Affinage

PITX1

Pituitary homeobox 1 · UniProt P78337

Length
314 aa
Mass
34.1 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 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

PITX1 is a bicoid-class homeodomain transcription factor that functions as a master regulator of hindlimb identity and as a tumor suppressor (PMID:10049363, PMID:15960973). In limb development, loss of Pitx1 transforms hindlimb toward forelimb morphology while misexpression in the wing bud confers hindlimb characteristics, placing it upstream of the hindlimb-restricted program through induction of Tbx4, HoxC10, and HoxC11 (PMID:10049363, PMID:10073939). Genome-wide binding shows Pitx1 associates broadly with limb enhancers and is enriched at hindlimb-specific cis-regulatory elements, directly binding Tbx4 hindlimb enhancers and driving the patterning, chondrogenic, and myogenic programs via direct targets including Sox9 and Six1 (PMID:23201014, PMID:28807899, PMID:29273440). Its developmental deployment is gated by opposing signals—FGF8 maintaining and BMP4 repressing Pitx1 expression—and its dosage is critical, as haploinsufficiency and disruption of the Pen enhancer produce clubfoot through altered 3D chromatin coordination and connective-tissue heterochrony (PMID:10625557, PMID:18082678, PMID:21775501, PMID:34903763). As a tumor suppressor, PITX1 dampens RAS signaling by transcriptionally activating the RAS-GTPase-activating protein RASAL1, activates the p53 promoter to drive apoptosis, and suppresses TERT transcription to limit telomerase activity (PMID:15960973, PMID:17762884, PMID:21300782). PITX1 also acts as a transcriptional repressor, antagonizing IRF3/IRF7-driven IFN-A induction and ERα activity through direct protein interactions (PMID:12242290, PMID:21868451). PITX1 transcription is controlled by multiple upstream inputs including E2F1–TFDP1, ERα, DUX4, and PHB1, while its translation is repressed by RHAU/DHX36 acting through microRNA machinery and by miR-19b targeting the 3'-UTR (PMID:17984056, PMID:21868451, PMID:24369427, PMID:25643913, PMID:27802335, PMID:23310948); its protein stability and transcriptional output are further tuned by c-Abl-mediated tyrosine phosphorylation and PTP1B-mediated dephosphorylation (PMID:20563669, PMID:26840794).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 Medium

    Establishing PITX1 as a transcriptional partner of the pituitary factor Pit-1 first placed it as a functional homeodomain transactivator on tissue-specific promoters.

    Evidence Yeast two-hybrid interaction and transfection reporter synergy with Pit-1

    PMID:8755540

    Open questions at the time
    • Did not define direct DNA-binding targets in vivo
    • Restricted to pituitary promoter context
  2. 1999 High

    Loss- and gain-of-function experiments answered whether Pitx1 specifies hindlimb identity, establishing it as a master regulator upstream of Tbx4 and hindlimb-restricted Hox genes.

    Evidence Mouse knockout with skeletal phenotype plus retroviral misexpression in chick wing bud, reading out Tbx4/HoxC10/HoxC11

    PMID:10049363 PMID:10073939

    Open questions at the time
    • Did not establish direct vs indirect regulation of Tbx4 at the time
    • Mechanism of forelimb/hindlimb selectivity unresolved
  3. 2000 Medium

    Bead implantation defined the upstream signals gating Pitx1, showing FGF8 maintains and BMP4 represses its expression during craniofacial/limb patterning.

    Evidence FGF8- and BMP4-soaked bead implantation in mouse explants with in situ readout, later extended in Pitx1-null embryos

    PMID:10625557 PMID:18082678

    Open questions at the time
    • Direct transcriptional effectors linking FGF8/BMP4 to the Pitx1 promoter not identified
    • Single-lab readout
  4. 2001 High

    In vivo promoter dissection demonstrated PITX1 binding sites are absolutely required for endocrine target promoter activity and act cooperatively with other factors.

    Evidence Transgenic mice and gonadotrope-cell transfection with site-specific LHbeta promoter mutagenesis; sst2 and salmon LHbeta reporter mapping

    PMID:11250922 PMID:11328855 PMID:12011080

    Open questions at the time
    • Cooperative mechanism with SF-1/Egr-1 not structurally resolved
    • Functional significance of DNA-bound phosphorylation undefined
  5. 2002 High

    Discovery of PITX1 repression of IFN-A promoters via IRF3/IRF7 interaction showed it can act as a transcriptional repressor through protein-protein contacts, not only as an activator.

    Evidence Co-IP, homeodomain/C-terminal domain mapping and luciferase repression assays

    PMID:12242290

    Open questions at the time
    • In vivo relevance to antiviral response not tested
    • Repressor cofactors beyond HDAC not fully mapped
  6. 2005 High

    A functional RNAi screen placed PITX1 as a tumor suppressor that dampens RAS signaling via transcriptional activation of RASAL1, defining a concrete oncogenic pathway it antagonizes.

    Evidence RNAi library screen, RAS pathway and transformation assays, qRT-PCR for RASAL1 across cell systems

    PMID:15960973

    Open questions at the time
    • Whether RASAL1 is a direct DNA-binding target not shown here
    • Tissue specificity of suppression undefined
  7. 2007 High

    Identification of direct p53 promoter activation and DUX4-driven PITX1 transcription extended PITX1 into pro-apoptotic output and revealed an upstream activator.

    Evidence ChIP, reporter, siRNA and apoptosis assays for p53; EMSA, mutagenesis and endogenous gene readout for DUX4

    PMID:17762884 PMID:17984056

    Open questions at the time
    • Integration of p53 activation with RAS/RASAL1 arm not addressed
    • Physiological context of DUX4-PITX1 axis limited to cell lines
  8. 2008 Medium

    Characterization of the homeodomain E130K missense mutation demonstrated dominant-negative disruption of PITX1 transactivation, linking specific residues to function.

    Evidence Luciferase transactivation assay with dose-response dominant-negative test

    PMID:18950742

    Open questions at the time
    • No in vivo phenotypic modeling of the mutation
    • Structural basis of dominant-negative effect not defined
  9. 2010 Medium

    Identification of c-Abl-mediated stabilization and SEDLIN nuclear interaction began to define post-translational and partner-based control of PITX1.

    Evidence c-Abl overexpression/imatinib with immunoblot and apoptosis assays; Co-IP and yeast two-hybrid for SEDLIN with disease-mutant validation

    PMID:20498720 PMID:20563669

    Open questions at the time
    • Direct vs indirect c-Abl phosphorylation unresolved
    • Functional consequence of SEDLIN-PITX1 interaction undefined
  10. 2011 High

    Direct TERT promoter suppression, ChIP-Seq enhancer mapping, ERα regulation, and a clubfoot haploinsufficiency model collectively cemented both the tumor-suppressor and dosage-sensitive developmental roles.

    Evidence EMSA/ChIP/TRAP for TERT; ChIP-Seq on hindlimbs; ChIP/reporter/RNAi for ERα; Pitx1+/- and -/- mice with micro-CT and expression analysis

    PMID:21300782 PMID:21775501 PMID:21868451 PMID:23201014

    Open questions at the time
    • Low penetrance of clubfoot mechanism unexplained at this stage
    • Relationship between developmental and tumor-suppressor target sets not unified
  11. 2013 High

    Defining PHB1 and the post-transcriptional RHAU repressor pathway revealed how PITX1 levels are constrained, with PHB1 silencing it in osteoarthritic chondrocytes and RHAU repressing its translation via microRNA machinery.

    Evidence Mass-spec/ChIP/gain-loss for PHB1 in OA mice; RNA-CoIP and Dicer/Ago2-dependent knockdown for RHAU

    PMID:23310948 PMID:24369427

    Open questions at the time
    • Specific microRNAs acting downstream of RHAU not identified
    • PHB1 regulatory link to E2F1 site not mechanistically integrated
  12. 2015 High

    Structural and functional dissection of G-quadruplex regulation and miR-19b targeting clarified the post-transcriptional logic linking PITX1 suppression to TERT upregulation in melanoma.

    Evidence NMR/SAXS/CD biophysics of RHAU N-domain with PITX1 G-quadruplex; 3'-UTR reporter and miR-19b manipulation with TERT readout

    PMID:25643913 PMID:26649896

    Open questions at the time
    • In vivo contribution of G-quadruplex recognition to PITX1 levels untested
    • Coordination between RHAU and miR-19b not directly compared
  13. 2016 High

    Discovery of E2F1–TFDP1 activation and PTP1B-mediated dephosphorylation defined the transcriptional driver and a phosphorylation-dependent stability switch governing PITX1 tumor-suppressor output.

    Evidence ChIP/DNA pulldown/RNAi for E2F1-TFDP1; in vitro phosphatase assay, site mutagenesis (Y160/Y175/Y179), reporter and xenograft for PTP1B/p120RasGAP

    PMID:26840794 PMID:27802335

    Open questions at the time
    • Whether c-Abl and PTP1B act on the same residues in the same context not resolved
    • Kinase responsible for the PTP1B-reversed sites not fully defined
  14. 2017 High

    Integrated ChIP-seq/RNA-seq in knockout hindlimbs answered which targets PITX1 directly controls, identifying Sox9 and Six1 within a conserved chondrogenic/myogenic program.

    Evidence ChIP-seq and RNA-seq on Pitx1-/- hindlimbs with cross-species Anolis comparison and transgenic replacement

    PMID:28807899 PMID:29273440

    Open questions at the time
    • How identical chromatin-state binding yields hindlimb-specific output not fully explained
    • Direct vs indirect status of all 440 candidate targets not validated
  15. 2019 High

    A series of studies broadened PITX1's repertoire to astrocyte differentiation via SOX9, squamous tumor self-renewal circuitry with SOX2/TRP63, telomerase co-repression with ZCCHC10, and skeletal homeostasis via Sirt1/Wnt regulators.

    Evidence EMSA/ChIP/reporter for SOX9; ChIP-seq/RNA-seq genetic circuit analysis with KLF4; FLAG pulldown for ZCCHC10; reporter and transgenic mouse for Sirt1/Sca-1/DKK1

    PMID:30713093 PMID:30837642 PMID:31404068 PMID:31783149 PMID:32759168

    Open questions at the time
    • Context determinants switching PITX1 between tumor-suppressor and tumor-propagating roles unclear
    • Mechanism of ZCCHC10 cooperativity at TERT undefined
  16. 2021 High

    Enhancer-level and partner studies refined how PITX1 dosage and repressor activity operate, linking Pen enhancer-driven 3D chromatin coordination to clubfoot and STAT3 interaction to osteosarcoma metastasis suppression.

    Evidence Single-cell transcriptomics, 4C and CRISPR enhancer deletion for Pen; Co-IP, exosome and macrophage co-culture assays for STAT3/LINC00662

    PMID:34903763 PMID:36334221

    Open questions at the time
    • Generality of enhancer-coordination mechanism to other PITX1 loci unknown
    • Direct STAT3 binding sites and ubiquitination link not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what molecular switches partition PITX1 between its tumor-suppressor and tumor-propagating activities and how its developmental target repertoire is reconciled with its cancer targets.
  • No unified model linking context-dependent cofactors to opposite cancer outcomes
  • Structural basis of homeodomain target selectivity across tissues not defined
  • In vivo integration of post-translational stability control with transcriptional output incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 5 GO:0098772 molecular function regulator activity 5
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-1266738 Developmental Biology 6 R-HSA-8953854 Metabolism of RNA 3 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 2
Partners
HIF1BIRF3IRF7SEDLINSMAD1SOX2STAT3ZCCHC10

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 PITX1 (P-OTX) was identified as interacting with the transactivation domain of the pituitary-specific POU domain protein Pit-1, and can independently activate as well as synergize with Pit-1 on pituitary-specific target gene promoters. Yeast two-hybrid / protein interaction assay; transient transfection reporter assays Proceedings of the National Academy of Sciences of the United States of America Medium 8755540
1999 Pitx1 gene deletion in mice causes striking hindlimb morphogenesis defects (altered tibia/fibula, patella, proximal tarsus) making the hindlimb resemble a forelimb, and decreases distal expression of the hindlimb-specific T-box factor Tbx4; misexpression of Pitx1 in chick wing bud induces Tbx4 and causes hindlimb-like morphological changes. Targeted gene knockout in mice; in situ hybridization; retroviral misexpression in chick wing bud Genes & development High 10049363
1999 Misexpression of Pitx1 in the chick wing bud induces distal expression of Tbx4, HoxC10, and HoxC11 (normally hindlimb-restricted), and transforms wing morphology toward hindlimb characteristics, placing Pitx1 upstream of Tbx4 in hindlimb identity specification. Retroviral misexpression in chick wing bud; in situ hybridization for downstream markers Science (New York, N.Y.) High 10073939
2000 FGF8 can induce/maintain Pitx1 expression in the developing mandible at E9.5, while BMP4 represses Pitx1 expression in mandibular mesenchyme, as demonstrated by bead implantation experiments. Bead implantation with FGF8- or BMP4-soaked beads in mouse embryo explants; in situ hybridization Developmental biology Medium 10625557
2001 A single Pitx1 binding site in the LHbeta promoter is absolutely required for promoter activity in transgenic mice; the Pitx1 element works cooperatively with SF-1 and Egr-1, and its absence eliminates both basal and GnRH-responsive transcription in vivo. Transgenic mice with mutant Pitx1-binding-site LHbeta promoter constructs; transient transfection in gonadotrope-derived LbetaT2 cells Molecular endocrinology (Baltimore, Md.) High 11328855
2001 Pitx1 and Pitx2c are required for cement gland formation in Xenopus laevis; antisense morpholino knockdown of both genes blocks ectopic cement gland formation induced by otx2, and this can be rescued by co-injection of Pitx mRNAs. Antisense morpholino oligonucleotide knockdown in Xenopus embryos; mRNA rescue experiments Genesis (New York, N.Y. : 2000) Medium 11477694
2001 Pitx1 activates the sst2 somatostatin receptor gene promoter in pituitary GH3 cells through two Pitx1 response sites including a CRE site. Transient transfection with luciferase reporter constructs and deletion mutants; competitive gel shift and supershift assays Endocrinology Medium 11250922
2002 Pitx1 represses virus-induced IFN-A gene promoters by physically interacting with IRF3 and IRF7 through its homeodomain, and the C-terminal repressor domains of Pitx1 mediate trans-repression of IRF3/IRF7 transcriptional activity. Co-immunoprecipitation; domain-mapping; luciferase reporter assays; histone deacetylase inhibitor experiments Molecular and cellular biology High 12242290
2002 Pitx1 transactivates the Chinook salmon LHbeta promoter through synergy with SF-1 (alone or combined with estrogen receptor), and through four upstream Pitx1 response elements that mediate basal and GnRH-responsive activity. Pitx1 can homodimerize, and binding of Pitx1 to multiple response elements induces conformational changes in the target DNA. Pitx1 is phosphorylated on three residues when bound to DNA. Transfection reporter assays; mammalian two-hybrid assay; circular permutation assay; in vitro binding/phosphorylation The Journal of biological chemistry Medium 12011080
2003 PITX1 positively autoregulates its own promoter in a DNA-binding and transactivation-domain-dependent manner; Pitx1, Pitx1b, Pitx2, and Otx1 all activate the PITX1 promoter in transfection studies. Transient transfection of PITX1 promoter-reporter constructs; transgenic mice; domain-mutant overexpression Neuroendocrinology Medium 14512705
2005 PITX1 suppresses RAS activity and tumorigenicity by transcriptionally activating RASAL1, a RAS-GTPase-activating protein; RNAi knockdown of PITX1 in primary human cells activates the RAS pathway and promotes transformation; restoration of PITX1 in wild-type-RAS colon cancer cells inhibits tumorigenicity. RNAi library screen; RAS pathway assays; colony formation/transformation assays; quantitative RT-PCR for RASAL1 Cell High 15960973
2007 DUX4 protein directly binds a 30-bp sequence in the PITX1 promoter (TAAT core essential) as shown by EMSA, and activates transcription of a PITX1 promoter-luciferase reporter as well as the endogenous PITX1 gene in C2C12 cells. EMSA; luciferase reporter assay; site-directed mutagenesis of TAAT core; endogenous PITX1 expression assay by RT-PCR Proceedings of the National Academy of Sciences of the United States of America High 17984056
2007 PITX1 directly activates the p53 promoter by binding two consensus PITX1 elements, increasing p53 mRNA and protein; a dominant-negative PITX1 mutant (R141P) represses p53 transcription; PITX1-induced apoptosis is p53-dependent. Luciferase reporter assay; ChIP; siRNA knockdown; apoptosis assays in MCF-7 cells Cell death and differentiation High 17762884
2007 BMP4 down-regulates Pitx1 expression in both mandibular mesenchyme and dental epithelium, as demonstrated by tissue recombination and bead implantation experiments in Pitx1-null mouse embryos. Tissue recombination; BMP4-bead implantation; in situ hybridization Developmental biology Medium 18082678
2008 A missense mutation PITX1 E130K (in the homeodomain) reduces PITX1 transactivation activity and suppresses wild-type PITX1 activity in a dose-dependent manner, indicating dominant-negative effects on transcription. Luciferase reporter transactivation assay; dominant-negative dose-response experiment American journal of human genetics Medium 18950742
2010 SEDLIN interacts with PITX1 in the nucleus; SEDT-causing SEDLIN mutations (except Asp47Tyr) abolish the interaction with PITX1 (and MBP1, SF1) as revealed in yeast lacking endogenous SEDLIN, while wild-type SEDLIN homodimerizes and the dimerization masks loss of interactions in mammalian cells. Co-immunoprecipitation in COS7 cells; yeast two-hybrid; nuclear/cytoplasmic fractionation; 3D structural modeling PloS one Medium 20498720
2010 c-Abl tyrosine kinase stabilizes Pitx1 protein in response to DNA damage at the post-transcriptional level and induces tyrosine phosphorylation of Pitx1 (directly or indirectly); inhibition of c-Abl kinase substantially attenuates Pitx1-mediated apoptosis. Overexpression of c-Abl; immunoblotting; c-Abl kinase inhibitor (imatinib) treatment; apoptosis assays Apoptosis : an international journal on programmed cell death Medium 20563669
2011 PITX1 suppresses TERT (hTERT and mouse Tert) transcription by directly binding to conserved sites in the TERT promoter both in vitro (EMSA/ChIP) and in vivo, ultimately reducing telomerase activity. cDNA microarray; luciferase reporter assay; EMSA; ChIP; telomerase activity assay (TRAP) Molecular and cellular biology High 21300782
2011 Pitx1 haploinsufficiency causes clubfoot in mice (8.9% penetrance in Pitx1+/- mice) associated with peroneal artery hypoplasia and reduced tibial/fibular bone volumes; in Pitx1-/- E12.5 hindlimb buds, skeletal muscle gene expression is significantly reduced, indicating a role in early muscle development. Pitx1 heterozygous and homozygous knockout mice; micro-CT; vascular imaging; gene expression analysis Human molecular genetics High 21775501
2011 Pitx1 broadly associates with limb enhancers by ChIP-Seq and is enriched on hindlimb-specific cis-regulatory elements; direct Pitx1 binding is confirmed at the Tbx4 hindlimb enhancers (HLEA and HLEB) and at a Tbx2 hindlimb enhancer, consistent with Tbx4, HoxC10, and HoxC11 being direct regulatory targets. ChIP-Seq on embryonic mouse hindlimbs; H3K27ac chromatin state mapping Developmental biology High 23201014
2011 PITX1 expression is regulated by ERα: E2 treatment robustly up-regulates PITX1 in ERα-positive breast cancer cells through ERα-dependent interaction between the proximal PITX1 promoter and an upstream enhancer; overexpressed PITX1 in turn selectively inhibits ERα transcriptional activity and modulates a subset of ERα target genes. ChIP; luciferase reporter assay; siRNA knockdown; quantitative RT-PCR; overexpression in breast cancer cell lines Molecular endocrinology (Baltimore, Md.) Medium 21868451
2013 RHAU (DHX36) RNA helicase binds the PITX1 mRNA via a non-quadruplex-forming region (not via the 3'-UTR G-quadruplexes directly) and suppresses PITX1 protein expression at the translational level; RHAU knockdown increases PITX1 protein with only marginal mRNA changes; RHAU-dependent repression requires argonaute-2 and Dicer, implicating microRNA machinery. RNA co-immunoprecipitation; siRNA knockdown of RHAU, Dicer, and Ago2; immunoblotting; qRT-PCR; EMSA with isolated G-quadruplex sequences Nucleic acids research High 24369427
2014 PITX1 associates with HIF-1β and is required for induction of specific HIF-1α-dependent target genes (JMJD2B, JMJD2A, JMJD2C, JMJD1B histone demethylases) but not all HIF-1 targets; PITX1 depletion reduces survival and proliferation in hypoxia. Co-immunoprecipitation; siRNA knockdown; gene expression analysis; apoptosis/proliferation assays under hypoxia Cell cycle (Georgetown, Tex.) Medium 25558831
2015 miR-19b represses PITX1 mRNA translation through a miR-19b binding site in the PITX1 3'-UTR, leading to up-regulation of hTERT expression; miR-19b is overexpressed in most melanoma cells and inversely correlated with PITX1 protein levels. Luciferase 3'-UTR reporter assay; miR-19b overexpression/inhibition; immunoblotting; qRT-PCR Scientific reports Medium 25643913
2015 The N-terminal specificity domain of RHAU recognizes the PITX1 mRNA G-quadruplex via the tetrad face; the RNA (but not DNA) G-quadruplex adopts a parallel orientation and interacts with RHAU's N-terminal domain. EMSA; UV-VIS spectroscopy; circular dichroism; dynamic light scattering; SAXS; NMR spectroscopy PloS one High 26649896
2016 PTP1B directly dephosphorylates PITX1 at tyrosine residues Y160, Y175, and Y179, destabilizing PITX1 protein and reducing its transcriptional activity toward p120RasGAP (RASA1); sorafenib inhibits PTP1B activity, thereby promoting PITX1 hyperphosphorylation and restoring p120RasGAP expression. Co-immunoprecipitation; in vitro phosphatase assay; site-directed mutagenesis of PITX1 phosphorylation sites; immunoblotting; luciferase reporter assay; xenograft tumor model Hepatology (Baltimore, Md.) High 26840794
2016 E2F1 directly binds the PITX1 proximal promoter at two specific sequences and activates PITX1 transcription; the E2F1-TFDP1 heterodimer is required for this activation, as TFDP1 knockdown inhibits E2F1-driven PITX1 expression. Luciferase reporter assay; ChIP; DNA pulldown; siRNA knockdown of TFDP1; qRT-PCR PloS one Medium 27802335
2017 Pitx1 directly controls the core hindlimb developmental program by binding to sites in a similar chromatin state in both forelimb and hindlimb, regulating patterning genes and the chondrogenic program; Pitx1-/- hindlimbs show impaired chondrogenesis consistent with direct transcriptional control of chondrogenic targets. ChIP-Seq; RNA-Seq expression profiling; Pitx1-/- mouse analysis; transgenic gene replacement strategy Development (Cambridge, England) High 28807899
2017 PITX1 promotes chondrogenesis and myogenesis in mouse hindlimbs through direct regulation of Sox9 and Six1, among 440 candidate targets identified by intersection of ChIP-seq binding and RNA-seq misexpression data in Pitx1-/- hindlimbs; 68 of these binding events are ultra-conserved between mouse and Anolis lizard. ChIP-seq; RNA-seq on Pitx1-/- and wild-type embryonic mouse hindlimbs; cross-species Anolis ChIP-seq comparison Developmental biology High 29273440
2018 Pitx1 physically interacts with Smad1, an intracellular transducer of BMP signaling, and functions as a transcriptional activator to inhibit BMP signaling through Pitx1-dependent follistatin expression; this inhibition is required for cement gland marker expression in Xenopus laevis. Co-immunoprecipitation (Pitx1-Smad1); luciferase reporter assay; morpholino knockdown; BMP pathway manipulation Developmental biology Medium 29530451
2019 PITX1 cooperates with SOX2 and TRP63 to maintain a transcriptional feed-forward circuit sustaining tumor propagating cell self-renewal in squamous cell carcinoma while inhibiting KLF4-dependent differentiation; conversely, KLF4 represses PITX1, SOX2, and TRP63, forming a bi-stable network. Gene targeting; ChIP-seq; RNA-seq; co-localization of PITX1 with SOX2 and TRP63 by ChIP-seq Cell stem cell High 30713093
2019 PITX1 protein interacts with ZCCHC10; co-expression of PITX1 and ZCCHC10 cooperatively suppresses hTERT transcription, while deletion of the PITX1 homeodomain abolishes both interaction with ZCCHC10 and hTERT suppression. FLAG pull-down assay; luciferase reporter assay; homeodomain deletion mutant analysis; immunoblotting in melanoma cell lines PloS one Medium 31404068
2019 PITX1 directly activates the SOX9 promoter through a unique PITX1 binding motif, driving astrocyte differentiation; PITX1 overexpression increases SOX9 expression and induces early astrocyte differentiation, while PITX1 knockdown blocks it. Luciferase reporter assay; EMSA; ChIP; siRNA knockdown; overexpression in human embryonic stem cell-derived astrocyte differentiation protocol The Journal of biological chemistry High 32759168
2019 PITX1 promotes Sirt1 gene transcription (luciferase assay); overexpression of Pitx1 in chondrocytes reduces cellular senescence, while Pitx1 knockdown increases senescence in lateral cartilage chondrocytes, linking Pitx1 to chondrocyte autophagy/senescence. Luciferase reporter assay for Sirt1; SA-β-GAL senescence staining; siRNA knockdown and overexpression in chondrocytes Bone Medium 31783149
2019 PITX1 overexpression in bone (transgenic mCol1α1-Pitx1 mice) causes senile osteoporosis by directly regulating mesenchymal progenitor self-renewal through Sca-1 (Ly6a) repression and indirectly inhibiting osteoclast differentiation by upregulating Wnt signaling inhibitors DKK1, SOST, and GSK3-β, with accumulation of phospho-β-catenin in osteoblasts. Transgenic mouse overexpression; in vivo/in vitro analyses; plasma DKK1 measurement; phospho-β-catenin immunoblotting Scientific reports Medium 30837642
2021 PITX1 interacts with transcription factor STAT3 and reduces STAT3 transcriptional activity, repressing LINC00662 expression in osteosarcoma; exosomal LINC00662 from PITX1-knockdown cells activates M2 macrophage polarization which secretes CCL22 to promote osteosarcoma EMT and metastasis. Co-immunoprecipitation (PITX1-STAT3); ubiquitination assay; rescue experiments; exosome isolation; macrophage co-culture; CCL22 cytokine measurement Clinical & experimental metastasis Medium 36334221
2021 Loss of the Pitx1 Pen enhancer leads to increased fractions of Pitx1 non/low-expressing cells due to failure of the locus to coordinate enhancer activities and 3D chromatin changes, causing localized heterochrony and loss of irregular connective tissue, producing a clubfoot phenotype. Single-cell transcriptomics; in-embryo cell tracing; 4C/3D chromatin conformation; CRISPR enhancer deletion Nature communications High 34903763
2013 Prohibitin 1 (PHB1) accumulates aberrantly in the nuclei of osteoarthritic chondrocytes, binds a distal E2F1 site in the PITX1 promoter, and overexpression of PHB1 in control chondrocytes inhibits endogenous PITX1 expression; PHB1 knockdown in OA chondrocytes restores PITX1. Luciferase promoter reporter assay; tandem mass spectrometry/protein sequencing of nuclear extracts; ChIP; gain/loss-of-function experiments; RT-PCR; immunohistochemistry in STR/Ort OA mice Arthritis and rheumatism High 23310948

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer. Science (New York, N.Y.) 744 20007865
1999 Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes & development 342 10049363
2007 DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. Proceedings of the National Academy of Sciences of the United States of America 298 17984056
2005 A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity. Cell 238 15960973
1999 Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity. Science (New York, N.Y.) 234 10073939
1996 P-OTX: a PIT-1-interacting homeodomain factor expressed during anterior pituitary gland development. Proceedings of the National Academy of Sciences of the United States of America 221 8755540
2000 Antagonistic signals between BMP4 and FGF8 define the expression of Pitx1 and Pitx2 in mouse tooth-forming anlage. Developmental biology 169 10625557
2008 Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation. American journal of human genetics 106 18950742
2008 Analysis and distribution of class 1 and class 2 integrons and associated gene cassettes among Escherichia coli isolates from swine, horses, cats and dogs collected in the BfT-GermVet monitoring study. The Journal of antimicrobial chemotherapy 79 18550679
2001 A single Pitx1 binding site is essential for activity of the LHbeta promoter in transgenic mice. Molecular endocrinology (Baltimore, Md.) 75 11328855
2013 The RNA helicase RHAU (DHX36) suppresses expression of the transcription factor PITX1. Nucleic acids research 70 24369427
2011 Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice. Human molecular genetics 65 21775501
2007 Transcriptional activation of p53 by Pitx1. Cell death and differentiation 65 17762884
2011 Identification of PITX1 as a TERT suppressor gene located on human chromosome 5. Molecular and cellular biology 63 21300782
2007 Methicillin-resistant Staphylococcus aureus and Staphylococcus pseudintermedius detected in the BfT-GermVet monitoring programme 2004-2006 in Germany. The Journal of antimicrobial chemotherapy 63 18096559
2012 Loss of desmocollin 1-3 and homeobox genes PITX1 and CDX2 are associated with tumor progression and survival in colorectal carcinoma. International journal of colorectal disease 62 22438068
2015 miR-19b regulates hTERT mRNA expression through targeting PITX1 mRNA in melanoma cells. Scientific reports 59 25643913
2000 Identification of two genetic groups in Bacteroides fragilis by multilocus enzyme electrophoresis: distribution of antibiotic resistance (cfiA, cepA) and enterotoxin (bft) encoding genes. Microbiology (Reading, England) 57 10832652
2007 Molecular basis of resistance to macrolides and lincosamides among staphylococci and streptococci from various animal sources collected in the resistance monitoring program BfT-GermVet. International journal of antimicrobial agents 56 17307339
2024 Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1. Protein & cell 54 38437016
2011 Pitx1 is necessary for normal initiation of hindlimb outgrowth through regulation of Tbx4 expression and shapes hindlimb morphologies via targeted growth control. Development (Cambridge, England) 51 22071103
2012 Pitx1 broadly associates with limb enhancers and is enriched on hindlimb cis-regulatory elements. Developmental biology 50 23201014
2007 Deletion of the Pitx1 genomic locus affects mandibular tooth morphogenesis and expression of the Barx1 and Tbx1 genes. Developmental biology 50 18082678
2000 A new subtype of the metalloprotease toxin gene and the incidence of the three bft subtypes among Bacteroides fragilis isolates in Japan. FEMS microbiology letters 49 10612750
2012 Conditional over-expression of PITX1 causes skeletal muscle dystrophy in mice. Biology open 43 23125914
2011 Analysis of bla(CTX-M)-carrying plasmids from Escherichia coli isolates collected in the BfT-GermVet study. Applied and environmental microbiology 43 21685166
2012 Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly. European journal of human genetics : EJHG 42 22258522
2019 Circular RNA circ-PITX1 promotes the progression of glioblastoma by acting as a competing endogenous RNA to regulate miR-379-5p/MAP3K2 axis. European journal of pharmacology 40 31493405
2017 Three FT and multiple CEN and BFT genes regulate maturity, flowering, and vegetative phenology in kiwifruit. Journal of experimental botany 38 28369532
2016 Protein tyrosine phosphatase 1B dephosphorylates PITX1 and regulates p120RasGAP in hepatocellular carcinoma. Hepatology (Baltimore, Md.) 38 26840794
2019 De Novo PITX1 Expression Controls Bi-Stable Transcriptional Circuits to Govern Self-Renewal and Differentiation in Squamous Cell Carcinoma. Cell stem cell 37 30713093
2018 A novel enhancer near the Pitx1 gene influences development and evolution of pelvic appendages in vertebrates. eLife 37 30499775
2002 Multiple mechanisms for Pitx-1 transactivation of a luteinizing hormone beta subunit gene. The Journal of biological chemistry 36 12011080
2017 Pitx1 directly modulates the core limb development program to implement hindlimb identity. Development (Cambridge, England) 34 28807899
2000 The alleles of the bft gene are distributed differently among enterotoxigenic Bacteroides fragilis strains from human sources and can be present in double copies. Journal of clinical microbiology 31 10655354
2024 Entero-toxigenic Bacteroides fragilis contributes to intestinal barrier injury and colorectal cancer progression by mediating the BFT/STAT3/ZEB2 pathway. Cell cycle (Georgetown, Tex.) 30 38273425
2020 Effect of acute exposure to ammonia and BFT alterations on Rhynchocypris lagowski: Digestive enzyme, inflammation response, oxidative stress and immunological parameters. Environmental toxicology and pharmacology 30 32416163
2020 Mutations Upstream of the TBX5 and PITX1 Transcription Factor Genes Are Associated with Feathered Legs in the Domestic Chicken. Molecular biology and evolution 29 32344431
2002 Modulation of bft expression by the Bacteroides fragilis pathogenicity island and its flanking region. Molecular microbiology 29 12180925
2011 The estrogen-regulated transcription factor PITX1 coordinates gene-specific regulation by estrogen receptor-alpha in breast cancer cells. Molecular endocrinology (Baltimore, Md.) 28 21868451
2001 Characterization of 5'-flanking region of rat somatostatin receptor sst2 gene: transcriptional regulatory elements and activation by Pitx1 and estrogen. Endocrinology 28 11250922
2007 Association of autism with polymorphisms in the paired-like homeodomain transcription factor 1 (PITX1) on chromosome 5q31: a candidate gene analysis. BMC medical genetics 27 18053270
2017 PITX1 promotes chondrogenesis and myogenesis in mouse hindlimbs through conserved regulatory targets. Developmental biology 25 29273440
2011 Activation of Paired-homeobox gene PITX1 by del(5)(q31) in T-cell acute lymphoblastic leukemia. Leukemia & lymphoma 25 21425961
2005 The distribution of the bft alleles among enterotoxigenic Bacteroides fragilis strains from stool specimens and extraintestinal sites. Anaerobe 25 16701617
2022 CRISPR-Cas9-mediated mutagenesis of kiwifruit BFT genes results in an evergrowing but not early flowering phenotype. Plant biotechnology journal 23 35796629
2019 MicroRNA-1204 promotes cell proliferation by regulating PITX1 in non-small-cell lung cancer. Cell biology international 23 30549141
2019 MiR-675 is frequently overexpressed in gastric cancer and enhances cell proliferation and invasion via targeting a potent anti-tumor gene PITX1. Cellular signalling 23 31260797
2013 Liebenberg syndrome is caused by a deletion upstream to the PITX1 gene resulting in transformation of the upper limbs to reflect lower limb characteristics. Gene 23 23587911
2018 Abnormal PITX1 gene methylation in adolescent idiopathic scoliosis: a pilot study. BMC musculoskeletal disorders 22 29743058
2011 PITX2 AND PITX1 regulate thyrotroph function and response to hypothyroidism. Molecular endocrinology (Baltimore, Md.) 22 21964592
2023 CRISPR/Cas9 mutants delineate roles of Populus FT and TFL1/CEN/BFT family members in growth, dormancy release and flowering. Tree physiology 21 36892416
2022 Serum Proteins, HMMR, NXPH4, PITX1 and THBS4; A Panel of Biomarkers for Early Diagnosis of Hepatocellular Carcinoma. Journal of clinical medicine 21 35456219
2019 H2AFY promoter deletion causes PITX1 endoactivation and Liebenberg syndrome. Journal of medical genetics 21 30711920
2019 The presence of antibiotic resistance genes and bft genes as well as antibiotic susceptibility testing of Bacteroides fragilis strains isolated from inpatients of the Infant Jesus Teaching Hospital, Warsaw during 2007-2012. Anaerobe 21 30844502
2010 SEDLIN forms homodimers: characterisation of SEDLIN mutations and their interactions with transcription factors MBP1, PITX1 and SF1. PloS one 21 20498720
2019 PITX1 protein interacts with ZCCHC10 to regulate hTERT mRNA transcription. PloS one 20 31404068
2016 E2F1 and TFDP1 Regulate PITX1 Expression in Normal and Osteoarthritic Articular Chondrocytes. PloS one 20 27802335
2007 Determination of bft gene subtypes in Bacteroides fragilis clinical isolates. Journal of clinical microbiology 20 17301286
2015 Biophysical Characterization of G-Quadruplex Recognition in the PITX1 mRNA by the Specificity Domain of the Helicase RHAU. PloS one 19 26649896
2002 Repression by homeoprotein pitx1 of virus-induced interferon a promoters is mediated by physical interaction and trans repression of IRF3 and IRF7. Molecular and cellular biology 19 12242290
2001 Pitx1 and Pitx2c are required for ectopic cement gland formation in Xenopus laevis. Genesis (New York, N.Y. : 2000) 19 11477694
2021 Circ-PITX1 Promotes the Progression of Non-Small Cell Lung Cancer Through Regulating the miR-1248/CCND2 Axis. OncoTargets and therapy 18 33727831
2021 Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer. Nature communications 18 34903763
1997 Backfoot, a novel homeobox gene, maps to human chromosome 5 (BFT) and mouse chromosome 13 (Bft). Genomics 18 9070926
2022 The circ-PITX1 promotes non-small cell lung cancer development via the miR-30e-5p/ITGA6 axis. Cell cycle (Georgetown, Tex.) 17 35007184
2014 PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia. Cell cycle (Georgetown, Tex.) 17 25558831
2021 Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30. Cell reports 16 34038721
2020 The transcription factor PITX1 drives astrocyte differentiation by regulating the SOX9 gene. The Journal of biological chemistry 16 32759168
2018 Disrupting the three-dimensional regulatory topology of the Pitx1 locus results in overtly normal development. Development (Cambridge, England) 16 29549111
2014 miR‑886‑3p upregulation in clear cell renal cell carcinoma regulates cell migration, proliferation and apoptosis by targeting PITX1. International journal of molecular medicine 16 25190136
2013 Morpholino treatment improves muscle function and pathology of Pitx1 transgenic mice. Molecular therapy : the journal of the American Society of Gene Therapy 16 24232919
2023 PITX1 plays essential functions in cancer. Frontiers in oncology 15 37841446
2022 PITX1 suppresses osteosarcoma metastasis through exosomal LINC00662-mediated M2 macrophage polarization. Clinical & experimental metastasis 15 36334221
2007 New emerging role of pitx1 transcription factor in osteoarthritis pathogenesis. Clinical orthopaedics and related research 15 17549029
2024 Biofloc Technology (BFT) in Aquaculture: What Goes Right, What Goes Wrong? A Scientific-Based Snapshot. Aquaculture nutrition 14 38239306
2019 Overexpression of Pitx1 attenuates the senescence of chondrocytes from osteoarthritis degeneration cartilage-A self-controlled model for studying the etiology and treatment of osteoarthritis. Bone 14 31783149
2015 Strong expression of paired-like homeodomain transcription factor 1 (PITX1) is associated with a favorable outcome in human osteosarcoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 14 25936343
2003 Pitx1 in vivo promoter activity and mechanisms of positive autoregulation. Neuroendocrinology 14 14512705
2022 Repositioning small molecule drugs as allosteric inhibitors of the BFT-3 toxin from enterotoxigenic Bacteroides fragilis. Protein science : a publication of the Protein Society 13 36173175
2020 Monitoring oxidative stress, immune response, Nrf2/NF-κB signaling molecules of Rhynchocypris lagowski living in BFT system and exposed to waterborne ammonia. Ecotoxicology and environmental safety 13 32853865
2019 Elevation of circ-PITX1 upregulates interleukin 17 receptor D expression via sponging miR-518a-5p and facilitates cell progression in glioma. Journal of cellular biochemistry 13 31069865
2018 Interaction between physical activity, PITX1 rs647161 genetic polymorphism and colorectal cancer risk in a Korean population: a case-control study. Oncotarget 13 29484135
2016 PITX1 is a novel predictor of the response to chemotherapy in head and neck squamous cell carcinoma. Molecular and clinical oncology 13 27330773
2010 Evaluation of the prevalence of enterotoxigenic Bacteroides fragilis and the distribution bft gene subtypes in patients with diarrhea. Anaerobe 12 20709181
2009 The role of the homeobox genes BFT and CDX2 in the pathogenesis of non-small cell lung cancer. Anticancer research 12 19414376
2021 PITX1 inhibits the growth and proliferation of melanoma cells through regulation of SOX family genes. Scientific reports 11 34526609
2017 Pitx1 determines characteristic hindlimb morphologies in cartilage micromass culture. PloS one 11 28746404
2016 Protein tyrosine phosphatase 1B targets PITX1/p120RasGAP thus showing therapeutic potential in colorectal carcinoma. Scientific reports 11 27752061
2013 Conserved regulation of hoxc11 by pitx1 in Anolis lizards. Journal of experimental zoology. Part B, Molecular and developmental evolution 11 24376195
2016 Expression of a hindlimb-determining factor Pitx1 in the forelimb of the lizard Pogona vitticeps during morphogenesis. Open biology 9 27784790
2018 Pitx1 regulates cement gland development in Xenopus laevis through activation of transcriptional targets and inhibition of BMP signaling. Developmental biology 8 29530451
2006 bft gene subtyping in enterotoxigenic Bacteroides fragilis isolated from children with acute diarrhea. Anaerobe 8 17166747
2019 Bone-Specific Overexpression of PITX1 Induces Senile Osteoporosis in Mice Through Deficient Self-Renewal of Mesenchymal Progenitors and Wnt Pathway Inhibition. Scientific reports 7 30837642
2019 DNA methylation pattern of the goat PITX1 gene and its effects on milk performance. Archives animal breeding 7 31807614
2010 The c-Abl tyrosine kinase stabilizes Pitx1 in the apoptotic response to DNA damage. Apoptosis : an international journal on programmed cell death 7 20563669
2020 Mandibular-pelvic-patellar syndrome is a novel PITX1-related disorder due to alteration of PITX1 transactivation ability. Human mutation 6 32598510
2017 Impact of G-quadruplex loop conformation in the PITX1 mRNA on protein and small molecule interaction. Biochemical and biophysical research communications 6 28412358
2013 Nuclear accumulation of prohibitin 1 in osteoarthritic chondrocytes down-regulates PITX1 expression. Arthritis and rheumatism 6 23310948
2006 Conservation of Pitx1 expression during amphibian limb morphogenesis. Biochemistry and cell biology = Biochimie et biologie cellulaire 5 16609707

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