High 8071351
1999 Ectopic co-expression of XPax-8 and the homeobox factor Xlim-1 synergistically induces ectopic pronephric kidney structures in Xenopus embryos (up to five-times normal complexity), whereas each gene alone has only a moderate effect; Pax-8 requires Xlim-1 (or equivalent cofactors) as a co-activator for efficient pronephric induction. Ectopic microinjection/overexpression in Xenopus embryos, morphological and molecular analysis of pronephric structures Developmental biology High 10491256
2000 Reintroduction of Pax8 alone into PCPy rat thyroid cells (which lost Pax8 upon oncogenic transformation) is sufficient to activate endogenous thyroglobulin, thyroperoxidase, and sodium/iodide symporter gene expression, demonstrating Pax8 as a direct activator of thyroid-specific gene expression at chromosomal loci. Pax8 and TTF-1 cooperate in activation of the thyroglobulin promoter. Retroviral re-expression of Pax8 in dedifferentiated thyroid cell line, RT-PCR/Northern analysis of endogenous thyroid genes, co-transfection assays with different Pax8 isoforms Proceedings of the National Academy of Sciences of the United States of America High 11069301
1996 Pax8 mRNA and protein expression in dog primary thyrocytes is increased by treatment with forskolin (a cAMP-elevating agent), suggesting that TSH/cAMP signalling upregulates Pax8 expression. Pax8 proteins are nuclear phosphoproteins, though neither their phosphorylation nor nuclear translocation appears to be highly regulated by cAMP. Northern blotting and immunoblotting of forskolin-treated primary thyrocytes, subcellular fractionation, phosphoprotein analysis Biochimica et biophysica acta Medium 8652674
2001 TGF-β1 decreases Pax-8 mRNA and protein levels and reduces Pax-8 DNA-binding activity in FRTL-5 thyroid cells, leading to suppression of thyroglobulin promoter activity; mutation of the Pax-8-binding site in the TG promoter abolishes both TGF-β1 and TSH responsiveness, and Pax-8 overexpression abolishes TGF-β1-mediated TG promoter suppression. Northern and Western blot analysis, gel mobility shift assay, reporter transfection with Pax-8 site mutation, Pax-8 overexpression rescue Endocrinology High 11145590
2005 The retinoblastoma protein (pRb) acts as a transcriptional coactivator of Pax8: pRb interacts with Pax8 and potentiates Pax8-mediated transcriptional activity at the thyroperoxidase promoter. RNAi-mediated knockdown of pRb reduces thyroperoxidase promoter activity at the Pax8-binding site. The adenoviral protein E1A inhibits Pax8 activity through its interaction with pRb. The Pax8/pRb synergy also regulates sodium/iodide symporter gene expression. Co-immunoprecipitation, reporter assays, RNAi knockdown of pRb, E1A inhibition experiments Oncogene High 16007137
2008 PAX8 directly binds the promoters of hTERT (telomerase catalytic subunit) and hTR (telomerase RNA component) genes in glioma cells (by EMSA and ChIP), upregulates their mRNA levels, and increases telomerase activity; PAX8 siRNA knockdown downregulates hTERT and hTR expression. EMSA, qPCR, telomerase activity assay, siRNA knockdown Cancer research Medium 18632625
2008 Pax8 is sumoylated at lysine residue 309 (the sole sumoylation site, matching a conserved psiKxE motif). A K309R substitution mutant is no longer sumoylated. PIASy acts as a SUMO E3 ligase for Pax8, increasing the fraction of sumoylated Pax8. Sumoylated Pax8 is targeted to SUMO nuclear bodies. Sumoylation controls steady-state Pax8 protein levels. In vitro and in vivo sumoylation assays, site-directed mutagenesis (K309R), co-transfection with PIASy, immunofluorescence for nuclear body localization Journal of molecular endocrinology High 18974227
2011 PAX8 transcriptionally activates the E2F1 promoter in cancer cells; silencing PAX8 reduces E2F1 expression and its target genes and causes proteasome-dependent destabilization of RB protein (without affecting RB1 mRNA). RB is recruited to the PAX8-binding site and participates in PAX8-mediated E2F1 transcription. PAX8-silenced cancer cells undergo G1/S arrest and senescence. PAX8 siRNA knockdown, luciferase reporter assays, ChIP for RB at PAX8-binding site, proteasome inhibitor rescue, flow cytometry cell-cycle analysis Oncogene High 21602887
2013 Pax8-specific silencing in thyroid epithelial cells induces apoptosis through a p53-dependent pathway involving caspase-3 activation and PARP cleavage. TP53INP1, a positive regulator of p53-dependent apoptosis, is a transcriptional target of Pax8 upregulated upon Pax8 knockdown. Silencing TP53INP1 abolishes Pax8 knockdown-induced apoptosis. Conversely, Pax8 overexpression increases proliferation and colony-forming efficiency. shRNA knockdown, apoptosis assays (caspase-3, PARP cleavage), overexpression proliferation assays, colony formation assays Cell death & disease Medium 23868062
2016 Pax8 is required for apical-basal polarity and lumen formation in thyroid follicle-like structures in 3D culture. Pax8 transcriptionally regulates cadherin-16 (Cdh16); silencing Pax8 reduces laminin and β1-integrin expression and disrupts cytoskeletal polarity. Silencing Cdh16 phenocopies Pax8 loss in 3D morphogenesis. 3D epithelial culture model, RNAi silencing of Pax8 and Cdh16, microarray differential expression, morphometric analysis, laminin/integrin immunostaining Journal of cell science Medium 27780871
2019 PAX8 occupies active enhancer elements genome-wide in RCC cells (determined by ChIP-seq) and controls expression of metabolic pathway genes. PAX8 recruits histone acetylation activity to enhancers that loop onto target gene promoters (exemplified by Ceruloplasmin/CP). Silencing PAX8 reduces RCC cell proliferation. ChIP-seq (PAX8 cistrome), 3C/Hi-C chromatin looping, histone acetylation assays, PAX8 knockdown proliferation assays Nature communications High 31431624
2019 PAX8 directly binds the 5'-flanking region of ITGB3 (Integrin β3) as shown by ChIP, positively regulating ITGB3 expression and consequently αvβ3 heterodimer presentation on the plasma membrane. PAX8 silencing reduces ovarian cancer cell migration, adhesion to fibronectin/collagen, and sensitizes non-adherent cells to anoikis. siRNA knockdown, ChIP with PAX8 antibody at ITGB3 promoter, adhesion/migration assays, anoikis resistance assays, flow cytometry for αvβ3 Cancer cell international Medium 31832016
2019 PAX8 positively regulates TP53 expression in high-grade serous ovarian carcinoma and its pro-proliferative role is mediated through gain-of-function mutant p53, which transcriptionally activates p21 localizing to the cytoplasm where it plays a non-canonical pro-proliferative role. PAX8 knockdown/overexpression, reporter assays, immunofluorescence for p21 localization, proliferation assays Oncogene Medium 29379162
2019 HDAC inhibitors reduce PAX8 expression in ovarian cancer cells by altering H3K27 acetylation occupancies and perturbing the super-enhancer topology at the PAX8 gene locus, thereby epigenetically downregulating PAX8 transcripts. PAX8 promotes ovarian cancer cell migration via an FGF18 autocrine axis. HDAC inhibitor treatment, H3K27ac ChIP-seq, super-enhancer analysis, PAX8 expression qPCR, migration assays eLife Medium 31050342
2021 PAX8 forms a protein complex with PRDM3 (MDS1-EVI1, encoded by the MECOM locus) in ovarian cancer cells. The interaction is mapped in vitro and in vivo by co-immunoprecipitation. Together PAX8 and PRDM3 co-occupy genomic sites and regulate a gene expression module involved in cell adhesion and extracellular matrix, supporting in vivo tumor growth. Co-immunoprecipitation (in vitro and in vivo), ChIP-seq for both proteins, gene expression profiling, in vivo xenograft models Nature communications High 33903593
2022 PAX8 forms a large chromatin remodeling complex and preferentially interacts with SOX17 in fallopian tube and ovarian carcinoma cells. Depleting either PAX8 or SOX17 reduces angiogenic factor secretion, alters tubule and capillary formation in vitro and in mouse models. Mechanistically, PAX8 and SOX17 suppress SERPINE1 (encoding an anti-angiogenic proteinase inhibitor), promoting secretion of pro-angiogenic factors. Protein complex purification from cells, co-immunoprecipitation, PAX8/SOX17 depletion, angiogenesis assays in vitro and in vivo, SERPINE1 expression analysis Science signaling High 35380877
2022 SOX17 physically interacts with PAX8 in ovarian cancer cell lines and clinical tumor specimens. The two transcription factors co-occupy overlapping genomic regions and co-regulate a common set of target genes involved in cell cycle and tissue morphogenesis. Genetic disruption of either factor inhibits neoplastic cell viability. Co-immunoprecipitation in cell lines and patient specimens, ChIP-seq co-localization, genetic knockdown, gene expression profiling Oncogene High 35124696
2022 The lineage transcription factor PAX8 is required for oncogenic signalling by VHL loss in ccRCC: HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a PAX8/HIF2A-controlled CCND1 enhancer. The ccRCC-protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and reduces CCND1 expression. PAX8 is also required for MYC expression from the 8q21.3-q24.3 amplicon region in ccRCC. ChIP-seq for PAX8 and HIF2A, CRISPR perturbations, analysis of patient samples, functional genomics screens, allele-specific reporter assays Nature High 35676472
2019 HBV X protein (HBx) stabilizes PAX8 protein by inhibiting Skp2-mediated ubiquitination and proteasomal degradation. The E3 ubiquitin ligase Skp2 directly interacts with the Prd domain of PAX8 via its LRR domain and ubiquitinates PAX8 at lysine 275. HBx interacts with Skp2 to inhibit its recognition of PAX8. Additionally, Aurora A kinase phosphorylates PAX8 at S209 and T277, compromising Skp2-mediated ubiquitination and thereby stabilizing PAX8. Co-immunoprecipitation, ubiquitination assays, domain-mapping experiments, site-directed mutagenesis (K275, S209, T277), kinase assays Oncogene High 31391550
2020 Pax8 (with Pax2) is required in adult renal collecting duct and medullary cells to maintain expression of urea transporters (Slc14a2) and aquaporins necessary for urine concentration. Conditional deletion of both Pax2 and Pax8 in adult mice causes severe polyuria. Pax8 expression in collecting duct cells is induced by high-salt levels, and Pax8 activates Slc14a2 by recruiting a histone methyltransferase complex to its promoter. Conditional knockout in adult mice, polyuria phenotype assessment, gene expression profiling, histone methyltransferase recruitment assay (ChIP) Journal of the American Society of Nephrology High 32381599
2004 Pax8 and Pax2a function synergistically downstream of Foxi1 and Dlx3b to specify the otic placode in zebrafish: combined loss of both Pax2a and Pax8 blocks ear development leaving only residual otic cells. pax8 expression is regulated by Foxi1 while pax2a is regulated by Dlx3b, providing two independent inputs into otic specification. Morpholino knockdown in zebrafish, genetic epistasis analysis, in situ hybridization Development High 15459102
2017 PAX8 missense mutations in the paired domain (G41V and D94N) found in congenital hypothyroidism patients were functionally characterized: G41V is unable to bind TG and TPO promoters or activate them; D94N can bind both promoters and activate TG but not TPO transcription. Both mutants act as dominant negatives, impairing wild-type PAX8 function. Cell transfection reporter assays, EMSA, induced mutagenesis, dominant-negative co-transfection experiments Oncotarget High 28060725
2021 PAX8 interacts with TAZ (a Hippo pathway effector) in ovarian cancer cells by co-immunoprecipitation, and PAX8 protein levels regulate the degradation rate of TAZ. ADSC-conditioned medium increases PAX8 expression in ovarian cancer cells, promoting proliferation via TAZ stability. Co-immunoprecipitation, PAX8 overexpression/knockdown, TAZ degradation assay, bioluminescence in vivo imaging Journal of cellular and molecular medicine Medium 33830648
2019 METTL3-mediated m6A modification controls PAX8 expression in thyroid cancer via the METTL3/PAX8/YTHDC1 axis; silencing METTL3 promotes thyroid cancer progression and dedifferentiation, at least partly through dysregulation of PAX8. METTL3 knockout mouse model, RNA-seq, in vitro knockdown/overexpression, m6A modification assays International journal of biological sciences Medium 38993572

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science (New York, N.Y.) 654 10958784
1990 Pax8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development (Cambridge, England) 417 1723950
2002 Nephric lineage specification by Pax2 and Pax8. Genes & development 412 12435636
2011 A comprehensive analysis of PAX8 expression in human epithelial tumors. The American journal of surgical pathology 362 21552115
2011 PAX 8 expression in non-neoplastic tissues, primary tumors, and metastatic tumors: a comprehensive immunohistochemical study. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 265 21317881
2002 Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas. The Journal of clinical endocrinology and metabolism 256 12161538
2002 PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. The American journal of surgical pathology 248 12170088
1994 Expression of thyroid-specific transcription factors TTF-1 and PAX-8 in human thyroid neoplasms. Cancer research 222 8062273
1992 PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors. Development (Cambridge, England) 221 1337742
2009 Expression of PAX8 in normal and neoplastic renal tissues: an immunohistochemical study. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 202 19525927
2000 Pax8 has a key role in thyroid cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 197 11069301
2007 Pax2 and pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney. Journal of the American Society of Nephrology : JASN 183 17314325
2011 Expression of PAX8 in normal and neoplastic tissues: a comprehensive immunohistochemical study. Applied immunohistochemistry & molecular morphology : AIMM 181 21285870
1993 Alternative splicing of Pax-8 gene transcripts is developmentally regulated and generates isoforms with different transactivation properties. Molecular and cellular biology 143 8413205
1996 C-terminal activating and inhibitory domains determine the transactivation potential of BSAP (Pax-5), Pax-2 and Pax-8. The EMBO journal 133 8617244
2010 Pax2 and Pax8 cooperate in mouse inner ear morphogenesis and innervation. BMC developmental biology 128 20727173
2004 Tissue-specific expression of cre recombinase from the Pax8 locus. Genesis (New York, N.Y. : 2000) 126 15048807
1999 Synergism between Pax-8 and lim-1 in embryonic kidney development. Developmental biology 122 10491256
2014 Pax-8-PPAR-γ fusion protein in thyroid carcinoma. Nature reviews. Endocrinology 116 25069464
2004 Pax8 and Pax2a function synergistically in otic specification, downstream of the Foxi1 and Dlx3b transcription factors. Development (Cambridge, England) 107 15459102
2012 Value of PAX 8 immunostaining in tumor diagnosis: a review and update. Advances in anatomic pathology 99 22498579
2008 Expression of PAX8 in nephrogenic adenoma and clear cell adenocarcinoma of the lower urinary tract: evidence of related histogenesis? The American journal of surgical pathology 92 18670350
2011 PAX2 and PAX8 expression in primary and metastatic müllerian epithelial tumors: a comprehensive comparison. The American journal of surgical pathology 91 21989345
1998 Ref-1 controls pax-8 DNA-binding activity. Biochemical and biophysical research communications 80 9813166
2012 PAX2 and PAX8 expression in primary and metastatic renal tumors: a comprehensive comparison. Archives of pathology & laboratory medicine 79 23194047
2011 PAX8 promotes tumor cell growth by transcriptionally regulating E2F1 and stabilizing RB protein. Oncogene 66 21602887
2022 The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer. Nature 65 35676472
2013 Use of PAX8 and GATA3 in diagnosing sarcomatoid renal cell carcinoma and sarcomatoid urothelial carcinoma. Human pathology 60 23453625
2010 The use of immunohistochemistry in the diagnosis of metastatic clear cell renal cell carcinoma: a review of PAX-8, PAX-2, hKIM-1, RCCma, and CD10. Advances in anatomic pathology 59 20966644
2012 Graded levels of Pax2a and Pax8 regulate cell differentiation during sensory placode formation. Development (Cambridge, England) 58 22745314
2014 PAX-8 expression in renal tumours and distant sites: a useful marker of primary and metastatic renal cell carcinoma? Journal of clinical pathology 57 25315900
2019 PAX8 activates metabolic genes via enhancer elements in Renal Cell Carcinoma. Nature communications 55 31431624
2013 Pax8 has a critical role in epithelial cell survival and proliferation. Cell death & disease 53 23868062
2011 Pax8 expression in thymic epithelial neoplasms: an immunohistochemical analysis. The American journal of surgical pathology 51 21836478
2020 Non-coding somatic mutations converge on the PAX8 pathway in ovarian cancer. Nature communications 49 32332753
2014 A role for PAX8 in the tumorigenic phenotype of ovarian cancer cells. BMC cancer 48 24766781
1995 Function of the homeo and paired domain proteins TTF-1 and Pax-8 in thyroid cell proliferation. The Journal of biological chemistry 47 7559458
2021 PAX8 and MECOM are interaction partners driving ovarian cancer. Nature communications 45 33903593
2019 Long non-coding RNA MACC1-AS1 promoted pancreatic carcinoma progression through activation of PAX8/NOTCH1 signaling pathway. Journal of experimental & clinical cancer research : CR 45 31391063
1996 Pax 8 expression in primary cultured dog thyrocyte is increased by cyclic AMP. Biochimica et biophysica acta 45 8652674
2022 The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17. Science signaling 44 35380877
1997 PAX 8 regulates human WT1 transcription through a novel DNA binding site. The Journal of biological chemistry 43 9388203
2018 PAX8 activates a p53-p21-dependent pro-proliferative effect in high grade serous ovarian carcinoma. Oncogene 42 29379162
2016 Pax8 controls thyroid follicular polarity through cadherin-16. Journal of cell science 42 27780871
1998 PAX 8 activates the enhancer of the human thyroperoxidase gene. The Biochemical journal 42 9512459
1994 Binding and activation of the promoter for the neural cell adhesion molecule by Pax-8. The Journal of biological chemistry 40 8071351
2008 PAX8 regulates telomerase reverse transcriptase and telomerase RNA component in glioma. Cancer research 39 18632625
2000 Expression of Pax-8, p53 and bcl-2 in human benign and malignant thyroid diseases. Anticancer research 39 10769673
2016 Expression quantitative trait loci in long non-coding RNA PAX8-AS1 are associated with decreased risk of cervical cancer. Molecular genetics and genomics : MGG 38 27225188
2019 PAX8 regulon in human ovarian cancer links lineage dependency with epigenetic vulnerability to HDAC inhibitors. eLife 36 31050342
2010 PAX8 discriminates ovarian metastases from adnexal tumors and other cutaneous metastases. Journal of cutaneous pathology 36 20492080
2019 PAX8-GLIS3 gene fusion is a pathognomonic genetic alteration of hyalinizing trabecular tumors of the thyroid. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 35 31273314
2015 Diagnostic significance of PAX8 in thyroid squamous cell carcinoma. Endocrine journal 35 26354716
2014 PAX8 expression in uterine adenocarcinomas and mesonephric proliferations. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 35 25083965
2017 The PAX8 cistrome in epithelial ovarian cancer. Oncotarget 34 29312534
2016 RAS Mutations, and RET/PTC and PAX8/PPAR-gamma Chromosomal Rearrangements Are Also Prevalent in Benign Thyroid Lesions: Implications Thereof and A Systematic Review. Thyroid : official journal of the American Thyroid Association 34 27750019
2017 Aberrant Pax-8 expression in well-differentiated papillary mesothelioma and malignant mesothelioma of the peritoneum: a clinicopathologic study. Human pathology 31 29241740
2016 Induction of TTF-1 or PAX-8 expression on proliferation and tumorigenicity in thyroid carcinomas. International journal of oncology 30 27573549
2015 PAX8 expression in ovarian surface epithelial cells. Human pathology 30 26079312
2010 Anaplastic thyroid carcinoma: morphologic findings and PAX-8 expression in cytology specimens. Acta cytologica 29 20968153
2004 The PAX8/PPAR gamma fusion oncogene as a potential therapeutic target in follicular thyroid carcinoma. Current drug targets. Immune, endocrine and metabolic disorders 29 15379724
1999 Co-operation between the PAI and RED subdomains of Pax-8 in the interaction with the thyroglobulin promoter. The Biochemical journal 29 9882622
2011 Immunoexpression of PAX 8 in endometrial cancer: relation to high-grade carcinoma and p53. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 28 21979593
2001 Pax-8 is essential for regulation of the thyroglobulin gene by transforming growth factor-beta1. Endocrinology 28 11145590
2019 PAX8 expression in high-grade serous ovarian cancer positively regulates attachment to ECM via Integrin β3. Cancer cell international 27 31832016
2005 Retinoblastoma protein acts as Pax 8 transcriptional coactivator. Oncogene 27 16007137
2022 PAX8 in the Junction between Development and Tumorigenesis. International journal of molecular sciences 26 35806410
2020 PAX8 expression and TERT promoter mutations in the nested variant of urothelial carcinoma: a clinicopathologic study with immunohistochemical and molecular correlates. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 26 31932679
2018 UnPAXing the Divergent Roles of PAX2 and PAX8 in High-Grade Serous Ovarian Cancer. Cancers 26 30096791
2016 Value of PAX-8 and SF-1 Immunohistochemistry in the Distinction Between Female Adnexal Tumor of Probable Wolffian Origin and its Mimics. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 26 26352548
2014 Role of PAX-8, CD5, and CD117 in distinguishing thymic carcinoma from poorly differentiated lung carcinoma. Applied immunohistochemistry & molecular morphology : AIMM 26 23958552
2019 A ceRNA Circuitry Involving the Long Noncoding RNA Klhl14-AS, Pax8, and Bcl2 Drives Thyroid Carcinogenesis. Cancer research 25 31558562
2003 Expression of pituitary hormones in the Pax8-/- mouse model of congenital hypothyroidism. Endocrinology 25 14617574
2021 PAX8 Expression in Breast Cancer. Applied immunohistochemistry & molecular morphology : AIMM 23 33208672
2021 PAX8-AS1 knockdown facilitates cell growth and inactivates autophagy in osteoblasts via the miR-1252-5p/GNB1 axis in osteoporosis. Experimental & molecular medicine 23 34012023
2020 Pax2 and Pax8 Proteins Regulate Urea Transporters and Aquaporins to Control Urine Concentration in the Adult Kidney. Journal of the American Society of Nephrology : JASN 23 32381599
2019 SOX13 dependent PAX8 expression promotes the proliferation of gastric carcinoma cells. Artificial cells, nanomedicine, and biotechnology 23 31353958
2006 PAX8 expression in human bladder cancer. Oncology reports 23 17016586
2019 Unexpected PAX8 Immunoreactivity in Metastatic High-grade Breast Cancer. Applied immunohistochemistry & molecular morphology : AIMM 22 30358609
2019 HBx regulates transcription factor PAX8 stabilization to promote the progression of hepatocellular carcinoma. Oncogene 22 31391550
2022 SOX17 and PAX8 constitute an actionable lineage-survival transcriptional complex in ovarian cancer. Oncogene 21 35124696
2021 Adipose-derived mesenchymal stem cells induced PAX8 promotes ovarian cancer cell growth by stabilizing TAZ protein. Journal of cellular and molecular medicine 21 33830648
2012 PAX8 and PAX5 are differentially expressed in B-cell and T-cell lymphomas. Histopathology 21 23163626
2020 Unraveling the Mysteries of PAX8 in Reproductive Tract Cancers. Cancer research 20 33361393
2015 PAX2 and PAX8 reliably distinguishes ovarian serous tumors from mucinous tumors. Applied immunohistochemistry & molecular morphology : AIMM 20 24992169
2017 Identification and characterization of novel PAX8 mutations in Congenital Hypothyroidism(CH) in a Chinese population. Oncotarget 19 28060725
2013 PAX8 and PAX2 expression in endocervical adenocarcinoma in situ and high-grade squamous dysplasia. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 19 23202787
2008 Pax8 protein stability is controlled by sumoylation. Journal of molecular endocrinology 19 18974227
2024 PAX8 expression in cancerous and non-neoplastic tissue: a tissue microarray study on more than 17,000 tumors from 149 different tumor entities. Virchows Archiv : an international journal of pathology 18 39105782
2020 Comparison of PAX8 Expression in Breast Carcinoma Using MRQ50 and BC12 Monoclonal Antibodies. Applied immunohistochemistry & molecular morphology : AIMM 18 31335489
2018 Diagnostic Utility of Pax8, Pax2, and NGFR Immunohistochemical Expression in Pediatric Renal Tumors. Applied immunohistochemistry & molecular morphology : AIMM 18 28426529
2018 CAIX and pax-8 Commonly Immunoreactive in Endolymphatic Sac Tumors: A Clinicopathologic Study of 26 Cases with Differential Considerations for Metastatic Renal Cell Carcinoma in von Hippel-Lindau Patients. Head and neck pathology 18 30291511
2016 Expression of PAX8 Target Genes in Papillary Thyroid Carcinoma. PloS one 18 27249794
2015 PAX8 pathogenic variants in Chinese patients with congenital hypothyroidism. Clinica chimica acta; international journal of clinical chemistry 18 26362610
2018 Transient PAX8 Expression in Islets During Pregnancy Correlates With β-Cell Survival, Revealing a Novel Candidate Gene in Gestational Diabetes Mellitus. Diabetes 17 30352879
2017 Long non-coding RNA PAX8-AS1 polymorphisms increase the risk of childhood acute lymphoblastic leukemia. Biomedical reports 17 29435279
2012 Pair-Box (PAX8) protein-positive expression is associated with poor disease outcome in women with endometrial cancer. British journal of cancer 17 22644304
2001 Thyroglobulin increases cell proliferation and suppresses Pax-8 in mesangial cells. Biochemical and biophysical research communications 17 11453662
2025 Targeting GPX4 to Induce Ferroptosis Overcomes Chemoresistance Mediated by the PAX8-AS1/GPX4 Axis in Intrahepatic Cholangiocarcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 16 40391780
2024 METTL3 regulates thyroid cancer differentiation and chemosensitivity by modulating PAX8. International journal of biological sciences 16 38993572

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