Affinage

PDX1

Pancreas/duodenum homeobox protein 1 · UniProt P52945

Length
283 aa
Mass
30.8 kDa
Annotated
2026-04-29
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDX1 is a homeodomain transcription factor that serves as a master regulator of pancreatic organogenesis, beta-cell identity, and glucose homeostasis. It binds cooperatively with cofactors including Pbx1–Prep1, Pax6, BETA2/E2A, and MafA to activate insulin, somatostatin, GLUT2, TFAM, Clec16a, and E-cadherin promoters, and recruits the H3K4 methyltransferase Set9 to convert RNA polymerase II from initiation to elongation mode at the insulin locus (PMID:8524276, PMID:10636926, PMID:16141209, PMID:26657766). PDX1 nuclear availability is controlled by SUMO-1 modification, JNK-dependent nuclear export via a defined NES, sequestration in palmitate-induced stress granules, and phosphorylation by GSK3 and CK2, while the SPOP/PCIF1 E3 adaptor targets it for proteasomal degradation through a phosphorylation-sensitive degron whose crystal structure has been resolved (PMID:14633849, PMID:33569632, PMID:30879985, PMID:30449689). Complete PDX1 loss causes pancreatic agenesis and haploinsufficiency leads to impaired beta-cell mass, ER stress susceptibility, defective mitophagy (via Clec16a–Nrdp1), reduced mitochondrial biogenesis (via TFAM), and circadian de-repression of NF-κB inflammatory programs, while gain-of-function drives acinar-to-ductal metaplasia through Stat3 (PMID:8631275, PMID:19855005, PMID:26085571, PMID:19656489, PMID:38171340, PMID:16751181). Homozygous and compound heterozygous PDX1 mutations cause neonatal diabetes and pancreatic agenesis in humans (PMID:20009086, PMID:30930126).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1995 High

    Before this work it was unknown how PDX1 achieved target-gene specificity; demonstration that PDX1 forms cooperative DNA-binding complexes with Pbx via its conserved FPWMK pentapeptide and homeodomain N-terminal arm established the cofactor-dependent binding paradigm for PDX1 target selection.

    Evidence In vitro DNA-binding assays, co-IP, and FPWMK/homeodomain mutagenesis on somatostatin promoter elements

    PMID:8524276

    Open questions at the time
    • Structural basis of Pbx–PDX1 cooperative complex not resolved
    • In vivo relevance of FPWMK motif not tested genetically
  2. 1996 High

    Whether PDX1 was essential for pancreas formation was unresolved; knockout mice lacking pdx-1 showed pancreatic agenesis with only rudimentary dorsal bud outgrowth, establishing PDX1 as indispensable for pancreatic progenitor proliferation and differentiation.

    Evidence Gene targeting (constitutive knockout mouse), histology, immunostaining, lacZ reporter

    PMID:8631275

    Open questions at the time
    • Cell-autonomous versus non-autonomous roles not distinguished
    • Which downstream targets mediate pancreatic outgrowth arrest unknown
  3. 1997 High

    The structural basis for PDX1 transactivation was undefined; mapping identified three conserved N-terminal subdomains required for synergistic insulin promoter activation with E2A bHLH factors, and upstream USF/E-box-dependent regulation of the PDX1 gene itself was demonstrated in vivo.

    Evidence GAL4-chimera mutagenesis in betaTC3, transgenic reporter mice with USF site mutations

    PMID:8567692 PMID:9199333

    Open questions at the time
    • Identity of all cofactors engaging the three subdomains unknown
    • Whether USF is the sole upstream regulator in vivo untested
  4. 1999 High

    How PDX1 reaches the nucleus was unknown; identification of a novel NLS within homeodomain helix 3, plus reconstitution of cooperative Pbx1–Prep1–PDX1 and Pax6–PDX1 complexes on the somatostatin enhancer, defined the nuclear targeting and combinatorial logic of PDX1 at endocrine-specific genes.

    Evidence GFP-tagged deletion/point mutants in COS-7 cells; EMSA with recombinant Pbx1/Prep1/PDX1; reporter assays with Pax6

    PMID:10094480 PMID:10429201 PMID:9933599

    Open questions at the time
    • NLS importin partner not identified
    • Relative contribution of each cofactor complex in vivo unknown
  5. 2000 High

    Whether PDX1 alone could activate high-level insulin transcription was unclear; combinatorial expression showed that PDX1 with BETA2/NeuroD and E2A synergistically activated insulin ~160-fold, and that the PDX1 transactivation domain confers beta-cell-specific, glucose-responsive activity that heterologous activation domains cannot replace.

    Evidence Combinatorial transfection in non-beta cells; GAL4-substituted enhancer reporters in beta and non-beta lines

    PMID:10636926 PMID:11117522

    Open questions at the time
    • Glucose-sensing mechanism of PDX1 transactivation domain unresolved
    • Direct physical contacts between PDX1 and BETA2 not mapped
  6. 2002 High

    The in vivo consequences of partial PDX1 loss were uncharacterized; haploinsufficient mice showed impaired GSIS, reduced GLUT2, defective mitochondrial NAD(P)H generation, increased beta-cell apoptosis with reduced Bcl-XL/Bcl-2, and failure of beta-cell mass expansion, while SUMO-1 modification was shown to promote PDX1 nuclear retention and transcriptional activity.

    Evidence Pdx1+/- mice with perfused pancreas, NAD(P)H imaging, TUNEL, caspase-3, Western blot; co-IP and RNAi for SUMO-1 in beta cells

    PMID:11781323 PMID:12488243 PMID:12697734

    Open questions at the time
    • SUMO-1 conjugation site(s) on PDX1 not mapped
    • Whether apoptosis is cell-autonomous or secondary to metabolic stress unclear
  7. 2002 High

    The signaling pathways upstream of PDX1 in beta-cell mass regulation were unknown; genetic epistasis showed that Pdx1 transgene rescues beta-cell mass and prevents diabetes in Irs2-/- mice, placing PDX1 downstream of IRS2/insulin signaling.

    Evidence Irs2-/- × Pdx1 transgenic and Pdx1+/- genetic crosses, glucose tolerance, histology

    PMID:11994408

    Open questions at the time
    • Biochemical mechanism linking IRS2 signaling to PDX1 expression/stability not defined
  8. 2003 High

    How oxidative stress impairs PDX1 function was unknown; identification of a functional NES (aa 82–94) and demonstration that JNK-dependent phosphorylation triggers CRM1-mediated nuclear export of PDX1 established a regulated nucleo-cytoplasmic shuttling mechanism.

    Evidence GFP-PDX1 live imaging, leptomycin B blockade, dominant-negative JNK, NES deletion mapping in HIT-T15 cells

    PMID:14633849

    Open questions at the time
    • Specific JNK phosphorylation site(s) on PDX1 not identified
    • Whether this mechanism operates in human islets not tested
  9. 2004 Medium

    The degradation machinery for PDX1 was unidentified; PCIF1/SPOP was discovered as a PDX1-interacting protein that alters its subnuclear distribution and inhibits its transactivation, initiating understanding of PDX1 proteostasis.

    Evidence Yeast two-hybrid identification, co-IP, reporter assays in MIN6

    PMID:15121856

    Open questions at the time
    • Whether SPOP mediates PDX1 ubiquitination and degradation not directly shown at this stage
    • Endogenous interaction stoichiometry unknown
  10. 2005 High

    The chromatin mechanism by which PDX1 activates insulin transcription was unknown; PDX1 was shown to recruit the H3K4 methyltransferase Set9 to the insulin promoter, linking PDX1 occupancy to histone methylation and RNA pol II elongation.

    Evidence Co-IP of PDX1–Set9, ChIP for H3K4me2 and pol II isoforms, siRNA knockdown of PDX1

    PMID:16141209

    Open questions at the time
    • Whether Set9 is required for all PDX1 target genes or only insulin unknown
    • Structural basis of PDX1–Set9 interaction unresolved
  11. 2006 High

    Consequences of ectopic/sustained PDX1 expression were undefined; constitutive PDX1 in all pancreatic lineages caused acinar-to-ductal metaplasia through cell-autonomous Stat3 activation, revealing a dosage-dependent oncogenic potential.

    Evidence Transgenic CAG-PDX1 mice, genetic Stat3 knockout epistasis, histology

    PMID:16751181

    Open questions at the time
    • How PDX1 activates Stat3 (direct transcriptional target vs. signaling) not resolved
    • Relevance to human pancreatic cancer initiation uncertain
  12. 2009 High

    PDX1's role beyond insulin gene regulation in beta-cell homeostasis was unclear; three studies collectively showed that PDX1 directly activates TFAM to maintain mitochondrial biogenesis and respiration, regulates a broad ER function gene program protecting against ER stress, and that excessive autophagy contributes to Pdx1-deficient beta-cell death.

    Evidence ChIP at TFAM promoter with adenoviral TFAM rescue; ChIP + microarray in Pdx1+/- and Min6 siRNA; Pdx1+/- × Becn1+/- genetic cross with autophagy inhibitors

    PMID:19654319 PMID:19656489 PMID:19855005

    Open questions at the time
    • Whether ER stress and mitochondrial defects are independent or interconnected consequences of PDX1 loss not resolved
    • Autophagy pathway specificity not defined
  13. 2009 Medium

    Whether homeodomain integrity is needed for PDX1 transactivation independently of DNA binding was untested; the E178G neonatal-diabetes mutation was shown to impair transactivation without affecting nuclear localization or chromatin occupancy, dissociating binding from activation.

    Evidence Genetic analysis of consanguineous family; recombinant protein functional assays in cell lines

    PMID:20009086

    Open questions at the time
    • Mechanism by which E178G disrupts transactivation despite normal occupancy unknown
    • Single family reported
  14. 2010 Medium

    Post-translational regulation of PDX1 by kinases beyond JNK was poorly characterized; CK2 was identified as a kinase phosphorylating PDX1 at Thr231/Ser232, modulating insulin promoter activity.

    Evidence In vitro kinase assay, phosphosite mutagenesis, insulin promoter reporters, CK2 inhibitor

    PMID:20339896

    Open questions at the time
    • In vivo relevance of CK2 phosphorylation not validated
    • Interplay with SPOP degron phosphorylation not examined
  15. 2011 High

    How PDX1 protein stability is maintained was unclear; RB was found to bind PDX1 via a conserved RB-interaction motif, stabilizing it against proteasomal degradation, and forced Pdx1 expression from the Neurog3 stage was shown to convert alpha cells to functional beta cells in vivo.

    Evidence Co-IP, RIM mutagenesis, proteasome inhibitor, RB conditional knockout; conditional Pdx1 transgene with Neurog3-Cre lineage tracing

    PMID:21399612 PMID:21852533

    Open questions at the time
    • Whether RB protection is direct or involves competition with SPOP not tested
    • Efficiency and completeness of alpha-to-beta conversion in adult animals unknown
  16. 2012 High

    The genome-wide direct target repertoire of PDX1 in primary islets was undefined; ChIP-seq in human and mouse islets revealed a conserved cistrome enriched for endocrine function, metabolic, and cell-survival genes.

    Evidence ChIP-seq in human and mouse islets with evolutionary conservation analysis

    PMID:22322596

    Open questions at the time
    • Functional validation of most identified targets not performed
    • Condition-dependent (e.g. glucose-stimulated) binding changes not captured
  17. 2015 High

    PDX1's control of mitochondrial quality and pancreatic lineage specification was incompletely understood; PDX1 was shown to regulate mitophagy through transcriptional control of Clec16a–Nrdp1, to directly activate E-cadherin for epithelial morphogenesis, and to cooperate genome-wide with Sox9 to activate pancreatic and repress intestinal gene programs.

    Evidence ChIP-seq at Clec16a with adenoviral rescue and mitophagy assays; ChIP at E-cadherin promoter with Pdx1-/- embryo analysis; ChIP-seq for Pdx1 and Sox9 with conditional knockouts

    PMID:26085571 PMID:26440894 PMID:26657766

    Open questions at the time
    • Whether Clec16a is rate-limiting for mitophagy in human islets unknown
    • Mechanism of Sox9–PDX1 cooperative binding not structurally defined
  18. 2018 High

    The structural basis for SPOP-mediated PDX1 degradation was unresolved; a crystal structure of the SPOP MATH domain bound to PDX1 residues 223–233 showed phosphorylation within the degron reduces SPOP binding, providing a mechanistic switch for PDX1 stability; concurrently, PDX1–ATF4/ATF5 complexes were found to co-occupy CARE motifs at stress/apoptosis genes.

    Evidence Crystal structure, ITC, NMR for SPOP–PDX1; co-IP, ChIP-seq, RNAseq, and Gpt2 knockout for ATF complexes

    PMID:30174228 PMID:30449689

    Open questions at the time
    • Identity of kinase(s) that phosphorylate the SPOP degron in vivo unknown
    • Whether ATF4/ATF5 partnership is stress-specific or constitutive not fully resolved
  19. 2019 High

    The pathogenic kinase targeting PDX1 under glucotoxicity was unidentified; GSK3 was shown to phosphorylate PDX1 in diabetic islets, and GSK3 inhibition rescued GSIS in human islets; separately, iPSC-modeled transactivation domain mutations (P33T, C18R) confirmed structure–function requirements for PDX1 in human beta-cell differentiation.

    Evidence Phosphoproteomics of diabetic mouse islets, GSK3 inhibitor rescue in human islets; isogenic iPSC differentiation with ChIP-seq and RNA profiling

    PMID:30879985 PMID:30930126

    Open questions at the time
    • Specific GSK3 phosphosites on PDX1 not all mapped
    • Whether GSK3 phosphorylation feeds into SPOP-dependent degradation not tested
  20. 2021 High

    How lipotoxicity disrupts PDX1 nuclear function was mechanistically undefined; palmitate was shown to trap PDX1 in cytoplasmic stress granules via PI3K/EIF2α-dependent disruption of nucleocytoplasmic transport, and disruption of stress granule assembly restored PDX1 nuclear localization and beta-cell function.

    Evidence Mass spectrometry of stress granule components, immunofluorescence, PI3K/EIF2α inhibitors, TIA1 knockout mice

    PMID:33569632

    Open questions at the time
    • Whether stress granule trapping occurs with unsaturated fatty acids unknown
    • Direct RNA targets of PDX1 within stress granules not characterized
  21. 2024 High

    Whether PDX1 integrates circadian and inflammatory programs was unknown; PDX1 was found to silence NF-κB at circadian enhancers through long-range chromatin contacts involving SIN3A, and Bmal1 ablation disrupted genome-wide PDX1 binding, establishing PDX1 as a circadian-inflammatory gatekeeper in beta cells.

    Evidence Single-cell ATAC-seq, ChIP-seq, Hi-C, Pdx1 hypomorphic mice, Bmal1 beta-cell knockout, IL-1β receptor antagonism

    PMID:38171340

    Open questions at the time
    • Whether circadian PDX1 binding dynamics are direct or Bmal1-dependent not fully separated
    • SIN3A recruitment mechanism to PDX1-bound sites not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) the complete phosphorylation code integrating GSK3, CK2, JNK, and SPOP-degron phosphorylation into a unified PDX1 stability/localization model; (2) the structural basis for PDX1 cooperative interactions with its diverse cofactor partners; (3) which PDX1 chromatin targets are dynamically regulated by glucose versus constitutively bound; and (4) the mechanism by which homeodomain mutations impair transactivation despite preserved DNA occupancy.
  • No integrated phosphorylation map of PDX1
  • No full-length PDX1 structure available
  • Glucose-responsive versus constitutive target binding not systematically resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 13 GO:0003677 DNA binding 9
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2
Pathway
R-HSA-74160 Gene expression (Transcription) 9 R-HSA-1266738 Developmental Biology 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 2
Partners
ATF4NEUROD1PAX6PBX1PREP1RB1SETD7SPOP

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 PDX-1 (mouse pdx-1) is required for pancreatic outgrowth and differentiation; null mutation leads to apancreatic mice with only limited dorsal bud outgrowth lacking insulin/amylase-positive cells, demonstrating PDX-1 is essential for pancreatic progenitor proliferation and differentiation. Gene targeting (knockout mouse), histology, immunostaining, lacZ reporter fusion Development High 8631275
1995 PDX-1/STF-1 binds cooperatively with the homeodomain cofactor Pbx to regulatory elements in the somatostatin promoter; cooperative binding requires both the conserved N-terminal FPWMK pentapeptide motif and the N-terminal arm of the PDX-1 homeodomain. In vitro DNA-binding assays, co-immunoprecipitation, mutational analysis of FPWMK motif and homeodomain Molecular and Cellular Biology High 8524276
1997 PDX-1 transactivation is mediated by three conserved N-terminal subdomains (amino acids 13-22, 32-38, 60-73); these same sequences are required for synergistic activation of insulin gene transcription with E2A-encoded bHLH proteins. GAL4-chimera transactivation assays, deletion/point mutagenesis, stable expression in betaTC3 cells Molecular and Cellular Biology High 9199333
1997 PDX-1/STF-1 gene expression in pancreatic islets requires an E-box element at -104 bp recognized by the helix-loop-helix/leucine zipper factor USF; point mutations disrupting USF binding impair STF-1 promoter activity in transgenic mice. Transgenic reporter mice, site-directed mutagenesis, EMSA The Journal of Biological Chemistry High 8567692
1997 PDX-1 (IDX-1) protein is markedly reduced (~80%) in islets from partially pancreatectomized hyperglycemic rats, coinciding with reduced GLUT2 and insulin mRNAs, suggesting PDX-1 loss mediates transcriptional dysfunction during chronic hyperglycemia. Western blot, quantitative RT-PCR, immunofluorescence on isolated islets Diabetes Medium 9000703
1997 HNF-3β activates and glucocorticoids repress PDX-1/STF-1 gene expression through a composite islet-specific enhancer; overexpression of HNF-3β suppresses glucocorticoid receptor-mediated inhibition of PDX-1 transcription. Transfection reporter assays, EMSA, overexpression in islet cell lines Molecular and Cellular Biology Medium 9111329
1999 PDX-1 bears a nuclear localization signal (NLS) that resides within helix 3 of the homeodomain; point mutations of basic residues in helix 3 abolish nuclear transport, identifying a novel class of NLS. EGFP-tagged deletion/point mutant constructs expressed in COS-7 cells, fluorescence microscopy, Western blot European Journal of Biochemistry High 10429201
1999 PDX1 and Pbx-Prep1 heterodimeric complex cooperatively activate the somatostatin mini-enhancer; Pbx1 and Prep1 bind cooperatively to the UE-A element and require co-expression of PDX1 binding to the adjacent TSEI element for strong transcriptional activation. EMSA with recombinant proteins, transient transfection reporter assays The Journal of Biological Chemistry High 9933599
1999 Pax6 and PDX1 form a functional complex on the somatostatin upstream enhancer; PDX1 potentiates Pax6-mediated activation, and simultaneous binding of PDX1 to the B-element and Pax6 to the C-element is required for beta/delta-cell-specific activity. EMSA, transient transfection reporter assays, site-directed mutagenesis FEBS Letters Medium 10094480
2000 PDX-1, BETA2/NeuroD, and E2A co-expressed in non-beta cells synergistically activate the insulin promoter ~160-fold; PDX-1 alone produces only modest activation, demonstrating that high-level insulin transcription requires cooperative interaction of all three factors. Transfection of non-beta cells with combinations of transcription factors, reporter gene assays The Journal of Biological Chemistry High 10636926
2000 The PDX-1 transactivation domain confers beta-cell-specific and glucose-responsive activation of the insulin gene through cooperative interactions with other enhancer-bound factors (E1 element activators); heterologous activation domains (VP16, E1A) cannot substitute functionally. GAL4-substituted insulin enhancer reporter assays in beta-cell and non-beta-cell lines, mutagenesis Molecular Endocrinology High 11117522
2002 Haploinsufficiency for PDX-1 impairs glucose-stimulated insulin secretion in mice by reducing PDX-1 and GLUT2 expression, diminishing NAD(P)H generation (~30%), and impairing mitochondrial function and intracellular Ca2+ mobilization in beta cells. PDX-1+/- mice, perfused pancreas secretion assays, NAD(P)H imaging, Western blot, glucose tolerance testing The Journal of Biological Chemistry High 11781323
2002 PDX-1 is modified by SUMO-1 in beta cells; this sumoylation contributes to the molecular mass shift from 31 to 46 kDa, promotes nuclear localization and stability of PDX-1, and is required for full insulin gene transcriptional activity. Transfection, co-immunoprecipitation, RNA interference against SUMO-1, proteasome inhibitor treatment, reporter assays American Journal of Physiology - Endocrinology and Metabolism Medium 12488243
2002 Transgenic expression of Pdx1 rescues beta cell mass and function and prevents diabetes in Irs2-/- mice, demonstrating that Pdx1 acts downstream of IRS2 signaling to maintain beta cell mass; Pdx1 haploinsufficiency accelerates diabetes onset in Irs2-/- mice. Genetic epistasis (Irs2-/- x Pdx1 transgenic and Pdx1+/- mice), glucose tolerance, histology The Journal of Clinical Investigation High 11994408
2003 PDX-1 is translocated from nucleus to cytoplasm in response to oxidative stress via a JNK-dependent mechanism; a nuclear export signal (NES) was identified at amino acids 82-94 of mouse PDX-1 that overrides the NLS, and this translocation is blocked by leptomycin B or dominant-negative JNK. Live-cell imaging of GFP-PDX-1, dominant-negative JNK expression, leptomycin B treatment, NES identification by deletion mapping in HIT-T15 cells Diabetes High 14633849
2003 Increased Pdx1+/- beta cell apoptosis (with reduced Bcl-XL and Bcl-2), abnormal islet architecture, and failure of beta cell mass expansion with age underlie the organ-level insulin secretion defect in Pdx1 heterozygous mice. TUNEL, active caspase-3 staining, Ca2+ imaging, single-cell patch-clamp, Western blot for Bcl-XL/Bcl-2 in Pdx1+/- islets The Journal of Clinical Investigation High 12697734
2004 PCIF1/SPOP, a POZ domain protein, interacts with the C-terminus of PDX-1 both in vitro and in vivo; coexpression of PCIF1 alters subnuclear distribution of PDX-1 and inhibits PDX-1 transactivation of target gene promoters in a C-terminus-dependent manner. Yeast two-hybrid (identification), co-immunoprecipitation, reporter assays, overexpression in MIN6 cells Molecular and Cellular Biology Medium 15121856
2005 Pdx-1 links histone H3-Lys-4 dimethylation to RNA polymerase II elongation at the insulin gene; Pdx-1 directly interacts with the methyltransferase Set9 (co-IP), recruits Set9 to the insulin promoter, and Pdx-1 knockdown reduces H3-Lys-4 dimethylation and shifts pol II from elongation to initiation isoform at the insulin locus. siRNA knockdown, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Pdx-1 and Set9), immunohistochemistry The Journal of Biological Chemistry High 16141209
2006 Persistent/constitutive PDX-1 expression in all pancreatic lineages causes acinar-to-ductal metaplasia through cell-autonomous activation of Stat3; genetic ablation of Stat3 in the transgenic pancreas profoundly suppresses the metaplastic phenotype. Transgenic overexpression (CAG-PDX1), genetic Stat3 knockout epistasis, histology Genes & Development High 16751181
2007 PDX-1 identifies and directly activates the TFAM (mitochondrial transcription factor A) gene in beta cells; PDX-1 deficiency reduces TFAM expression, decreases mtDNA copy number and respiratory chain activity, and impairs ATP synthesis and glucose-stimulated insulin secretion; adenoviral TFAM restoration rescues these defects. Dominant-negative Pdx1 adenovirus, transcript profiling, ChIP (PDX-1 occupancy at TFAM), adenoviral TFAM rescue in rat islets, mtDNA measurement Cell Metabolism High 19656489
2009 Pdx1 regulates beta cell susceptibility to ER stress; Pdx1-deficient beta cells show ER stress markers and enhanced ER stress-associated apoptosis; chromatin occupancy and expression microarray analysis reveal that Pdx1 directly regulates a broad set of ER function genes including those involved in disulfide bond formation, protein folding, and the unfolded protein response. High-fat diet Pdx1+/- model, Min6 siRNA knockdown, chromatin occupancy ChIP, expression microarray, ER stress markers PNAS High 19855005
2009 Increased autophagy contributes to Pdx1-deficiency-induced beta cell death; inhibition of autophagy (pharmacological or Becn1 haploinsufficiency) prolongs survival of Pdx1-deficient MIN6 cells and improves glucose tolerance and beta cell mass in Pdx1+/- mice on high-fat diet. Lentiviral shRNA knockdown of Pdx1 in MIN6, autophagy inhibitors, Pdx1+/- x Becn1+/- genetic cross, metabolic testing The Journal of Biological Chemistry Medium 19654319
2010 Protein kinase CK2 phosphorylates Pdx-1 at Thr231 and Ser232, and this phosphorylation regulates the transcriptional activity of Pdx-1 at the insulin promoter; inhibition of CK2 elevates insulin release from pancreatic beta cells. In vitro kinase assay with Pdx-1 fragments, phosphorylation site mutagenesis, insulin promoter reporter assays, CK2 inhibitor treatment Cellular and Molecular Life Sciences Medium 20339896
2011 The retinoblastoma protein RB associates with and stabilizes Pdx-1 through a conserved RB-interaction motif (RIM) in Pdx-1; point mutations in the RIM reduce RB-Pdx-1 complex formation and promote proteasomal degradation of Pdx-1; RB occupies promoters of beta-cell-specific genes and RB deficiency reduces Pdx-1 expression and pancreas size in vivo. Co-immunoprecipitation, point mutagenesis of RIM, proteasome inhibitor experiments, ChIP, RB conditional knockout mice The EMBO Journal High 21399612
2011 Forced Pdx1 expression from the Neurogenin-3 stage onward causes postnatal conversion of alpha cells (glucagon/Arx-positive) through a glucagon-insulin double-positive intermediate to cells indistinguishable from normal beta cells; this context-dependent reprogramming requires Pdx1 activity in Neurog3+ cells but not in mature glucagon-expressing cells. Conditional Pdx1 transgene (Neurog3-Cre driver), lineage tracing, immunostaining, genetic epistasis Genes & Development High 21852533
2012 Genome-wide ChIP-seq of Pdx1 in human and mouse islets identifies a conserved cistrome enriched for genes involved in endocrine function, metabolic disorders, signaling pathways, and cell survival, defining the direct transcriptional targets mediating Pdx1's role in islet function. ChIP-seq in human and mouse islets, evolutionary conservation analysis Molecular Endocrinology High 22322596
2015 Pdx1 regulates mitophagy in pancreatic beta cells through transcriptional control of Clec16a and its downstream target Nrdp1 (E3 ubiquitin ligase); loss of Pdx1 impairs autophagosome-lysosome fusion during mitophagy, and restoration of Clec16a rescues mitochondrial trafficking, respiration, and glucose-stimulated insulin secretion. ChIP-seq (Pdx1 occupancy at Clec16a), expression microarray, adenoviral Clec16a rescue, mitophagy flux assays, Pdx1+/- islets Diabetes High 26085571
2015 Pdx1 and Sox9 cooperatively bind regulatory sequences near pancreatic and intestinal differentiation genes, jointly activating pancreatic lineage genes and repressing the intestinal lineage; genetic studies show dual and cooperative roles for both factors in pancreatic lineage induction. ChIP-seq (Pdx1 and Sox9 occupancy), genetic epistasis with conditional knockouts, gene expression analysis Cell Reports High 26440894
2015 Pdx1 directly binds and activates the E-cadherin (Cdh1) promoter via two conserved binding sites; Pdx1 is required in vivo for maintenance of E-cadherin expression, actomyosin complex activity, and epithelial cell shape during pancreatic tubulogenesis. ChIP (Pdx1 at E-cad promoter), reporter assays, Pdx1-/- mouse embryo analysis, immunostaining Development High 26657766
2018 SPOP (PCIF1) binds directly to Pdx1 residues 223-233 with low micromolar affinity via its MATH domain; the SPOP-Pdx1 crystal structure shows an extended interface; phosphorylation of Pdx1 within this region reduces its affinity for SPOP, providing a regulatory mechanism controlling Pdx1 ubiquitination and proteasomal degradation. Crystal structure of SPOP-Pdx1 complex, isothermal titration calorimetry (ITC), NMR spectroscopy Structure High 30449689
2018 PDX1 forms stress-inducible complexes with ATF4 and ATF5 in beta cells; these complexes co-occupy composite C/EBP-ATF (CARE) motifs at stress and apoptosis genes (including Gpt2, Chac1, Slc7a1); PDX1-ATF complex governs beta cell survival, and deficiency of Gpt2 reduces stress-induced apoptosis. Co-immunoprecipitation, ChIP-seq, RNAseq (shRNA knockdown of Pdx1, Atf4, Atf5), caspase-3 activation assay Molecular Metabolism High 30174228
2019 GSK3 kinase phosphorylates Pdx1 in diabetic islets; pharmacological GSK3 inhibition rescues glucose-stimulated insulin secretion in human islets under glucotoxicity, identifying GSK3-PDX1 as a key pathogenic signaling axis. Mass spectrometry-based phosphoproteomics of diabetic mouse islets, GSK3 inhibitor treatment of human islets, GSIS assays Cell Metabolism High 30879985
2019 Point mutations in the PDX1 transactivation domain (P33T, C18R) impair beta-cell differentiation and function; iPSC modeling shows these mutations reduce expression of PDX1-bound target genes including MNX1, PDX1 itself (autoregulation), and MEG3/NNAT in pancreatic progenitors. iPSC lines with engineered mutations, beta-cell differentiation protocol, ChIP-seq (PDX1 occupancy), RNA expression profiling Molecular Metabolism High 30930126
2021 Saturated fatty acids (palmitic acid) trap PDX1 in cytoplasmic stress granules in beta cells by disrupting nucleocytoplasmic transport via a PI3K/EIF2α-dependent mechanism; PDX1 was identified as a stress granule component by mass spectrometry; disruption of stress granule assembly (PI3K/EIF2α inhibitors or TIA1 deletion) restores PDX1 nuclear localization and ameliorates beta cell dysfunction. Mass spectrometry of stress granule components, immunofluorescence, nucleocytoplasmic transport reporters, PI3K/EIF2α inhibitors, TIA1 knockout mice Diabetologia High 33569632
2021 OGT (O-GlcNAc transferase) regulates beta cell mitochondrial morphology and bioenergetics partly through Pdx1; constitutive OGT deletion reduces Pdx1 levels, and overexpression of Pdx1 in OGT-deficient islets rescues mitochondrial morphology, insulin content, and mitochondrial function. Conditional OGT knockout mice, islet proteomics, adenoviral Pdx1 overexpression rescue, oxygen consumption rate assay Diabetes Medium 34462257
2024 PDX1 silences NF-κB at circadian and inflammatory enhancers in beta cells through long-range chromatin contacts involving SIN3A; PDX1 hypomorphic mice show de-repression of NF-κB and impaired nocturnal glucose tolerance; Bmal1 ablation disrupts genome-wide PDX1 and NF-κB DNA binding, and antagonizing the IL-1β receptor (NF-κB target) improves insulin secretion in Pdx1 hypomorphic islets. Single-cell ATAC-seq atlas of human islets, ChIP-seq, 3D chromatin analysis (Hi-C/proximity ligation), Pdx1 hypomorphic mice, Bmal1 beta-cell knockout, pharmacological IL-1β receptor antagonism Cell Metabolism High 38171340
2009 E178G substitution in the PDX1 homeodomain causes neonatal diabetes by reducing Pdx1 transactivation activity despite normal nuclear localization, expression level, and chromatin occupancy, demonstrating that homeodomain integrity is required for transcriptional activation independently of DNA binding. Genetic analysis of consanguineous family, recombinant protein functional assays (transcriptional activation, nuclear localization, chromatin occupancy) in cell lines Diabetes Medium 20009086

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development (Cambridge, England) 1292 8631275
1997 A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice. Diabetes 457 9133560
2002 Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion. The Journal of biological chemistry 332 11781323
2003 Increased islet apoptosis in Pdx1+/- mice. The Journal of clinical investigation 294 12697734
1999 The homeodomain protein IDX-1 increases after an early burst of proliferation during pancreatic regeneration. Diabetes 280 10078550
2009 Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress. Proceedings of the National Academy of Sciences of the United States of America 188 19855005
2003 Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun NH(2)-terminal kinase. Diabetes 183 14633849
2004 Regulated expression of pdx-1 promotes in vitro differentiation of insulin-producing cells from embryonic stem cells. Diabetes 182 15047618
2009 Pdx1 and other factors that regulate pancreatic beta-cell survival. Diabetes, obesity & metabolism 177 19817786
2011 Context-specific α- to-β-cell reprogramming by forced Pdx1 expression. Genes & development 165 21852533
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