Affinage

SP4

Transcription factor Sp4 · UniProt Q02446

Length
784 aa
Mass
82.0 kDa
Annotated
2026-06-10
89 papers in source corpus 39 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SP4 is a C2H2 zinc-finger transcription factor that binds GC-/GT-rich and Sp-like cis-elements to activate or repress target promoters, with predominant expression and function in neurons and the heart (PMID:8321243, PMID:17316402). Through an N-terminal glutamine-rich activation domain it acts as a transcriptional activator, but unlike SP1 it cannot drive synergistic activation from adjacent sites and is repressed by SP3, while SP1/SP3 can competitively antagonize SP4 at shared binding sites (PMID:7559627, PMID:9867805, PMID:15781457). SP4 shows target selectivity distinct from other Sp factors, specifically activating the rod beta-PDE and opsin promoters in retinal neurons in cooperation with CRX, with which it physically interacts via its zinc-finger domain (PMID:11943774, PMID:15781457). In neurons SP4 is the predominant Sp-family factor and couples neuronal activity to gene programs governing dendrite patterning, synaptic receptor composition, and energy metabolism: it represses neurotrophin-3 (NT3) and activates Nwk2/Fchsd1 to limit dendritic branching and control surface NMDAR NR1, and it directly regulates NR1, the AMPA subunit GluA2 (Gria2), GABAA subunits Gabra1/Gabra2, serine racemase (Srr), and Na+/K+-ATPase subunit genes (PMID:17535924, PMID:19555762, PMID:25045015, PMID:24219545, PMID:24576410, PMID:26469128, PMID:32603878, PMID:20634195). SP4 activity is tightly controlled post-translationally — by NMDAR-dependent PP1/2A dephosphorylation of S770 (a phosphorylation that serves as both a maturation switch and a degradation signal), by STIM1/store-operated Ca2+ entry-driven ubiquitin-proteasome degradation under hyperpolarized conditions, by calpain cleavage upon glutamate receptor activation, by O-GlcNAcylation of its transactivation domain, and by lithium-dependent stabilization (PMID:17316402, PMID:22017217, PMID:24894994, PMID:24475768, PMID:26431879, PMID:26049820). In the heart, SP4/HF-1b binds the HF-1b/MEF-2 element to drive ventricular chamber-specific MLC-2v expression and acts in both cardiomyogenic and neural-crest lineages to specify the conduction system via Cx40 and trkC (PMID:8321243, PMID:8289802, PMID:16430881). Sp4-null and hypomorphic mice show postnatal lethality, growth retardation, dentate gyrus developmental defects, reduced NMDAR NR1, impaired LTP, and sensorimotor gating and memory deficits, establishing SP4 as essential for viability and neurodevelopment (PMID:8660867, PMID:11532028, PMID:15558077, PMID:16899055, PMID:20634195). Beyond its neuronal and cardiac roles, SP4 also participates in disease-associated transcriptional programs, including regulation of VEGF, TRPV1, and Wnt/β-catenin signaling in cancer and other contexts (PMID:15883203, PMID:30811405, PMID:37768180).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1993 High

    Established SP4/HF-1b as a sequence-specific C2H2 zinc-finger DNA-binding protein and transcriptional activator, identifying it as a component of an endogenous cardiac nuclear binding activity at the MLC-2 promoter.

    Evidence cDNA cloning, DNA-binding and reporter assays, characterization of endogenous cardiac complex

    PMID:8321243

    Open questions at the time
    • Did not establish in vivo requirement
    • Did not define non-cardiac targets
  2. 1994 High

    Demonstrated in vivo that the HF-1b element is required for ventricular chamber-specific MLC-2v expression, linking SP4 binding to cardiac developmental gene control.

    Evidence Transgenic mouse lines with site-directed promoter mutations

    PMID:8289802

    Open questions at the time
    • Element shared with MEF-2; did not isolate SP4-specific contribution
    • Mechanism of chamber specificity unresolved
  3. 1995 High

    Defined the SP4 activation domain architecture and its functional distinctions from SP1, showing SP4 lacks synergy across adjacent sites and is repressible by SP3.

    Evidence Cotransfection and domain mutagenesis in Sp-null Drosophila SL2 cells

    PMID:7559627

    Open questions at the time
    • Did not identify physiological target genes
    • Cell-context dependence not addressed
  4. 1996 High

    Showed SP4 is required for organismal viability, growth, and male reproductive behavior, separating its physiology from other Sp factors despite shared DNA-binding specificity.

    Evidence Sp4 knockout mice with histological and behavioral analysis

    PMID:11532028 PMID:8660867

    Open questions at the time
    • Causal target genes for each phenotype unknown
    • Tissue-specific contributions not dissected
  5. 2002 High

    Identified the first SP4-specific target gene (beta-PDE) and showed SP4, not SP1/SP3, drives this retinal promoter, and that SP4 interacts with CRX, establishing combinatorial neuronal target selectivity.

    Evidence Promoter analysis, purified TBP/TFIIB binding, co-IP, ChIP in retina

    PMID:11943774 PMID:15781457

    Open questions at the time
    • Structural basis of SP4-CRX interaction undefined
    • Generalizability of CRX cooperation to other targets unknown
  6. 2006 High

    Defined SP4 as the predominant neuronal Sp factor and identified NT-3 as a direct neuronal target, linking SP4 to neurodevelopment and the dentate gyrus.

    Evidence EMSA, ChIP, dominant-negative and siRNA in cortical neurons; null-mouse developmental analysis

    PMID:16899055 PMID:17059557

    Open questions at the time
    • Whether SP4 activates or represses NT3 differs by context (cf. #12)
    • Upstream signals controlling SP4 in dentate cells unknown
  7. 2007 High

    Established SP4 as a transcriptional controller of activity-dependent dendrite pruning requiring its DNA-binding activity, and revealed glutamate-triggered calpain cleavage as an activity-coupled regulatory event.

    Evidence RNAi/overexpression with DBD mutant in cerebellar granule neurons; purified calpain cleavage and ischemia model

    PMID:17316402 PMID:17535924

    Open questions at the time
    • Functional consequence of calpain cleavage products not resolved
    • Direct dendrite-controlling target genes not yet identified at this stage
  8. 2009 High

    Resolved a direct SP4 effector for dendrite patterning by showing SP4 represses the NT3 promoter in cerebellar granule neurons, with NT3 neutralization rescuing the knockdown phenotype.

    Evidence Reporter assays, siRNA, ChIP, NT3 neutralization, morphology analysis

    PMID:19555762

    Open questions at the time
    • Activator vs repressor role of SP4 at NT3 appears context-dependent across neuron types
    • Promoter elements distinguishing the two outcomes undefined
  9. 2010 Medium

    Connected SP4 dosage to synaptic function by showing reduced SP4 lowers NMDAR NR1 and impairs LTP and spatial memory.

    Evidence Western blot, IHC, LTP recordings, behavior in hypomorphic mice

    PMID:20634195

    Open questions at the time
    • Direct vs indirect regulation of NR1 not distinguished here
    • Single-lab characterization
  10. 2013 High

    Expanded SP4's neuronal program to bioenergetics by identifying Na+/K+-ATPase subunit genes as activity-coupled SP4 targets.

    Evidence EMSA, ChIP, promoter mutation, KD/OE with depolarization/TTX paradigms

    PMID:24219545

    Open questions at the time
    • Coordination with other metabolic regulators unresolved
    • In vivo relevance to neuronal energy balance not tested
  11. 2014 High

    Defined a multi-layered post-translational control network setting SP4 abundance and activity (S770 phosphorylation via NMDAR/PP1-2A, STIM1/SOCE-driven ubiquitin-proteasome degradation) and identified the SP4-Nwk2-NMDAR1 dendrite-surface axis plus the GluA2 target.

    Evidence Phosphomimetic/non-phosphorylatable mutants, STIM1 KD/CA, ubiquitylation assays, ChIP/rescue, EMSA/qPCR in neurons

    PMID:24475768 PMID:24576410 PMID:24894994 PMID:25045015

    Open questions at the time
    • E3 ligase mediating SP4 ubiquitylation not identified
    • Kinase phosphorylating S770 not identified
  12. 2015 High

    Broadened SP4's neuronal receptor program to GABAA and serine-racemase systems, refined S770 as a degradation signal, identified O-GlcNAcylation and CpG methylation as additional regulatory layers, and placed SP4 function in GABAergic neurons upstream of ketamine sensitivity.

    Evidence EMSA/ChIP/mutagenesis, mutant stability assays, OGT co-expression, methylation reporter assays, cell-type-specific Cre rescue

    PMID:22017217 PMID:26037489 PMID:26049820 PMID:26188176 PMID:26431879 PMID:26469128

    Open questions at the time
    • O-GlcNAc and lithium-stabilization mechanisms are Medium-confidence/single-lab
    • Specific O-GlcNAc sites not mapped
  13. 2024 Medium

    Extended SP4 regulation to alternative splicing, showing SRSF3/NXF1-driven exon inclusion generates a long, transactivation-competent isoform with tumor-suppressive transcriptional activity, contrasting with pro-tumorigenic SP4 targets in other cancers.

    Evidence Splicing analysis, isoform-specific functional assays, SMAD4/PHF14 reporter and rescue experiments

    PMID:37768180 PMID:39222664 PMID:40792019

    Open questions at the time
    • Context-dependence of SP4's pro- vs anti-tumor roles unresolved
    • Single-lab mechanistic studies

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identities of the kinase that phosphorylates S770 and the E3 ligase mediating activity-dependent SP4 ubiquitylation, and how the multiple post-translational inputs are integrated to set distinct SP4 transcriptional outputs in vivo, remain unresolved.
  • No S770 kinase identified
  • No SP4 E3 ligase identified
  • Integration of phosphorylation, ubiquitylation, calpain cleavage, and O-GlcNAc not reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 11 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-112316 Neuronal System 7 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4
Partners
CRXOGTSP1SP3STIM1

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 SP4 functions as a transcriptional activator through its N-terminal glutamine-rich region, but unlike SP1, cannot act synergistically through adjacent binding sites. SP4 can serve as a target for SP1 activation domains in a superactivation assay, and SP4-mediated transcriptional activation can be repressed by SP3. Cotransfection experiments in Drosophila SL2 cells (lacking endogenous Sp factors), deletion/domain analysis, superactivation assay The Journal of biological chemistry High 7559627
1993 HF-1b (SP4) is a C2H2 zinc finger protein that binds sequence-specifically to the HF-1b/MEF-2 site in the MLC-2 promoter and functions as a transcriptional activator of the MLC-2 promoter in transient assays; it is a component of the endogenous HF-1b/MEF-2 binding activity in cardiac muscle cells. cDNA cloning, sequence-specific DNA binding assays, transient transfection reporter assays, characterization as component of endogenous cardiac nuclear binding activity Molecular and cellular biology High 8321243
1999 SP4 zinc finger domain binds selectively to the core GC-rich cis-elements of the ADH5/FDH minimal promoter but cannot activate transcription in Drosophila SL2 cells lacking endogenous Sp factors; SP4 represses SP1-mediated transcriptional activation by competing for the same binding sites. Drosophila SL2 cotransfection, mutagenesis of core cis-elements, competitive binding/competition assays The Journal of biological chemistry High 9867805
1994 HF-1b (SP4) element functions as a positive regulatory element required for ventricular chamber-specific expression of the MLC-2v gene in vivo; mutations in HF-1b/MEF-2 disrupt ventricular-specific expression in transgenic mice. Transgenic mouse lines with site-directed mutations in MLC-2-luciferase fusion genes Molecular and cellular biology High 8289802
1996 Sp4 is required for normal murine growth, viability, and male reproductive behavior; homozygous Sp4 knockout mice show postnatal lethality (two-thirds die within days), growth retardation, and failure of males to copulate despite intact spermatogenesis. Gene targeting by homologous recombination (knockout mice), in situ hybridization, Northern blot, behavioral observation Developmental biology High 8660867
2001 Sp4 null mice (deletion of N-terminal activation domain exons) show postnatal lethality, growth retardation, male breeding failure, smaller thymus/spleen/uterus in females, and delayed female sexual maturation, demonstrating physiological functions distinct from Sp1 and Sp3 despite overlapping DNA-binding specificity. Targeted gene deletion (knockout), histology, phenotypic characterization Genes to cells High 11532028
2002 SP4, but not SP1 or SP3, specifically activates the rod cGMP-phosphodiesterase beta-subunit (beta-PDE) promoter through the beta/GC element (-59/-49); this defines the first specific SP4 target gene. The beta/TA sequence within the -45/-23 region binds purified TBP and TFIIB cooperatively. Promoter deletion analysis, transcriptional activation assays, gel mobility shift assays with purified TBP and TFIIB, mutagenesis The Journal of biological chemistry High 11943774
2005 SP4 activates both the rod opsin and beta-PDE promoters in retinal neurons; SP1 and SP3 competitively repress SP4-mediated activation of the beta-PDE promoter. SP4 physically interacts with the photoreceptor transcription factor CRX via its zinc finger domain (and CRX homeodomain), and both SP4 and CRX are bound to the rod opsin and beta-PDE promoters in retinal chromatin. Transient transfection reporter assays, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), in situ hybridization, immunohistochemistry The Journal of biological chemistry High 15781457
2005 Reduced Sp4 expression (hypomorphic allele) causes hippocampal vacuolization, age-dependent decrease in neurotrophin-3 expression in dentate granule cells, and deficits in sensorimotor gating and contextual memory; all phenotypes are rescued by Cre-dependent restoration of Sp4 expression. Hypomorphic allele generation, Cre-dependent rescue strategy, in situ hybridization, behavioral testing (prepulse inhibition, contextual memory) Molecular psychiatry High 15558077
2006 HF-1b/SP4 is required in the cardiomyogenic lineage for Cx40 expression in the conduction system, and is separately required in neural crest-derived cells for atrial and atrioventricular function through regulation of the neurotrophin receptor trkC. Cre-Lox conditional knockout in ventricular and neural crest cell lineages, Cx40 immunohistochemistry, electrophysiological studies Developmental biology High 16430881
2007 Knockdown of SP4 in cerebellar granule neurons leads to increased dendritic branching and failure of activity-dependent pruning; overexpression of wild-type SP4 (but not a DNA-binding domain mutant) promotes dendritic pruning even without depolarization, demonstrating SP4 controls dendritic patterning via its transcriptional activity. RNA interference knockdown in dissociated culture and cerebellar cortex, overexpression with DNA-binding domain mutant, time-course morphological analysis, depolarization experiments Proceedings of the National Academy of Sciences of the United States of America High 17535924
2007 Glutamate receptor activation causes calpain-mediated cleavage of SP4 (and SP3) in neurons; purified calpain I cleaves SP4 into products retaining G-C/T binding activity, consistent with products observed in glutamate-treated neurons. SP4 (with SP3) is the predominant Sp-family factor in cerebral neurons (unlike glial cells which express SP1/SP3). Western blot, immunofluorescence, DNA-binding supershift assays, purified calpain I cleavage assay, calpain inhibitors, in vivo ischemia/reperfusion model Journal of neurochemistry High 17316402
2009 SP4 directly represses neurotrophin-3 (NT3) promoter activity in cerebellar granule neurons; SP4 overexpression reduces NT3 promoter activity and knockdown increases it; SP4 binds the NT3 promoter in vivo (ChIP). NT3 sequestration blocks dendritic branch addition upon SP4 knockdown, demonstrating SP4-dependent repression of NT3 limits dendritic branching. Promoter reporter assays, siRNA knockdown, ChIP, NT3 neutralization experiments, dendritic morphology analysis Molecular and cellular neurosciences High 19555762
2006 In cortical neurons, SP4 (and SP3) bind to tandemly repeated GC-boxes (-100 to -60 bp) in the NT-3 gene promoter B; dominant-negative SP4 and SP4 siRNA reduce NT-3 promoter activity, while SP4 overexpression increases it, identifying NT-3 as a direct SP4 target gene in neurons. EMSA, ChIP, dominant-negative constructs, siRNA knockdown, reporter assays Journal of neurochemistry High 17059557
2011 In rat cerebellar granule neurons, SP4 (but not SP1) is polyubiquitinated and degraded by the proteasome under non-depolarizing conditions; lithium stabilizes SP4 protein, providing a mechanism by which neuronal activity and lithium can control gene expression. Polyubiquitination assay, proteasome inhibitor treatment, Western blot in rat cerebellar granule neurons Bipolar disorders Medium 22017217
2014 Store-operated Ca2+ entry (SOCE), maximally activated under resting (hyperpolarized) conditions in cerebellar granule neurons, promotes ubiquitylation and proteasomal degradation of SP4. Knockdown of the ER Ca2+ sensor STIM1 blocks SP4 degradation; constitutively active STIM1 decreases SP4 abundance under depolarizing conditions, placing STIM1/SOCE upstream of SP4 protein stability. SOCE pharmacological inhibitors, STIM1 knockdown, constitutively active STIM1 expression, ubiquitylation assay, Western blot Science signaling High 24894994
2014 SP4 is phosphorylated at serine 770 (S770); this phosphorylation is reduced by membrane depolarization and by NMDA receptor stimulation via protein phosphatase 1/2A. A phosphomimetic S770 mutant impairs SP4-dependent maturation of cerebellar granule neuron primary dendrites, whereas a non-phosphorylatable mutant behaves like wild type. Site-directed mutagenesis (phosphomimetic and non-phosphorylatable mutants), NMDA stimulation/inhibition, protein phosphatase inhibitors, dendritic morphology analysis Journal of neurochemistry High 24475768
2014 SP4 activates transcription of Nervous Wreck 2 (Nwk2/Fchsd1); Nwk2 mediates SP4-dependent regulation of dendrite patterning and cell-surface expression of NMDAR subunit NR1. Knockdown of Nwk2 phenocopies SP4 knockdown (increased primary dendrites), exogenous Nwk2 rescues Sp4-depleted neuron dendrite number, and Nwk2 restores NR1 surface levels in SP4-depleted neurons. ChIP, reporter assays, siRNA knockdown, rescue by exogenous Nwk2, surface NR1 measurement, dendritic morphology analysis in cerebellar granule neurons Developmental neurobiology High 25045015
2013 SP4 regulates transcription of Na+/K+-ATPase subunit genes Atp1a1, Atp1a3, and Atp1b1 in neurons; SP4 silencing blocks KCl-induced upregulation of these genes and SP4 overexpression rescues TTX-induced suppression, establishing SP4 as a regulator coupling neuronal activity to energy consumption. EMSA and supershift assays, ChIP, promoter mutational analysis, overexpression, shRNA/RNAi, real-time qPCR, depolarization/TTX paradigms in primary neurons The European journal of neuroscience High 24219545
2014 SP4, but not SP1 or SP3, specifically regulates the AMPA receptor subunit Gria2 (GluA2) gene in neurons, functioning in parallel with NRF-1; other AMPA subunit genes (Gria1, 3, 4) are not regulated by SP4. EMSA and supershift assays, ChIP, promoter mutations, real-time qPCR, Western blot, overexpression and shRNA in primary neurons Biochimica et biophysica acta High 24576410
2015 SP4 specifically regulates transcription of GABAA receptor subunit genes Gabra1 (α1) and Gabra2 (α2), but not Gabra3 (α3), in neurons; SP4 binding sites on these genes are conserved across rats, humans, and mice. EMSA and supershift assays, ChIP, promoter mutational analysis, real-time qPCR, overexpression and shRNA of SP4, Western blot, functional assays in primary neurons Biochimica et biophysica acta High 26469128
2015 O-GlcNAc modification is present on SP4 (and SP3 but not SP2); the modification resides primarily in the N-terminal transactivation domain and functionally inhibits SP4 transcriptional activity. O-GlcNAc transferase (OGT) adds these modifications to SP4. O-GlcNAc enrichment of protein fractions, co-expression with OGT in E. coli, O-GlcNAc-specific antibody detection, deletion mutants, reporter gene assays, co-immunoprecipitation Biochemical and biophysical research communications Medium 26431879
2015 SP4 S770 phosphorylation inversely correlates with SP4 protein levels; a phosphomimetic truncated SP4 mutant significantly decreases SP4 steady-state levels while a non-phosphorylatable mutant shows increased stability in cultured cerebellar granule neurons, indicating S770 phosphorylation serves as a degradation signal. Phospho-mimetic and non-phosphorylatable mutant expression in rat cerebellar granule neurons, Western blot, stability analysis European neuropsychopharmacology Medium 26049820
2015 SP4 represses the 5-HT1A receptor gene promoter via a conserved -681 CpG site within an Sp1-like element; DNA methylation of this site attenuates SP4-induced repression, providing an epigenetic mechanism by which stress-induced methylation increases 5-HT1A expression by antagonizing SP4 repressor activity. Reporter assays with SP4 overexpression, site-directed mutagenesis, methylation-specific functional assays, ChIP-like binding assays Neurobiology of disease Medium 26188176
2006 SP4 null mutant mice show reduced cell proliferation specifically in the hippocampus (but not cerebellum) in the first postnatal week, decreased dendritic growth and arborization of dentate granule cells in vitro, and reduced dentate granule cell density and synaptophysin levels in adults, demonstrating SP4 predominantly regulates dentate gyrus development. Sp4 null knockout mice, cell proliferation assays, hippocampal cultures in vitro, immunohistochemistry for synaptophysin Genes, brain, and behavior High 16899055
2005 COX-2 inhibitors (celecoxib, nimesulfide, NS-398) cause enhanced proteasome-dependent ubiquitination and degradation of SP1 and SP4 proteins (but not SP2 or SP3) in colon cancer cells, leading to decreased VEGF expression through GC-rich proximal promoter elements. Western blot (protein levels), mRNA analysis, proteasome inhibitor (gliotoxin), ubiquitination assay, VEGF promoter deletion analysis, transfection in SW-480 and other colon cancer cells Molecular pharmacology Medium 15883203
2017 Methylmercury (MeHg) activates a p38/Sp1-Sp4/HDAC4/BDNF pathway: p38 MAPK phosphorylation increases SP1 and SP4 protein expression, which drive HDAC4 gene expression; HDAC4 then binds the BDNF promoter IV to reduce BDNF mRNA, promoting neuronal death. Silencing p38, SP1, or SP4 reverses MeHg-induced HDAC4 upregulation. Western blot, siRNA knockdown of p38/Sp1/Sp4/HDAC4, ChIP (HDAC4 on BDNF promoter IV), pharmacological p38 blockade, cell death assay Frontiers in neuroscience Medium 28154524
2019 SP4 positively regulates expression of the pain-transducing channel TRPV1 in dorsal root ganglion (DRG) neurons; Sp4+/- mice with 50% reduction in Sp4 show reduced DRG TRPV1 mRNA, reduced capsaicin responses, and fail to develop persistent inflammatory thermal hyperalgesia, mechanical hypersensitivity, or persistent neuropathic cold/mechanical hypersensitivity. Sp4 heterozygous mutant mice, qPCR for TRPV1 mRNA, capsaicin neuronal response assays, inflammatory and neuropathic pain behavioral models PloS one Medium 30811405
2020 SP4 directly binds SP-binding elements in the serine racemase (Srr) promoter and controls its constitutive expression in neurons; overexpression of SP4 increases and knockdown decreases Srr mRNA and SR protein; mutation of SP-binding elements in the promoter significantly decreases luciferase activity. Luciferase reporter assays, site-directed mutagenesis, ChIP, overexpression and siRNA knockdown in Neuro-2a cells Biochimica et biophysica acta. Gene regulatory mechanisms Medium 32603878
2025 In CuCl2-treated neurons, SP4 co-localizes with histone deacetylase HD11 on the BCL-W promoter, causing histone H3 hypo-acetylation and transcriptional repression of anti-apoptotic BCL-W; siRNA against SP4 prevents HD11 binding to BCL-W and its downregulation. Double knockdown of SP1 and SP4 completely reverses CuCl2-induced cell death. ChIP (SP4 and HD11 on BCL-W promoter), histone acetylation analysis, siRNA knockdown, co-localization assay, cell death assay in SH-SY5Y and cortical neurons Neurochemistry international Medium 40185277
2024 SP4 directly activates PHF14 gene transcription by binding to the PHF14 promoter region, promoting Wnt/β-catenin signaling and ESCC progression; PHF14 overexpression rescues the anti-proliferative effects of SP4 knockdown. ChIP (SP4 on PHF14 promoter), luciferase reporter assays, siRNA knockdown of SP4, overexpression of PHF14 rescue, Western blot for Wnt/β-catenin pathway Molecular cancer research Medium 37768180
2024 SRSF3 binds SP4 exon 3 to promote inclusion, generating a long SP4 isoform (L-SP4) that suppresses RCC malignancy by transcriptionally activating SMAD4; the short isoform (S-SP4, lacking the transactivation domain) does not suppress malignancy. NXF1 facilitates this SRSF3-mediated alternative splicing of SP4. SRSF3 overexpression, RNA splicing analysis, L-SP4 vs S-SP4 isoform functional assays, SMAD4 reporter assays, NXF1 knockdown Biochimica et biophysica acta. Molecular cell research / iScience Medium 39222664 40792019
2001 The mouse Sp4 gene promoter lacks a TATA box, resides in a CpG island, and contains multiple Sp1 and MAZ binding sites; ectopic expression of Sp1 and MAZ (but not Sp3) suppresses Sp4 promoter activity in a dose-dependent manner, indicating autoregulatory control. Promoter deletion analysis, transfection assays, transcription start site mapping Gene Medium 11245974
2010 Reduced SP4 expression in Sp4 hypomorphic mice decreases the level of the NR1 subunit of NMDA receptors in hippocampus, as shown by western blot and immunohistochemistry; these mice also display impaired spatial learning/memory and markedly reduced long-term potentiation (LTP) in hippocampal CA1. Western blot, immunohistochemistry, LTP recordings in hippocampal slices, spatial learning/memory behavioral assays in hypomorphic mice Human molecular genetics Medium 20634195
2015 Restoration of Sp4 specifically in forebrain GABAergic inhibitory neurons rescues ketamine-induced hyperlocomotion in Sp4 hypomorphic mice, but restoration in forebrain excitatory neurons does not; neither rescue restores sensorimotor gating, placing SP4 function in GABAergic neurons upstream of ketamine sensitivity. Cre-LoxP cell-type-specific rescue (vGAT-Cre vs. CamKII-Cre), behavioral testing for locomotion and prepulse inhibition The international journal of neuropsychopharmacology High 26037489
2009 SP4 is constitutively bound to the GC-box in the argininosuccinate synthetase (AS) promoter under both normal and arginine-depleted conditions in melanoma cells (ChIP assay); SP4 functions as a positive transcriptional regulator of AS expression together with c-Myc. Chromatin immunoprecipitation (ChIP), c-Myc overexpression, HIF-1α cotransfection, reporter assays Molecular cancer therapeutics Medium 19934275
2022 SP4 regulates PTTG1IP (PBF) gene transcription by binding to SP4 response elements in the -212 to +7 bp PTTG1IP promoter; overexpression of SP4 increases PTTG1IP transcription and protein in HeLa cells. Luciferase reporter assay, EMSA, SP4 overexpression in HeLa cells DNA and cell biology Low 36383136
2023 EZH2 epigenetically activates SP4 expression in human peritoneal mesothelial cells via regulation of DNMT3B-mediated CpG methylation of the SP4 promoter (-170 bp site) in IL-6/sIL-6R signaling, leading to increased VEGF production and angiogenesis. EZH2 overexpression/silencing, DNMT3B and SP4 expression measurement, methylation analysis of SP4 promoter CpG site, VEGF measurement, tube formation assay, in vivo 5/6Nx rat model International journal of medical sciences Medium 36619221

Source papers

Stage 0 corpus · 89 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Functional analyses of the transcription factor Sp4 reveal properties distinct from Sp1 and Sp3. The Journal of biological chemistry 193 7559627
1996 Sp4, a member of the Sp1-family of zinc finger transcription factors, is required for normal murine growth, viability, and male fertility. Developmental biology 156 8660867
2009 Resistance to arginine deiminase treatment in melanoma cells is associated with induced argininosuccinate synthetase expression involving c-Myc/HIF-1alpha/Sp4. Molecular cancer therapeutics 115 19934275
2005 Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expression in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins. Molecular pharmacology 101 15883203
1999 Sp3 and Sp4 can repress transcription by competing with Sp1 for the core cis-elements on the human ADH5/FDH minimal promoter. The Journal of biological chemistry 99 9867805
2022 Solvent Precipitation SP3 (SP4) Enhances Recovery for Proteomics Sample Preparation without Magnetic Beads. Analytical chemistry 82 35848328
2016 Specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 are non-oncogene addiction genes in cancer cells. Oncotarget 82 26967243
1993 A novel, tissue-restricted zinc finger protein (HF-1b) binds to the cardiac regulatory element (HF-1b/MEF-2) in the rat myosin light-chain 2 gene. Molecular and cellular biology 77 8321243
2005 Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization. Molecular psychiatry 72 15558077
2004 Peroxisome proliferator-activated receptor gamma-dependent activation of p21 in Panc-28 pancreatic cancer cells involves Sp1 and Sp4 proteins. Endocrinology 69 15345676
1994 Positive regulatory elements (HF-1a and HF-1b) and a novel negative regulatory element (HF-3) mediate ventricular muscle-specific expression of myosin light-chain 2-luciferase fusion genes in transgenic mice. Molecular and cellular biology 66 8289802
2007 Transcription factor Sp4 regulates dendritic patterning during cerebellar maturation. Proceedings of the National Academy of Sciences of the United States of America 65 17535924
2006 Impaired postnatal development of hippocampal dentate gyrus in Sp4 null mutant mice. Genes, brain, and behavior 58 16899055
2014 Store-operated calcium entry promotes the degradation of the transcription factor Sp4 in resting neurons. Science signaling 54 24894994
2015 Chronic mild stress and antidepressant treatment alter 5-HT1A receptor expression by modifying DNA methylation of a conserved Sp4 site. Neurobiology of disease 53 26188176
2009 Transcription factor SP4 is a susceptibility gene for bipolar disorder. PloS one 52 19401786
2001 Complex phenotype of mice homozygous for a null mutation in the Sp4 transcription factor gene. Genes to cells : devoted to molecular & cellular mechanisms 51 11532028
2007 Glutamate receptor activation evokes calpain-mediated degradation of Sp3 and Sp4, the prominent Sp-family transcription factors in neurons. Journal of neurochemistry 44 17316402
2011 The transcription factor SP4 is reduced in postmortem cerebellum of bipolar disorder subjects: control by depolarization and lithium. Bipolar disorders 43 22017217
2009 Purification and concentration of a rhamnolipid biosurfactant produced by Pseudomonas aeruginosa SP4 using foam fractionation. Bioresource technology 41 19716289
2005 Sp4 is expressed in retinal neurons, activates transcription of photoreceptor-specific genes, and synergizes with Crx. The Journal of biological chemistry 40 15781457
2017 p38/Sp1/Sp4/HDAC4/BDNF Axis Is a Novel Molecular Pathway of the Neurotoxic Effect of the Methylmercury. Frontiers in neuroscience 38 28154524
2010 Reduced NMDAR1 expression in the Sp4 hypomorphic mouse may contribute to endophenotypes of human psychiatric disorders. Human molecular genetics 35 20634195
2005 Regulation of expression of the chorionic gonadotropin/luteinizing hormone receptor gene in the human myometrium: involvement of specificity protein-1 (Sp1), Sp3, Sp4, Sp-like proteins, and histone deacetylases. The Journal of clinical endocrinology and metabolism 33 15788387
2002 The rod cGMP-phosphodiesterase beta-subunit promoter is a specific target for Sp4 and is not activated by other Sp proteins or CRX. The Journal of biological chemistry 33 11943774
2022 Coexisting autoantibodies against transcription factor Sp4 are associated with decreased cancer risk in patients with dermatomyositis with anti-TIF1γ autoantibodies. Annals of the rheumatic diseases 32 36008132
2015 GlyT-1 Inhibition Attenuates Attentional But Not Learning or Motivational Deficits of the Sp4 Hypomorphic Mouse Model Relevant to Psychiatric Disorders. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 32 25907107
2014 From pre-DP, post-DP, SP4, and SP8 Thymocyte Cell Counts to a Dynamical Model of Cortical and Medullary Selection. Frontiers in immunology 30 24592261
1991 Isolation of cDNA for a Xenopus sperm-specific basic nuclear protein (SP4) and evidence for expression of SP4 mRNA in primary spermatocytes. Experimental cell research 29 2015853
2014 Increased SP4 and SP1 transcription factor expression in the postmortem hippocampus of chronic schizophrenia. Journal of psychiatric research 28 25175639
2013 Regulation of Na(+)/K(+)-ATPase by neuron-specific transcription factor Sp4: implication in the tight coupling of energy production, neuronal activity and energy consumption in neurons. The European journal of neuroscience 28 24219545
2007 Sp3 and sp4 transcription factor levels are increased in brains of patients with Alzheimer's disease. Neuro-degenerative diseases 28 17934324
2013 Reduced expression of SP1 and SP4 transcription factors in peripheral blood mononuclear cells in first-episode psychosis. Journal of psychiatric research 27 23941741
2009 Sp4-dependent repression of neurotrophin-3 limits dendritic branching. Molecular and cellular neurosciences 27 19555762
2006 Regulation of neurotrophin-3 gene transcription by Sp3 and Sp4 in neurons. Journal of neurochemistry 26 17059557
2013 Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia. PloS one 25 23823008
2006 Distinct roles of HF-1b/Sp4 in ventricular and neural crest cells lineages affect cardiac conduction system development. Developmental biology 24 16430881
2006 R5020 and RU486 act as progesterone receptor agonists to enhance Sp1/Sp4-dependent gene transcription by an indirect mechanism. Molecular endocrinology (Baltimore, Md.) 24 17192405
2001 Characterization and promoter analysis of the mouse gene for transcription factor Sp4. Gene 24 11245974
2006 lin-35/Rb and the CoREST ortholog spr-1 coordinately regulate vulval morphogenesis and gonad development in C. elegans. Developmental biology 22 17070797
2014 Transcription factor Sp4 regulates expression of nervous wreck 2 to control NMDAR1 levels and dendrite patterning. Developmental neurobiology 21 25045015
2005 Knockout of the neural and heart expressed gene HF-1b results in apical deficits of ventricular structure and activation. Cardiovascular research 21 15907824
2021 Over-representation of potential SP4 target genes within schizophrenia-risk genes. Molecular psychiatry 20 34750502
2014 Phosphorylation of the transcription factor Sp4 is reduced by NMDA receptor signaling. Journal of neurochemistry 19 24475768
2014 Specificity protein 4 (Sp4) regulates the transcription of AMPA receptor subunit GluA2 (Gria2). Biochimica et biophysica acta 19 24576410
2022 Metabolomics-Based Profiling, Antioxidant Power, and Uropathogenic Bacterial Anti-Adhesion Activity of SP4TM, a Formulation with a High Content of Type-A Proanthocyanidins. Antioxidants (Basel, Switzerland) 14 35883725
2020 Sp4 controls constitutive expression of neuronal serine racemase and NF-E2-related factor-2 mediates its induction by valproic acid. Biochimica et biophysica acta. Gene regulatory mechanisms 13 32603878
2015 Transcription factor SP4 phosphorylation is altered in the postmortem cerebellum of bipolar disorder and schizophrenia subjects. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 13 26049820
2015 Specificity protein 4 (Sp4) transcriptionally regulates inhibitory GABAergic receptors in neurons. Biochimica et biophysica acta 13 26469128
1999 A PEA3 site flanked by SP1, SP4, and GATA sites positively regulates the differentiation-dependent expression of Brachyury in embryonal carcinoma P19 cells. Biochemical and biophysical research communications 12 9920775
2019 Transcription factor Sp4 is required for hyperalgesic state persistence. PloS one 11 30811405
2005 SP4, a novel anti-cyclin D1 rabbit monoclonal antibody, is a highly sensitive probe for identifying mantle cell lymphomas bearing the t(11;14)(q13;q32) translocation. Applied immunohistochemistry & molecular morphology : AIMM 11 16280660
2015 O-GlcNAc modification of Sp3 and Sp4 transcription factors negatively regulates their transcriptional activities. Biochemical and biophysical research communications 10 26431879
2023 EZH2 promotes angiogenesis in peritoneal dialysis by epigenetically activating SP4 expression in the IL-6/sIL-6R signalling pathway. International journal of medical sciences 9 36619221
2024 Differences in Protein Capture by SP3 and SP4 Demonstrate Mechanistic Insights of Proteomics Cleanup Techniques. Journal of proteome research 8 39161190
2021 Thalidomide Suppresses Angiogenesis Through the Signal Transducer and Activator of Transcription 3/SP4 Signaling Pathway in the Peritoneal Membrane. Frontiers in physiology 8 34539435
2012 Genetics and expression analysis of the specificity protein 4 gene (SP4) in patients with Alzheimer's disease and frontotemporal lobar degeneration. Journal of Alzheimer's disease : JAD 8 22614877
2024 The Novel A-Type Proanthocyanidin-Rich Phytocomplex SP4™ Acts as a Broad-Spectrum Antiviral Agent against Human Respiratory Viruses. International journal of molecular sciences 7 39000477
2020 Characterisation of pectin and optimization of pectinase enzyme from novel Streptomyces fumigatiscleroticus VIT-SP4 for drug delivery and concrete crack-healing applications: An eco-friendly approach. Saudi journal of biological sciences 7 33304164
2007 Association of the Asn306Ser variant of the SP4 transcription factor and an intronic variant in the beta-subunit of transducin with digenic disease. Molecular vision 7 17356515
2022 Dual bio-degradative pathways of di-2-ethylhexyl phthalate by a novel bacterium Burkholderia sp. SP4. World journal of microbiology & biotechnology 6 36526923
2018 Ketamine independently modulated power and phase-coupling of theta oscillations in Sp4 hypomorphic mice. PloS one 6 29513708
1999 New phenolic antioxidants of PYA and PYE class increase the resistance S. cerevisiae strain SP4, its SOD- and catalase-deficient mutants to lipophilic oxidants. Folia microbiologica 6 11097024
2025 [Electroacupuncture of "Gongsun" (SP4) alleviates oxidative stress injury and promotes normal follicle development by regulating keap1/Nrf2/HO-1 signaling in rats with premature ovarian insufficiency]. Zhen ci yan jiu = Acupuncture research 5 39961757
2024 SP4 Facilitates Esophageal Squamous Cell Carcinoma Progression by Activating PHF14 Transcription and Wnt/Β-Catenin Signaling. Molecular cancer research : MCR 5 37768180
2015 Restoration of Sp4 in Forebrain GABAergic Neurons Rescues Hypersensitivity to Ketamine in Sp4 Hypomorphic Mice. The international journal of neuropsychopharmacology 5 26037489
2015 Role played by the SP4 gene in schizophrenia and major depressive disorder in the Han Chinese population. The British journal of psychiatry : the journal of mental science 5 26450579
2009 [Association of Sp4 gene polymorphism with pathological tortuosity of internal carotid arteries]. Kardiologiia 5 19656107
2021 Overlapping and non-overlapping roles of the class-I histone deacetylase-1 corepressors LET-418, SIN-3, and SPR-1 in Caenorhabditis elegans embryonic development. Genes & genomics 4 33740234
1995 Structure of genes for sperm-specific nuclear basic protein (SP4) in Xenopus laevis. Biochimica et biophysica acta 4 8541323
2022 The FOXP4-AS1/miR-3130-3p/SP4 feedback loop is associated with prostate cancer. Cellular and molecular biology (Noisy-le-Grand, France) 3 37114256
2021 Truncation of 3' CCND1 by t(11;22) leads to negative SP4 CCND1 immunohistochemistry in blastoid mantle cell lymphoma. Blood advances 3 33570637
1981 Placenta-associated plasma protein-A (PAPP-A, SP4) in trophoblastic tumours. Acta pathologica et microbiologica Scandinavica. Section A, Pathology 3 6164245
2025 Sp4/HD11 and Sp1/HAT-p300 complexes induce apoptotic cell death in CuCl2-treated neurons by modulating histone acetylation on BCL-W and BAX promoters. Neurochemistry international 2 40185277
2025 NXF1 suppresses progression of endometrial cancer by interacting with the SRSF3 to regulate SP4 splicing. iScience 2 40792019
2024 SRSF3 suppresses RCC tumorigenesis and progression via regulating SP4 alternative splicing. Biochimica et biophysica acta. Molecular cell research 2 39222664
2023 SPR-1/CoREST facilitates the maternal epigenetic reprogramming of the histone demethylase SPR-5/LSD1. Genetics 2 36655746
2022 The genetic polymorphisms in the SP4 gene and the risk of gastric cancer. Future oncology (London, England) 2 36346067
2017 Cloning, expression and identification of KTX-Sp4, a selective Kv1.3 peptidic blocker from Scorpiops pococki. Cell & bioscience 2 29142737
2001 In vivo roles of RORalpha and Sp4 in the regulation of murine prosaposin gene. DNA and cell biology 2 11879571
1995 The occurrence of a gene-encoded variant of nuclear basic protein (SP4) in sperm of Xenopus laevis. Biochemical and biophysical research communications 2 7677774
2024 The Relationship Between Anti-Cell Division Cycle and Apoptosis Regulator 1 Autoantibodies, Anti-Sp4 Autoantibodies, and Cancer in Anti-Transcription Intermediary Factor 1γ-Positive Dermatomyositis. ACR open rheumatology 1 39370373
2026 Differential SP4 expression and HSP60 abundance in buccal swabs from patients with schizophrenia. Science advances 0 41779859
2025 Anti-Sp4 and anti-CCAR1 autoantibodies in UK vs US patients with adult and juvenile-onset anti-TIF1γ-positive myositis. Rheumatology (Oxford, England) 0 39514366
2025 Partial rescue of schizophrenia-related phenotypes in young adult Sp4 hypomorphic mice. Journal of psychiatric research 0 40339225
2024 Differences in Protein Capture by SP3 and SP4 Demonstrate Mechanistic Insights of Proteomics Clean-up Techniques. bioRxiv : the preprint server for biology 0 38559195
2024 Efficacy of the combination of water aerobics and metacognitive training on psychological and physical health variables and their relationship with SP1 and SP4 biomarkers in people with psychosis: a study protocol. Frontiers in psychology 0 38919799
2022 Sp4 Regulates PTTG1IP Gene Transcription and Expression. DNA and cell biology 0 36383136
1996 Relative amounts of basic nuclear proteins SP4 and SP5 in Xenopus laevis sperm correlate with gene copy number. Development, growth & differentiation 0 37281109

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