Affinage

SPDEF

SAM pointed domain-containing Ets transcription factor · UniProt O95238

Length
335 aa
Mass
37.5 kDa
Annotated
2026-06-10
77 papers in source corpus 46 papers cited in narrative 46 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

SPDEF (PDEF) is an epithelium-specific ETS transcription factor that serves as a master regulator of secretory cell differentiation across airway, intestinal, gastric, and ocular epithelia (PMID:19759516, PMID:19549527, PMID:20801882, PMID:23665202). Its ETS domain binds GGAT-containing DNA, and structural work shows that Ser308 and Gln311 confer preferential recognition of thymine at the +4 position, distinguishing SPDEF's sequence specificity from other ETS factors (PMID:15882048). In the intestine SPDEF acts downstream of ATOH1/Math1, amplifying ATOH1-dependent transcription to drive terminal differentiation of goblet and Paneth cells while inhibiting crypt proliferation (PMID:19549527, PMID:19786015, PMID:28174757). In the airway it operates downstream of STAT6 in the IL-13 signaling cascade, where it cooperates with NKX2-1/TTF-1 and induces a secretory gene program (Foxa3, Agr2, Gcnt3, Muc5ac, Muc5b) that produces goblet cell metaplasia, mucin hypersecretion, and Th2 inflammation (PMID:17347682, PMID:19759516, PMID:21275604, PMID:25866971, PMID:29579396, PMID:31596609). SPDEF is also required for gastric antral mucous gland maturation and for conjunctival goblet cell differentiation, with its loss producing mucosal hyperplasia and a dry-eye phenotype (PMID:20801882, PMID:23665202). SPDEF activity is gated post-translationally by CDK11-mediated phosphorylation that triggers ubiquitin-proteasome degradation, an event antagonized by GADD45α/γ (PMID:26885618), and transcriptionally by TGFβ/Smad3 repression, GATA6 repression, and promoter DNA methylation (PMID:25377551, PMID:24472151, PMID:37900138). In cancer SPDEF is context-dependent: it suppresses prostate metastasis by directly repressing MMP9/MMP13 and CCL2 and inducing E-cadherin, and blocks proliferation by interfering with FOXM1 auto-regulation (PMID:20550708, PMID:22761428, PMID:23449978, PMID:25254494, PMID:29477409); in colorectal cancer it binds β-catenin to displace it from TCF1/TCF3 and silence Wnt target genes, acting as a tumor suppressor (PMID:23376423, PMID:28390865). Conversely, SPDEF acts oncogenically in other contexts, where AR-driven expression promotes MAD1 degradation and MYC activation in ER-negative breast cancer and it transcriptionally upregulates targets including BIRC5, GALNT7, and ELOVL2 (PMID:30217192, PMID:37633945, PMID:42263887, PMID:41420920).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2005 High

    Defining the structural basis of SPDEF's DNA recognition established how this ETS factor achieves its distinct target specificity, separating it functionally from other ETS proteins.

    Evidence X-ray crystallography of the SPDEF ETS domain bound to the PSA promoter site at 2.0 Å

    PMID:15882048

    Open questions at the time
    • Structure of full-length SPDEF and its pointed/linker domains not solved
    • No structural basis for protein-protein interactions (β-catenin, NKX2-1) defined
  2. 2005 Medium

    Identification of NKX-3.1 as a binding partner that suppresses SPDEF transactivation showed early that SPDEF activity is modulated by homeodomain co-regulators.

    Evidence Yeast two-hybrid domain mapping plus transactivation reporter assays in prostate tumor cells

    PMID:15523673

    Open questions at the time
    • Physiological relevance of NKX-3.1 suppression in vivo not tested
    • Genome-wide effect of the interaction unknown
  3. 2007 High

    Linking SPDEF to airway secretory differentiation revealed its role as an inducer of goblet cell metaplasia downstream of STAT6 and in partnership with TTF-1.

    Evidence Transgenic mouse overexpression, protein interaction and reporter assays, in vivo goblet cell analysis

    PMID:17347682

    Open questions at the time
    • Direct promoter targets in airway not mapped in this study
    • Whether TTF-1 interaction is required for all downstream genes unclear
  4. 2009 High

    Genetic loss-of-function across intestine, lung, and colon established SPDEF as the obligatory terminal differentiation factor for goblet and Paneth lineages, acting downstream of ATOH1/Math1 and inducing a defined secretory gene set.

    Evidence Spdef knockout mice, lineage tracing, transgenic gain-of-function, microarray profiling, shRNA in LS174T cells

    PMID:19549527 PMID:19759516 PMID:19786015

    Open questions at the time
    • Direct vs indirect target distinction not fully resolved at this stage
    • Mechanism of secretory progenitor arrest unknown
  5. 2010 High

    Mapping direct promoter targets (p21, MMP9) and the gastric mucous-gland requirement defined SPDEF as both a cell-cycle/invasion suppressor and a tissue-protective differentiation factor.

    Evidence EMSA/ChIP/promoter deletion for p21, promoter reporter and zymography for MMP9, Spdef KO gastric histology

    PMID:20139077 PMID:20550708 PMID:20801882

    Open questions at the time
    • Context determinants of suppressive vs permissive targeting not defined
    • Gastric secretory target network incompletely mapped
  6. 2012 High

    In vivo metastasis models with effector rescue established SPDEF as a metastasis suppressor in prostate cancer acting through MMP9/MMP13 repression.

    Evidence Experimental metastasis models with stable expression/knockdown and MMP9/MMP13 re-expression rescue

    PMID:22761428

    Open questions at the time
    • Whether MMP repression is direct transcriptional or indirect not fully resolved here
    • Relative contribution of additional effectors unquantified
  7. 2013 High

    SPDEF's tumor-suppressive program was extended to direct E-cadherin induction and a DNA-binding-independent β-catenin/TCF interaction, and to a conjunctival differentiation requirement, defining its dual transcriptional and protein-interaction modes.

    Evidence ChIP and reporter for E-cadherin with siRNA rescue; Co-IP of SPDEF with β-catenin and multiple CRC mouse models; Spdef KO conjunctival/dry-eye phenotype

    PMID:23376423 PMID:23449978 PMID:23665202 PMID:23764000

    Open questions at the time
    • Structural basis of β-catenin/SPDEF interaction undefined
    • Switch between DNA-binding and protein-tethering modes unexplained
  8. 2014 High

    Identification of upstream regulators (Smad3/TGFβ, GATA6, p53 variant) established that SPDEF is a tightly controlled transcriptional node, while its repression of FOXM1 auto-regulation explained its anti-proliferative output.

    Evidence Smad3 ChIP and Tgfbr2 conditional KO; GATA6 ChIP and Gata6/Spdef double KO rescue; p53-PRD knock-in mice; transgenic SPDEF prostate models with Foxm1 rescue

    PMID:24472151 PMID:25254494 PMID:25377551 PMID:25429397

    Open questions at the time
    • Integration of competing upstream inputs in a single tissue not modeled
    • How FOXM1 repression coexists with FOXM1 positive feedback in other tissues unexplained
  9. 2015 High

    SPDEF was shown to be required not only for goblet cell formation but for the downstream Th2 inflammatory cascade, connecting epithelial differentiation to allergic immune recruitment.

    Evidence Spdef KO and conditional expression with HDM challenge, cytokine profiling, immune cell flow cytometry

    PMID:25866971

    Open questions at the time
    • Direct vs goblet-cell-secondary induction of Il33/Tslp/Csf2 not separated
    • Mechanism of DC recruitment downstream of SPDEF unknown
  10. 2016 High

    Defining post-translational and epigenetic control (CDK11p58 phosphorylation/degradation antagonized by GADD45; G9A/DNMT promoter silencing) and the requirement for ATOH1 co-occupancy clarified how SPDEF abundance and activity are set.

    Evidence Kinase/ubiquitination/Co-IP assays for CDK11p58-GADD45; engineered ZF/dCas9 epigenetic editing of the SPDEF promoter; ATOH1 ChIP-seq and epistasis

    PMID:26885618 PMID:28011616 PMID:28174757

    Open questions at the time
    • E3 ligase acting on phosphorylated SPDEF not identified
    • Endogenous signals controlling SPDEF promoter methylation in development unknown
  11. 2017 High

    Mechanistic dissection of the AR-SPDEF axis and the β-catenin displacement mechanism showed SPDEF can repress targets (TGFBI) and induce quiescence through DNA-binding-independent enhancer eviction.

    Evidence AR antagonist/patient tissue analysis for TGFBI; Co-IP, ChIP displacement, colonoids, domain-mapped truncations for β-catenin/TCF

    PMID:28390865 PMID:28811384

    Open questions at the time
    • Selectivity for cell-cycle vs stem-cell enhancers mechanistically unexplained
    • Generalizability of DNA-binding-independent mode to other tissues untested
  12. 2018 Medium

    A series of studies revealed SPDEF's context-dependent oncogenic outputs (AR-driven MAD1 degradation/MYC activation, FoxM1 positive feedback) and additional secretory targets (TFF3, Muc5b regulation), broadening the catalogue of direct targets and partners.

    Evidence Co-IP/ChIP for AR-PDEF-MAD1; reciprocal luciferase for SPDEF-FoxM1 feedback; ChIP/reporter for TFF3 and miR-448/DOT1L; Spdef/Scnn1b mouse mucin analysis

    PMID:29555969 PMID:29579396 PMID:29848555 PMID:30076647 PMID:30217192 PMID:33328586

    Open questions at the time
    • Determinants that flip SPDEF between tumor-suppressive and oncogenic programs not defined
    • Several target relationships from single-lab Co-IP/ChIP without reciprocal validation
  13. 2020 High

    CRISPR knockout in primary human bronchial epithelium provided dose-dependent causal confirmation that SPDEF is required for IL-13-driven MUC5AC, goblet differentiation, and impaired mucociliary clearance.

    Evidence CRISPR/Cas9 sgRNA in primary HBECs with mucin, differentiation, and mucociliary clearance readouts

    PMID:31596609

    Open questions at the time
    • Direct airway promoter targets not mapped genome-wide here
    • Therapeutic windows for SPDEF inhibition in disease untested
  14. 2025 Medium

    Expansion of SPDEF's oncogenic target repertoire across multiple carcinomas (GALNT7, ELOVL2, BIRC5, NR4A1, S100A16) consolidated its role as a context-dependent transcriptional driver of proliferation, lipid reprogramming, and survival.

    Evidence ChIP/luciferase with site-directed mutagenesis and effector rescue across breast, renal, lung, HNSCC, kidney fibrosis, and pancreatic models

    PMID:34667150 PMID:37633945 PMID:38520747 PMID:39736520 PMID:41420920 PMID:42263887

    Open questions at the time
    • Why the same factor activates pro-tumor targets in some tissues and represses them in others remains unresolved
    • Several target claims rest on single-lab evidence without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • The central unresolved question is what molecular context (cofactors, chromatin state, post-translational modification, partner availability) switches SPDEF between its tumor-suppressive/differentiation program and its oncogenic program in the same DNA-binding factor.
  • No unifying model linking partner choice (β-catenin, AR, FOXM1, MAD1) to output direction
  • Genome-wide context-specific cistromes not compared across tissues
  • Structural basis of partner switching unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 1
Partners
ARCDK11BCTNNB1FOXM1GADD45AMAD1L1NKX2-1SMAD3

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 SPDEF protein interacts with the C-terminal domain of thyroid transcription factor 1 (TTF-1/NKX2-1) and activates transcription of genes expressed selectively in airway epithelial cells (Sftpa, Scgb1a1, Foxj1, Sox17). Expression of SPDEF in respiratory epithelium caused goblet cell hyperplasia with induction of acidic and neutral mucins in vivo, and SPDEF induction after allergen/IL-13 exposure was dependent on STAT6. Transgenic mouse overexpression, protein-protein interaction assays, transcriptional reporter assays, in vivo goblet cell differentiation analysis The Journal of clinical investigation High 17347682
2009 SPDEF is required for pulmonary goblet cell differentiation: deletion of mouse Spdef abolishes goblet cells in tracheal/laryngeal submucosal glands and in conducting airway epithelium after allergen exposure. SPDEF in Clara cells drives goblet cell differentiation (without cell proliferation) and induces downstream genes Foxa3, Agr2, and Gcnt3. SPDEF and FOXA3 are colocalized in goblet cells of patients with chronic lung diseases. Spdef knockout mice, cell-lineage tracing, inducible transgenic expression in Clara cells, gene expression profiling, immunofluorescence colocalization The Journal of clinical investigation High 19759516
2009 SPDEF acts downstream of Math1 (ATOH1) in intestinal epithelium to promote terminal differentiation of goblet and Paneth cells. Loss of Spdef in mice severely impairs maturation of goblet and Paneth cells and leads to accumulation of immature secretory progenitors. SPDEF positively and negatively regulates a subset of goblet and Paneth cell genes including Cryptdins, Mmp7, Ang4, Kallikreins, and Muc2. Spdef knockout mice, histological analysis, DNA microarray profiling, genetic epistasis (Spdef downstream of Math1) Gastroenterology High 19549527
2009 SPDEF is required for activation of goblet cell-associated genes (AGR2, MUC2, RETLNB, SPINK4) in colon cancer cells treated with Notch/gamma-secretase inhibitor. Transgenic SPDEF expression expands intestinal goblet cells while reducing Paneth, enteroendocrine, and absorptive enterocytes, and inhibits proliferation of intestinal crypt cells without inducing apoptosis. shRNA knockdown in LS174T cells with Notch inhibition, intestinal transgenic mouse expression, proliferation and apoptosis assays Experimental cell research High 19786015
2005 The 2.0 Å crystal structure of the PDEF/SPDEF ETS domain in complex with its natural high-affinity DNA binding site in the PSA promoter reveals that the serine at position 308 and glutamine at position 311 confer preferential binding to thymine at the +4 position of its binding site, explaining SPDEF's distinct DNA sequence recognition compared to other ETS family members. X-ray crystallography at 2.0 Å resolution, protein-DNA complex structure determination Biochemistry High 15882048
2005 NKX-3.1 interacts with PDEF/SPDEF and suppresses PDEF-mediated transactivation of the PSA promoter. The interaction requires the homeodomain and a C-terminal tyrosine-rich 21 amino acid sequence of NKX-3.1, and the ETS domain plus a linker region between the ETS and pointed domains of PDEF. Deletion of the C-terminal 21 amino acids of NKX-3.1 abolishes suppression of PDEF transactivation in prostate tumor cells. Yeast two-hybrid deletion analysis, transactivation reporter assays in prostate tumor cells Journal of cellular biochemistry Medium 15523673
2007 Reduced PDEF/SPDEF expression in prostate cancer cells causes morphological change, increased migration and invasiveness reminiscent of EMT, and triggers a transcriptional program of genes involved in TGFβ pathway, migration, invasion, adhesion, and epithelial dedifferentiation. siRNA/shRNA knockdown in prostate cancer cell lines, migration/invasion assays, transcriptional profiling Cancer research Medium 17483333
2006 PDEF/SPDEF directly represses the survivin promoter and reduces endogenous survivin expression in breast cancer cells. shRNA-mediated silencing of PDEF upregulates survivin and increases cell growth and resistance to drug-induced apoptosis; ectopic PDEF expression inhibits survivin promoter activity. Loss of PDEF in MCF-7 cells enhanced xenograft tumor formation in vivo. Promoter-luciferase reporter assay, shRNA knockdown, Western blot, mouse xenograft model Breast cancer research and treatment Medium 16897429
2010 PDEF/SPDEF directly regulates p21/CIP1 expression by binding to an Ets DNA binding site at -2118 bp of the p21 promoter, as demonstrated by EMSA, ChIP, and promoter deletion analysis. PDEF-mediated p21 induction blocks cell cycle progression at G1/S and reduces Cdk2 activity. siRNA silencing of p21 in PDEF-expressing cells rescued cell growth in vitro and tumor growth in vivo. Promoter deletion analysis, EMSA, ChIP, siRNA rescue, orthotopic mammary tumor model The Journal of biological chemistry High 20139077
2010 PDEF/SPDEF downregulates MMP9 promoter activity, suppresses MMP9 mRNA expression, and reduces MMP9 activity in prostate cancer cells. Re-introduction of PDEF reduces invasiveness in 3D cultures and decreases FAK phosphorylation, cell migration, colony formation, and cellular invasiveness; PDEF knockdown has the opposite effects. Promoter reporter assay, mRNA expression, gelatin zymography, 3D culture invasion, migration assays, Western blot (FAK phosphorylation) Molecular cancer Medium 20550708
2010 Spdef is required for terminal maturation of antral mucous gland cells in the stomach, regulating expression of Muc6 and Tff2 and the number of secretory granules. Spdef knockout mice develop antral mucosal hyperplasia preceded by inflammatory cell infiltration, indicating SPDEF protects against gastric inflammation. Spdef knockout mice, histology, immunohistochemistry, in situ hybridization, transcriptional profiling The Journal of biological chemistry High 20801882
2011 SPDEF-specific knockdown reduces IL-13-induced MUC5AC expression in human airway epithelial cells, associated with decreased AGR2 and CLCA1 expression, and enhanced FOXA2 expression. The repression of STAT6 inhibits SPDEF and MUC5AC induction by IL-13, placing SPDEF downstream of STAT6 in the IL-13 signaling cascade. siRNA knockdown in human airway epithelial cells, qRT-PCR, Western blot, STAT6 inhibition experiments Cell communication & adhesion Medium 21275604
2012 SPDEF suppresses tumor metastasis in vivo: stable SPDEF expression in PC3-Luc cells reduces disseminated tumor cell survival at secondary sites and micrometastasis formation; SPDEF knockdown in LNCaP-Luc cells increases metastasis. SPDEF selectively downregulates MMP9 and MMP13 in prostate cancer cells, and forced MMP9 or MMP13 expression rescues the invasive phenotype in SPDEF-expressing cells, indicating SPDEF's anti-invasive effects are mediated in part through MMP9/MMP13 suppression. Experimental metastasis models (tail vein injection), stable SPDEF expression and shRNA knockdown, in vitro migration/invasion rescue assays with MMP9/MMP13 re-expression The Journal of biological chemistry High 22761428
2013 Spdef null mice completely lack conjunctival goblet cells, display increased corneal fluorescein staining and tear volume consistent with dry eye, and show downregulation of goblet cell genes (Muc5ac, Tff1, Gcnt3) along with upregulation of keratinization and proinflammatory genes. Spdef is required for conjunctival goblet cell differentiation. Spdef knockout mice, histology, fluorescein staining, tear volume measurement, microarray analysis The American journal of pathology High 23665202
2013 SPDEF interacts with β-catenin to block its transcriptional activity in colorectal cancer cell lines, resulting in lower levels of cyclin D1 and c-MYC. SPDEF inhibits β-catenin target gene expression in mouse colon tumors. Loss of SPDEF is observed in ~85% of human colorectal tumors, and Spdef(-/-) mice develop ~3-fold more colon tumors than controls in multiple CRC models. Co-immunoprecipitation of SPDEF with β-catenin, reporter assays, Spdef(-/-);Apc(Min/+) and AOM/DSS mouse models, inducible SPDEF expression in established adenomas Gastroenterology High 23376423
2013 PDEF/SPDEF promotes luminal epithelial lineage-specific gene expression in the mammary gland. PDEF transcription is inversely regulated by ER and GATA3. PDEF is essential for luminal breast cancer cell survival and is required in models of endocrine resistance. shRNA knockdown, gene expression profiling, luminal breast cancer cell viability assays, endocrine resistance models Cancer cell Medium 23764000
2013 SPDEF directly occupies the E-cadherin promoter and acts as a transcriptional inducer of E-cadherin in prostate cancer cells, as shown by ChIP and luciferase reporter assay. Stable SPDEF expression increases E-cadherin; SPDEF knockdown decreases E-cadherin. siRNA-mediated knockdown of E-cadherin blocks SPDEF's anti-migratory/anti-invasive effects, indicating E-cadherin is a key effector of SPDEF's metastasis-suppressive activity. ChIP assay, luciferase reporter assay, siRNA rescue experiments, stable overexpression and knockdown, migration/invasion assays The Journal of biological chemistry High 23449978
2014 SPDEF inhibits prostate carcinogenesis by binding to and suppressing the transcriptional activity of the Foxm1 promoter, specifically interfering with Foxm1 auto-regulation at the -745/-660 bp region. This reduces expression of Foxm1 target genes (Cdc25b, Cyclin B1, Cyclin A2, Plk-1, AuroraB, CKS1, Topo2alpha). Re-expression of Foxm1 rescues proliferation in SPDEF-positive cancer cells. Transgenic mice with prostate-specific SPDEF loss/gain-of-function, promoter binding assays, mRNA/protein expression analysis, Foxm1 rescue experiments in vitro and in vivo PLoS genetics High 25254494
2014 TGFβ signaling restricts conjunctival goblet cell differentiation by repressing Spdef transcription: Smad3 binds two distinct sites on the Spdef promoter and TGFβ treatment inhibits SPDEF activation. Loss of TGFβ receptor II in keratin 14+ epithelia causes conjunctival goblet cell expansion with increased SPDEF expression. Gain-of-function Spdef in K14+ cells causes ectopic goblet cell formation in the eyelid and cornea. Conditional Tgfbr2 knockout mice, Smad3 ChIP on Spdef promoter, TGFβ treatment of K14+ cells, inducible Spdef transgenic mice Development (Cambridge, England) High 25377551
2014 A p53(Arg) variant (proline-to-arginine substitution in the proline-rich domain, PRD) displays higher affinity binding to and activation of the SPDEF promoter compared to p53(Pro), resulting in enhanced SPDEF and Bcl-2 expression and increased mucous cell metaplasia in mice with targeted p53 PRD replacement. Promoter reporter assays, targeted replacement of p53 PRD in mice on two genetic backgrounds, mucous cell quantification, SPDEF/Bcl-2 expression analysis Nature communications Medium 25429397
2015 SPDEF is required for goblet cell differentiation and pulmonary Th2 inflammation in response to house dust mite (HDM): both are decreased in neonatal and adult Spdef(-/-) mice. SPDEF expression promotes DC recruitment, induces Il33, Csf2, Tslp, Ccl20, and subsequently recruits Th2 lymphocytes, group 2 innate lymphoid cells, and eosinophils to the lung. Spdef knockout mice with HDM challenge, neonatal conditional SPDEF/FOXA3 expression, airway hyperresponsiveness measurement, cytokine/chemokine expression profiling, immune cell flow cytometry The Journal of clinical investigation High 25866971
2016 ATOH1 directly regulates Spdef in the adult intestine (ChIP-seq), and SPDEF amplifies ATOH1-dependent transcription but cannot independently initiate transcription of ATOH1 target genes. Functional epistasis experiments in transgenic mice establish that SPDEF acts downstream of ATOH1 to specify intestinal secretory cell differentiation. ChIP-seq, RNA-seq, cell sorting, transgenic mice with epistasis experiments Cellular and molecular gastroenterology and hepatology High 28174757
2016 CDK11p58 directly interacts with and phosphorylates SPDEF on serine residues, leading to ubiquitination and degradation of SPDEF through the proteasome pathway. CDK11p58-mediated SPDEF degradation increases prostate cancer cell migration and invasion. GADD45α and GADD45γ directly interact with CDK11p58, inhibit its kinase activity, thereby preventing SPDEF phosphorylation and degradation, and reducing cancer cell migration. Co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, siRNA knockdown, migration/invasion assays, proteasome inhibitor experiments Oncotarget High 26885618
2016 Targeted epigenetic silencing of the SPDEF promoter using zinc finger and CRISPR/dCas9 platforms fused to repressors (KRAB, DNA methyltransferases, histone methyltransferase G9A) reduces SPDEF mRNA and protein expression in human lung epithelial cells, with concomitant inhibition of downstream mucus-related genes AGR2 and MUC5AC. G9A-mediated silencing was mitotically stable. Epigenetic editing with engineered zinc finger and dCas9-repressor fusions, mRNA/protein expression, mitotic stability assay American journal of physiology. Lung cellular and molecular physiology Medium 28011616
2017 SPDEF is a transcriptional repressor of TGFBI: AR signaling stimulates SPDEF activity, which represses TGFBI expression. ADT/AR antagonism or TGFBI overexpression inhibits SPDEF activity and enhances prostate cancer cell proliferation and EMT. In prostate cancer patient tissue samples, ADT reduces nuclear SPDEF abundance and increases TGFBI production. Cell line experiments, SPDEF overexpression/knockdown, AR antagonist treatment, patient tissue analysis before/after ADT, xenograft models with TGFBI knockdown Science signaling Medium 28811384
2017 SPDEF disrupts β-catenin binding to TCF1 and TCF3 via protein-protein interaction (independent of SPDEF DNA-binding capacity), displacing β-catenin from enhancer regions of cell cycle genes (but not stem cell activity genes), inducing quiescence in CRC cells. This was confirmed in mouse and human normal and tumor-derived colonoids and CRC cell lines. Co-immunoprecipitation, ChIP assay, inducible SPDEF expression in CRC cells and colonoids, truncated SPDEF constructs, subcutaneous xenografts in NSG mice, transgenic mouse CRC models Gastroenterology High 28390865
2018 SPDEF recognizes the CCL2 promoter and transcriptionally represses CCL2 expression in prostate cancer cells. AR signaling inhibits CCL2 through a SPDEF-mediated mechanism; inactivation of AR reduces SPDEF, which elevates CCL2 and promotes EMT. Ectopic SPDEF expression reduced EMT and rescued CCL2 expression changes. Promoter binding assays (ChIP/luciferase implied by mechanistic claim), SPDEF overexpression/knockdown, EMT marker analysis, prostate cancer cell lines with spontaneous EMT, patient tissue analysis Biochimica et biophysica acta. Molecular basis of disease Medium 29477409
2018 SPDEF regulates baseline Muc5b expression in respiratory epithelia (nasopharynx and airways but not olfactory Bowman glands). Spdef-deficient mice exhibit region-specific reductions in Muc5b, nasopharyngeal plugs, and reduced tracheal mucociliary clearance. In Scnn1b-transgenic (mucoobstructive) mice, loss of Spdef reduces Muc5ac but not Muc5b, demonstrating distinct regulatory roles for the two mucins. Spdef knockout mice, Spdef x Scnn1b-Tg double mutant mice, BAL analysis, mucociliary clearance measurement, Muc5ac/Muc5b quantification American journal of respiratory cell and molecular biology High 29579396
2018 CDK11B promotes ubiquitin-proteasome-mediated degradation of SPDEF in hepatocellular carcinoma (HCC) cells, as shown by Co-IP and ubiquitination-IP assays. SPDEF binds the miR-448 promoter (by ChIP) and activates miR-448 transcription, which in turn inhibits DOT1L expression, promoting self-renewal of HCC stem cells. Co-immunoprecipitation, ubiquitination-IP, ChIP assay, sphere formation assay, xenograft tumor model Cancer gene therapy Medium 33328586
2018 SPDEF directly binds the TFF3 promoter (by ChIP) and activates TFF3 transcription in intestinal epithelial cells. Nucleotide-mediated upregulation of SPDEF induces TFF3 expression, promoting wound healing and intestinal barrier function through TFF3-mediated PI3K/Akt, ERK1/2, p38, and JAK/STAT signaling pathways. ChIP assay, promoter reporter assay, wound healing assay, TEER measurement, IPEC-J2 cell model, in vivo piglet weaning model Scientific reports Medium 29555969
2018 AR transcriptionally activates PDEF/SPDEF expression in ER-negative breast cancer cells, and PDEF promotes MAD1 protein degradation, thereby upregulating MYC-mediated gene transcription. Co-immunoprecipitation and ChIP assays validated AR-PDEF and PDEF-MAD1 regulatory interactions. Simultaneous inhibition of AR and PDEF further suppressed tumor proliferation compared to AR inhibition alone. Co-immunoprecipitation, ChIP assay, Western blot, RT-qPCR, immunofluorescence, in vitro and in vivo tumor proliferation assays Molecular cancer Medium 30217192
2018 PDEF/SPDEF directly regulates cytokeratin 18 (CK18) transcription through the GGAT motif within CK18's putative promoter region (ChIP-seq). PDEF upregulates epithelial/luminal differentiation genes and suppresses Twist1 and stemness/EMT-related genes. CK18 knockdown increases Twist1, suggesting PDEF regulates Twist1 in part via CK18. Loss of PDEF and gain of Twist1 occur during prostate cancer progression in the TRAMP mouse model. ChIP-seq analysis, microarray/GSEA, CK18 siRNA knockdown, TRAMP mouse model, clinical cohort expression analysis Molecular cancer research : MCR Medium 29848555
2019 SPDEF function is regulated by DNA methylation of its promoter: hypermethylation of SPDEF CpG islands in CRPC cell lines (PC3, DU145) silences SPDEF expression, while castrate-sensitive LNCaP cells show hypomethylated SPDEF promoter. Treatment with demethylating agent 5-aza-2'-deoxycytidine or DNMT1/3A/3B siRNA knockdown partially restores SPDEF expression and decreases cell migration and invasion. Bisulfite sequencing, 5-aza-dC treatment, DNMT siRNA knockdown, wound-healing assay, Boyden-chamber invasion assay, qRT-PCR, immunoblotting Frontiers in endocrinology Medium 37900138
2020 CRISPR/Cas9-mediated targeting of SPDEF in primary human bronchial epithelial cells (HBECs) proportionally decreases MUC5AC expression in IL-13-stimulated cells; near-complete SPDEF knockout abolishes IL-13-induced MUC5AC expression, goblet cell differentiation, and IL-13-induced impairment of mucociliary clearance. CRISPR/Cas9 sgRNA-rCas9 electroporation in primary HBECs, MUC5AC quantification, goblet cell differentiation assay, mucociliary clearance measurement American journal of respiratory cell and molecular biology High 31596609
2021 SPDEF directly binds to the NR4A1 promoter and transcriptionally activates NR4A1 expression in HNSCC cells, as shown by ChIP-qPCR and dual luciferase reporter assay. SPDEF overexpression inhibits HNSCC cell viability, colony formation, and induces G0/G1 arrest; NR4A1 silencing blocks the suppressive effect of SPDEF. SPDEF suppresses AKT, MAPK, and NF-κB signaling via NR4A1. ChIP-qPCR, dual luciferase reporter assay, NR4A1 siRNA rescue, xenograft tumor growth model, cell cycle analysis International journal of oral science Medium 34667150
2023 SPDEF directly binds the GALNT7 promoter (ChIP assay) and transcriptionally activates GALNT7 expression in luminal breast cancer cells. SPDEF overexpression enhances proliferation, migration, invasion, and stemness of luminal BC cells; the effect is mediated by GALNT7, as GALNT7 silencing reverses SPDEF-driven phenotypes. ChIP assay, dual luciferase reporter assay, shRNA GALNT7 knockdown rescue, in vitro functional assays, in vivo xenograft, serum GALNT7 ELISA in patients Cell death & disease Medium 37633945
2024 SPDEF transcriptionally activates NR4A1 in the kidney: SPDEF overexpression improves UUO-induced renal fibrosis in mice and TGF-β1-induced fibrosis in HK-2 cells by upregulating NR4A1. NR4A1 knockdown exacerbates UUO-induced fibrosis. Adenoviral NR4A1 knockdown in mouse kidney, SPDEF overexpression in UUO model, TGF-β1 fibrosis model in HK-2 cells, fibrosis marker analysis Molecular medicine (Cambridge, Mass.) Medium 39736520
2024 SPDEF binds to the -141 bp site of the ELOVL2 promoter (dual-luciferase reporter + ChIP-qPCR + site-directed mutagenesis abolishing activation) and transcriptionally activates ELOVL2, driving lipid metabolic reprogramming and tumor progression in clear cell renal cell carcinoma. Altering ELOVL2 expression partially rescues or mimics SPDEF-driven phenotypes. Dual-luciferase reporter assay, ChIP-qPCR, promoter site-directed mutagenesis, ELOVL2 rescue experiments, lipid accumulation assays Biochimica et biophysica acta. Molecular basis of disease Medium 42263887
2025 SPDEF transcriptionally activates BIRC5 (survivin) in non-small cell lung cancer cells by directly binding the BIRC5 promoter (luciferase and ChIP assays). SPDEF depletion impairs invasion, migration, and clonogenicity while inducing apoptosis; BIRC5 reconstitution rescues these phenotypes. BIRC5 activates the Wnt/β-catenin pathway in NSCLC cells. Luciferase reporter assay, ChIP assay, siRNA/shRNA knockdown, BIRC5 reconstitution rescue, xenograft tumor model Mutation research Medium 41420920
2018 SPDEF regulates MUC5AC expression in a STAT6-dependent manner in the airway: IL-13 induces SPDEF via STAT6, and SPDEF knockdown reduces IL-13-induced MUC5AC. In OVA-allergic mice, Lactobacillus rhamnosus 76 alleviated mucus secretion by downregulating STAT6/p-STAT6 and SPDEF protein expression, placing SPDEF downstream of STAT6 in mucus regulatory cascade. OVA mouse allergic model, IL-13-stimulated 16HBE cells, Western blot, RT-qPCR, LR76 treatment Immunobiology Low 37515878
2009 PDEF/SPDEF is required for growth inhibition and reduced migration of colon cancer cells; re-expression in colon cancer cells alters cell cycle (increased G1/S populations) and increases apoptosis. ChIP studies show p21 and urokinase plasminogen activator (uPA) are direct PDEF transcriptional targets in colon cancer cells. PDEF re-expression in colon cancer cells, cell cycle analysis, apoptosis assay, migration assay, ChIP for p21 and uPA promoters Journal of cellular biochemistry Medium 19830706
2014 GATA6 directly occupies a locus 40 kb upstream of the Spdef transcription start site in human Caco-2 cells, consistent with direct transcriptional repression of Spdef. Conditional Gata6 knockout mice upregulate Spdef, and additional deletion of Spdef (Gata6/Spdef double KO) rescues the crypt cell proliferation defect of Gata6 KO mice, establishing Spdef as a downstream effector of GATA6-regulated crypt proliferation. GATA6 ChIP in Caco-2 cells, conditional Gata6 KO mice, Gata6/Spdef double KO mice, crypt proliferation analysis BMC molecular biology Medium 24472151
2016 miR-125b directly targets SPDEF at the post-transcriptional level (validated by dual-luciferase reporter assay). In airway epithelial cells, miR-125b overexpression decreases SPDEF protein, inhibiting goblet cell differentiation and mucus hypersecretion; intranasal delivery of miR-125b mimic in HDM-allergic mice decreased SPDEF protein levels and goblet cell differentiation. Dual-luciferase reporter assay (3'UTR), miR-125b mimic overexpression in cells and intranasal delivery in mice, Western blot, goblet cell quantification European journal of pharmacology Medium 27112664
2018 SPDEF forms a positive feedback regulatory loop with FoxM1 in gastric cancer cells: SPDEF binds the FoxM1 promoter (dual luciferase assay) and activates FoxM1 transcription; FoxM1 also binds the SPDEF promoter to upregulate SPDEF. FoxM1 overexpression rescues SPDEF siRNA-mediated proliferation inhibition in gastric cancer cells. Dual luciferase reporter assay, siRNA knockdown, rescue overexpression experiments, xenograft model Journal of cellular biochemistry Medium 30076647
2019 PDEF/SPDEF modulates YAP1 activity in prostate cancer cells: PDEF expression increases phospho-YAP1 (Ser127) and cytoplasmic YAP1 localization, and GSEA reveals inhibition of YAP1 target genes, suggesting cross-talk between PDEF and the Hippo signaling pathway. PDEF transfection in PC3 and DU145 cells, phospho-YAP1 Western blot, immunofluorescence localization, GSEA of mRNA expression data Pharmaceuticals (Basel, Switzerland) Low 31835563
2025 SPDEF drives pancreatic adenocarcinoma progression by transcriptionally activating S100A16: SPDEF enhances S100A16 transcription (mechanistic analysis) which activates the PI3K/AKT signaling pathway to promote migration, proliferation, and invasion of PAAD cells. TCGA data analysis, in vitro cell proliferation/migration/apoptosis assays, transcriptomic analysis of SPDEF target genes, S100A16 rescue experiments Biomolecules & biomedicine Low 38520747

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production. The Journal of clinical investigation 352 19759516
2007 SPDEF regulates goblet cell hyperplasia in the airway epithelium. The Journal of clinical investigation 234 17347682
2009 The ets-domain transcription factor Spdef promotes maturation of goblet and paneth cells in the intestinal epithelium. Gastroenterology 219 19549527
2009 SAM pointed domain ETS factor (SPDEF) regulates terminal differentiation and maturation of intestinal goblet cells. Experimental cell research 170 19786015
2015 Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation. The Journal of clinical investigation 141 25866971
2018 ELF3, ELF5, EHF and SPDEF Transcription Factors in Tissue Homeostasis and Cancer. Molecules (Basel, Switzerland) 99 30200227
2011 Interleukin-13 induces mucin 5AC production involving STAT6/SPDEF in human airway epithelial cells. Cell communication & adhesion 82 21275604
2013 Spdef null mice lack conjunctival goblet cells and provide a model of dry eye. The American journal of pathology 81 23665202
2014 SPDEF inhibits prostate carcinogenesis by disrupting a positive feedback loop in regulation of the Foxm1 oncogene. PLoS genetics 77 25254494
2007 Reduced PDEF expression increases invasion and expression of mesenchymal genes in prostate cancer cells. Cancer research 77 17483333
2016 Transcriptional Regulation by ATOH1 and its Target SPDEF in the Intestine. Cellular and molecular gastroenterology and hepatology 74 28174757
2005 Novel role for PDEF in epithelial cell migration and invasion. Cancer research 72 16357167
2013 PDEF promotes luminal differentiation and acts as a survival factor for ER-positive breast cancer cells. Cancer cell 57 23764000
2018 Androgen deprivation therapy-induced epithelial-mesenchymal transition of prostate cancer through downregulating SPDEF and activating CCL2. Biochimica et biophysica acta. Molecular basis of disease 54 29477409
2017 Loss of SPDEF and gain of TGFBI activity after androgen deprivation therapy promote EMT and bone metastasis of prostate cancer. Science signaling 52 28811384
2010 Loss of PDEF, a prostate-derived Ets factor is associated with aggressive phenotype of prostate cancer: regulation of MMP 9 by PDEF. Molecular cancer 51 20550708
2016 Targeted epigenetic editing of SPDEF reduces mucus production in lung epithelial cells. American journal of physiology. Lung cellular and molecular physiology 44 28011616
2012 The transcription factor SPDEF suppresses prostate tumor metastasis. The Journal of biological chemistry 44 22761428
2014 TGFβ signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium. Development (Cambridge, England) 42 25377551
2010 Requirement of the epithelium-specific Ets transcription factor Spdef for mucous gland cell function in the gastric antrum. The Journal of biological chemistry 42 20801882
2013 SPDEF functions as a colorectal tumor suppressor by inhibiting β-catenin activity. Gastroenterology 41 23376423
2006 Prostate-derived Ets transcription factor (PDEF) downregulates survivin expression and inhibits breast cancer cell growth in vitro and xenograft tumor formation in vivo. Breast cancer research and treatment 39 16897429
2017 SPDEF Induces Quiescence of Colorectal Cancer Cells by Changing the Transcriptional Targets of β-catenin. Gastroenterology 38 28390865
2017 Aberrant DNA methylation and expression of SPDEF and FOXA2 in airway epithelium of patients with COPD. Clinical epigenetics 38 28450970
2020 Efficient RNP-directed Human Gene Targeting Reveals SPDEF Is Required for IL-13-induced Mucostasis. American journal of respiratory cell and molecular biology 35 31596609
2011 Prostate derived ETS factor (PDEF): a putative tumor metastasis suppressor. Cancer letters 31 21764212
2010 Transcriptional regulation of p21/CIP1 cell cycle inhibitor by PDEF controls cell proliferation and mammary tumor progression. The Journal of biological chemistry 31 20139077
2021 SPDEF suppresses head and neck squamous cell carcinoma progression by transcriptionally activating NR4A1. International journal of oral science 29 34667150
2014 A genetic variant of p53 restricts the mucous secretory phenotype by regulating SPDEF and Bcl-2 expression. Nature communications 28 25429397
2018 Role of Spdef in the Regulation of Muc5b Expression in the Airways of Naive and Mucoobstructed Mice. American journal of respiratory cell and molecular biology 27 29579396
2009 PDEF is a negative regulator of colon cancer cell growth and migration. Journal of cellular biochemistry 27 19830706
2005 Analysis of the 2.0 A crystal structure of the protein-DNA complex of the human PDEF Ets domain bound to the prostate specific antigen regulatory site. Biochemistry 27 15882048
2018 CRISPR/Cas9-mediated knockout of the PDEF gene inhibits migration and invasion of human gastric cancer AGS cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 30576937
2016 miR-125b inhibits goblet cell differentiation in allergic airway inflammation by targeting SPDEF. European journal of pharmacology 26 27112664
2020 Double Agent: SPDEF Gene with Both Oncogenic and Tumor-Suppressor Functions in Breast Cancer. Cancer management and research 24 32547225
2019 Glutamate Ionotropic Receptor Kainate Type Subunit 3 (GRIK3) promotes epithelial-mesenchymal transition in breast cancer cells by regulating SPDEF/CDH1 signaling. Molecular carcinogenesis 24 30977227
2019 A high AR:ERα or PDEF:ERα ratio predicts a sub-optimal response to tamoxifen therapy in ERα-positive breast cancer. Cancer chemotherapy and pharmacology 24 31297554
2005 Structural and functional analysis of domains mediating interaction between NKX-3.1 and PDEF. Journal of cellular biochemistry 22 15523673
2018 AR-PDEF pathway promotes tumour proliferation and upregulates MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative breast cancer. Molecular cancer 21 30217192
2021 Resveratrol inhibits MUC5AC expression by regulating SPDEF in lung cancer cells. Phytomedicine : international journal of phytotherapy and phytopharmacology 18 34139546
2018 SPDEF is overexpressed in gastric cancer and triggers cell proliferation by forming a positive regulation loop with FoxM1. Journal of cellular biochemistry 18 30076647
2023 SPDEF enhances cancer stem cell-like properties and tumorigenesis through directly promoting GALNT7 transcription in luminal breast cancer. Cell death & disease 16 37633945
2019 ZBTB46, SPDEF, and ETV6: Novel Potential Biomarkers and Therapeutic Targets in Castration-Resistant Prostate Cancer. International journal of molecular sciences 15 31181727
2011 PDEF in prostate cancer. The Prostate 15 21796651
2009 Proteomic analysis of a PDEF Ets transcription factor-interacting protein complex. Journal of proteome research 15 19203193
2018 Nucleotide-mediated SPDEF modulates TFF3-mediated wound healing and intestinal barrier function during the weaning process. Scientific reports 14 29555969
2020 Involvement of CDK11B-mediated SPDEF ubiquitination and SPDEF-mediated microRNA-448 activation in the oncogenicity and self-renewal of hepatocellular carcinoma stem cells. Cancer gene therapy 13 33328586
2018 Examination of methylation changes of VIM, CXCR4, DOK7, and SPDEF genes in peripheral blood DNA in breast cancer patients. Indian journal of cancer 13 30829272
2013 High SPDEF may identify patients who will have a prolonged response to androgen deprivation therapy. The Prostate 13 24375440
2013 The transcription factor sterile alpha motif (SAM) pointed domain-containing ETS transcription factor (SPDEF) is required for E-cadherin expression in prostate cancer cells. The Journal of biological chemistry 12 23449978
2023 Lactobacillus rhamnosus 76 alleviates airway inflammation in ovalbumin-allergic mice and improves mucus secretion by down-regulating STAT6/SPDEF pathway. Immunobiology 11 37515878
2018 Allele-Specific Methylation of SPDEF: A Novel Moderator of Psychosocial Stress and Substance Abuse. The American journal of psychiatry 11 30525907
2016 Signatures of prostate-derived Ets factor (PDEF) in cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 11 27612480
2012 AZGP1 and SPDEF mRNA expression differentiates breast carcinoma from ovarian serous carcinoma. Virchows Archiv : an international journal of pathology 11 23242172
2018 Prostate-Derived Ets Factor (PDEF) Inhibits Metastasis by Inducing Epithelial/Luminal Phenotype in Prostate Cancer Cells. Molecular cancer research : MCR 10 29848555
2016 GADD45α and γ interaction with CDK11p58 regulates SPDEF protein stability and SPDEF-mediated effects on cancer cell migration. Oncotarget 10 26885618
2022 The role of SPDEF in cancer: promoter or suppressor. Neoplasma 8 35951453
2018 Clinical significance of PDEF factor expression and its relation to androgen receptor in ER- breast cancer. Histopathology 8 29969155
2014 Spdef deletion rescues the crypt cell proliferation defect in conditional Gata6 null mouse small intestine. BMC molecular biology 8 24472151
2012 PDEF downregulates stathmin expression in prostate cancer. International journal of oncology 8 22378487
2023 Regulation of SPDEF expression by DNA methylation in advanced prostate cancer. Frontiers in endocrinology 7 37900138
2004 Developmental expression pattern of D-ets4, the Drosophila homologue of human Pdef. Gene expression patterns : GEP 6 15567727
2024 SPDEF ameliorates UUO-induced renal fibrosis by transcriptional activation of NR4A1. Molecular medicine (Cambridge, Mass.) 5 39736520
2025 Gut microbiota regulates intestinal goblet cell response and mucin production by influencing the TLR2-SPDEF axis in an enteric parasitic infection. Mucosal immunology 4 40164286
2019 Prostate-Derived ETS Factor (PDEF) Modulates Yes Associated Protein 1 (YAP1) in Prostate Cancer Cells: A Potential Cross-Talk between PDEF and Hippo Signaling. Pharmaceuticals (Basel, Switzerland) 4 31835563
2010 PDEF and PDEF-induced proteins as candidate tumor antigens for T cell and antibody-mediated immunotherapy of breast cancer. Immunologic research 4 19763888
2021 Bee Venom Prevents Mucin 5AC Production through Inhibition of AKT and SPDEF Activation in Airway Epithelia Cells. Toxins 3 34822557
2025 CpG dinucleotide methylation of the SPDEF gene as a blood-based epigenetic biomarker for prostate cancer diagnosis. BMC urology 2 40457266
2021 Structural analysis of the peptidoglycan editing factor PdeF from Bacillus cereus ATCC 14579. Biochemical and biophysical research communications 2 34735878
2026 Epigenetic Dysregulation of the NKX2-1/SPDEF Axis Drives Persistent Goblet Cell Differentiation and Epithelial Barrier Dysfunction in Chronic Obstructive Pulmonary Disease. Respirology (Carlton, Vic.) 1 41559520
2024 SPDEF drives pancreatic adenocarcinoma progression via transcriptional upregulation of S100A16 and activation of the PI3K/AKT signaling pathway. Biomolecules & biomedicine 1 38520747
2017 Clinical significance of PSMA, TERT and PDEF in malignant tumors of the prostate. European review for medical and pharmacological sciences 1 28829509
2026 The RNA-binding protein Imp1 promotes a Spdef transcriptional program and mucus fucosylation during necrotizing enterocolitis. bioRxiv : the preprint server for biology 0 41659389
2026 The RNA-binding protein Imp1 promotes a Spdef transcriptional program and mucus fucosylation during necrotizing enterocolitis. American journal of physiology. Gastrointestinal and liver physiology 0 42242905
2026 SPDEF promotes clear cell renal cell carcinoma progression by transcriptionally activating ELOVL2-mediated lipid metabolic reprogramming. Biochimica et biophysica acta. Molecular basis of disease 0 42263887
2025 Assessing the Tumor Suppressive Impact and Regulatory Mechanisms of SPDEF Expression in Breast Cancer. Cancers 0 41228349
2025 SPDEF-mediated BIRC5 transcriptional activation enhances non-small cell lung cancer progression. Mutation research 0 41420920

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