Affinage

NKX3-1

Homeobox protein Nkx-3.1 · UniProt Q99801

Length
234 aa
Mass
26.4 kDa
Annotated
2026-04-29
100 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NKX3-1 is an androgen-regulated, prostate-specific homeodomain transcription factor that functions as a haploinsufficient tumor suppressor by maintaining epithelial differentiation, protecting against oxidative and genotoxic stress, and restraining oncogenic signaling. It binds a TAAGTA consensus sequence to repress targets such as TWIST1, RAMP1, and VEGF-C, and activates others including IGFBP-3, recruiting chromatin-modifying cofactors (HDAC1, p300/PCAF, G9a) to regulate histone acetylation and methylation at target loci (PMID:10871372, PMID:17602165, PMID:27339988, PMID:19258508). NKX3-1 enhances DNA damage repair by activating ATM kinase and topoisomerase I, promoting homology-directed repair that suppresses TMPRSS2-ERG rearrangements, and protects mitochondrial function through HSPA9-mediated mitochondrial import and regulation of electron transport chain gene transcription (PMID:23890999, PMID:17234752, PMID:25977336, PMID:33893149). Its protein stability is tightly controlled by stabilizing phosphorylation (CK2 at Thr89/Thr93; Pim-1) and destabilizing phosphorylation (DYRK1B at Ser185; LIMK2), with inflammatory cytokine-induced Ser196 phosphorylation triggering TOPORS-mediated ubiquitination, while nuclear PTEN opposes degradation by dephosphorylating Ser185 (PMID:16581776, PMID:25777618, PMID:18757402, PMID:31213464).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    Establishing NKX3-1 as a prostate-specific, androgen-regulated homeoprotein answered what tissue and hormonal context governs its expression, framing all subsequent functional studies.

    Evidence RNase protection, in situ hybridization, castration, and androgen-stimulation experiments in mouse prostate and LNCaP cells

    PMID:9142502 PMID:9537602

    Open questions at the time
    • Cis-regulatory elements mediating androgen regulation not mapped
    • Protein-level regulation not addressed
  2. 1999 High

    Targeted disruption showing prostatic hyperplasia and dysplasia even in heterozygotes established NKX3-1 as a haploinsufficient tumor suppressor, resolving its loss-of-function phenotype.

    Evidence Nkx3.1 knockout mice with histopathology and tissue recombinants

    PMID:10215624 PMID:11002344

    Open questions at the time
    • Molecular targets mediating growth suppression unknown
    • Whether loss alone drives cancer or requires cooperating events
  3. 2000 High

    Identification of the TAAGTA consensus binding site and demonstration of transcriptional repression defined NKX3-1's DNA-binding specificity and mode of transcriptional action.

    Evidence Binding site selection, EMSA, and luciferase reporter assays

    PMID:10871372

    Open questions at the time
    • Genome-wide binding sites not mapped
    • Cofactors mediating repression unidentified
  4. 2002 High

    Genetic cooperativity between Nkx3.1 and Pten loss, mediated by synergistic Akt activation, placed NKX3-1 within the PI3K-AKT tumor suppression pathway.

    Evidence Compound mutant mice with phospho-Akt Western blot and histopathology

    PMID:11854455

    Open questions at the time
    • Whether NKX3-1 directly modulates PTEN expression or signaling not resolved
    • Downstream Akt effectors responsible for cooperativity unidentified
  5. 2005 High

    Demonstration that Nkx3.1 loss deregulates oxidative stress enzymes and increases 8-OHdG revealed a protective role against oxidative DNA damage, a key early cancer-promoting event.

    Evidence Gene expression profiling and 8-OHdG immunohistochemistry in Nkx3.1 null and compound mutant mice

    PMID:16061659

    Open questions at the time
    • Direct versus indirect transcriptional control of antioxidant genes not distinguished
    • Functional rescue by restoring individual target genes not tested
  6. 2006 High

    Multiple studies in 2006 defined NKX3-1's cofactor interactions and post-translational regulation: CK2α′ phosphorylation at Thr89/Thr93 stabilizes the protein; NKX3-1 associates with HDAC1 to increase p53 acetylation; and structural analysis of a hereditary mutation (T164A) demonstrated homeodomain destabilization.

    Evidence In vitro kinase assays with MS, Co-IP for HDAC1, NMR spectroscopy of T164A mutant homeodomain, functional rescue in Pten-null mice

    PMID:16201967 PMID:16397218 PMID:16581776 PMID:16697957 PMID:16814806

    Open questions at the time
    • Identity of the kinase responsible for destabilizing Ser185 phosphorylation not yet known
    • How HDAC1 sequestration by NKX3-1 mechanistically increases p53 acetylation not fully resolved
  7. 2007 High

    Discovery that NKX3-1 directly binds and activates topoisomerase I, and recruits p300/PCAF for histone acetylation at dosage-sensitive loci, provided the first enzymatic and chromatin-remodeling partners explaining its DNA-damage and transcriptional functions.

    Evidence Affinity pulldown, co-IP, in vitro Topo I activity assays, ChIP for histone acetylation, HDAC inhibitor rescue

    PMID:17234752 PMID:17602165 PMID:18077445

    Open questions at the time
    • Whether Topo I activation and chromatin remodeling are functionally linked
    • Structural basis of NKX3-1–Topo I interaction unknown
  8. 2008 High

    Mapping the inflammation-triggered degradation pathway—TNF-α-induced Ser196 phosphorylation leading to TOPORS-mediated ubiquitination—explained how inflammation accelerates NKX3-1 loss in prostate cancer.

    Evidence Site-directed mutagenesis (S196A, S185A), cytokine treatment, ubiquitination and half-life assays

    PMID:18757402

    Open questions at the time
    • Kinase responsible for Ser196 phosphorylation not identified
    • In vivo inflammation model not used
  9. 2009 High

    Identification of IGFBP-3 as a transcriptional target that mediates NKX3-1's attenuation of IGF-I/PI3K/AKT signaling connected NKX3-1 tumor suppression to a defined growth factor signaling axis.

    Evidence Microarray, stable transfection, siRNA knockdown of IGFBP-3, Western blot for IGF pathway phosphorylation

    PMID:19258508

    Open questions at the time
    • Direct binding of NKX3-1 to IGFBP-3 regulatory elements not shown by ChIP at the time
    • Contribution of IGFBP-3 versus other targets to in vivo tumor suppression not separated
  10. 2010 High

    NKX3-1 was shown to localize to DNA damage sites and activate ATM kinase autophosphorylation, establishing a direct mechanistic role in the DNA damage response beyond Topo I activation; concurrently, genome-wide ChIP-seq revealed extensive co-occupancy with AR and FoxA1.

    Evidence Immunofluorescence co-localization, ATM kinase assays, siRNA/overexpression, ChIP-seq in LNCaP cells

    PMID:20395202 PMID:22083957

    Open questions at the time
    • ATM–NKX3-1 physical interaction not yet mapped to specific domains
    • How co-occupancy with AR/FoxA1 is mechanistically organized at enhancers
  11. 2010 High

    In T-ALL, NKX3-1 was identified as a direct target of the TAL1-LMO-Ldb1 oncogenic complex, revealing a non-prostate proliferative function where NKX3-1 promotes leukemic growth via miR-17-92.

    Evidence ChIP at NKX3-1 promoter, siRNA/shRNA knockdown, in vivo leukemia engraftment

    PMID:20855495

    Open questions at the time
    • Targets of NKX3-1 besides miR-17-92 in T-ALL not characterized
    • Whether NKX3-1 functions as tumor suppressor or oncogene is context-dependent and not reconciled
  12. 2013 High

    A cluster of studies refined the DNA-damage mechanism: NKX3-1 Tyr222 phosphorylation upon damage enables direct ATM binding and DNA-damage-independent ATM activation; NKX3-1 also modulates Topo I by inhibiting its resolvase activity while enhancing full-length enzyme activity; and NKX3-1 binds the ERG breakpoint to suppress TMPRSS2-ERG rearrangements by favoring homology-directed repair.

    Evidence Co-IP with phospho-mutants, in vitro ATM kinase assay, reconstituted Topo I domain assays, ChIP at ERG breakpoint, FISH for loci juxtaposition

    PMID:23557481 PMID:23890999 PMID:25977336

    Open questions at the time
    • Kinase responsible for Tyr222 phosphorylation not identified
    • Structural basis of NKX3-1–ATM interaction unknown
  13. 2013 High

    Pim-1 kinase was identified as a stabilizer of NKX3-1, phosphorylating multiple residues including Ser185, counteracting the destabilizing pathway and adding complexity to NKX3-1 turnover regulation.

    Evidence Mass spectrometry of phosphosites, Pim-1 inhibitor treatment, mutational analysis, protein half-life assays

    PMID:23129228

    Open questions at the time
    • How Pim-1-mediated phosphorylation at the same site (Ser185) stabilizes while other kinases destabilize is not mechanistically reconciled
  14. 2015 High

    DYRK1B was identified as the kinase that phosphorylates NKX3-1 Ser185 to trigger steady-state degradation, resolving a long-standing question about the kinase mediating the constitutive turnover pathway.

    Evidence siRNA library screen, in vitro kinase assay, co-IP, protein half-life assay, DYRK1B inhibitors

    PMID:25777618

    Open questions at the time
    • Whether DYRK1B inhibitors can stabilize NKX3-1 in vivo to suppress cancer not tested
    • Interplay between DYRK1B, Pim-1, and CK2 at overlapping sites not resolved
  15. 2016 High

    NKX3-1 gain-of-function was shown to respecify seminal vesicle epithelium toward a prostate fate via interaction with the G9a histone methyltransferase and activation of UTY/KDM6c, establishing the chromatin mechanism underlying NKX3-1's role as a master regulator of prostate identity.

    Evidence In vivo renal graft respecification, Co-IP of NKX3-1–G9a, gene expression profiling, loss-of-function mice

    PMID:27339988

    Open questions at the time
    • Genome-wide targets of the NKX3-1–G9a complex not mapped
    • Whether G9a interaction is required for tumor suppression not tested
  16. 2018 High

    NKX3-1 was shown to activate endogenous OCT4 downstream of IL-6–STAT3 signaling and substitute for OCT4 in iPSC reprogramming, revealing a previously unsuspected role in pluripotency circuits.

    Evidence Heterokaryon reprogramming, siRNA knockdown, STAT3 inhibition, iPSC generation from mouse and human fibroblasts

    PMID:30013107

    Open questions at the time
    • Mechanism by which NKX3-1 activates OCT4 transcription not defined
    • Whether this function relates to prostate stem cell biology not addressed
  17. 2019 High

    Nuclear PTEN was identified as a phosphatase that directly dephosphorylates NKX3-1 Ser185, opposing DYRK1B and stabilizing NKX3-1 protein; this explained why PTEN loss leads to rapid NKX3-1 protein decline and connected two major prostate tumor suppressors in a single post-translational circuit.

    Evidence Co-IP (PTEN–NKX3-1), nuclear localization mutants, protein half-life assay, gene-targeted mice

    PMID:31213464

    Open questions at the time
    • PTEN's phosphatase activity on NKX3-1 not reconstituted with purified components
    • Whether lipid phosphatase and NKX3-1 phosphatase activities are coordinated
  18. 2021 High

    NKX3-1 was shown to be imported into mitochondria via HSPA9 to regulate mitochondrial-encoded ETC gene transcription and restore oxidative phosphorylation, providing a mechanistic basis for its protection against oxidative stress and cancer initiation.

    Evidence Mitochondrial fractionation, HSPA9 Co-IP, mitochondrial transcription assay, genetically engineered mice, human organotypic cultures

    PMID:33893149

    Open questions at the time
    • How a homeodomain protein binds mitochondrial DNA promoters is not structurally defined
    • Relative contribution of mitochondrial versus nuclear functions to tumor suppression not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the NKX3-1–ATM and NKX3-1–mitochondrial DNA interactions, the kinase responsible for damage-induced Tyr222 phosphorylation, how the same Ser185 site mediates opposing stability outcomes depending on kinase context, whether pharmacological stabilization of NKX3-1 (via DYRK1B inhibitors) prevents cancer in vivo, and how NKX3-1's prostate-specific tumor-suppressive versus T-ALL-promoting activities are determined by cellular context.
  • Structural basis of NKX3-1–ATM interaction
  • Kinase for Tyr222 phosphorylation unidentified
  • In vivo therapeutic efficacy of NKX3-1 stabilization not tested
  • Context-dependent oncogene vs tumor suppressor function not mechanistically resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-73894 DNA Repair 4 R-HSA-162582 Signal Transduction 2 R-HSA-4839726 Chromatin organization 2
Partners
ARATMDYRK1BG9AHDAC1PTENTOP1TOPORS

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 NKX3.1 encodes a 38 kDa homeoprotein with DNA binding properties similar to other Nkx family members; it is expressed in a prostate-specific and androgen-regulated manner, with castration significantly reducing expression, establishing androgen dependence for maintenance. RNase protection analysis, in situ hybridization, castration experiments Developmental dynamics High 9142502
1997 NKX3.1 mRNA is induced 6–7 fold by androgens in LNCaP cells within 12 hours, at the level of transcription and independent of de novo protein synthesis, establishing androgen receptor-mediated transcriptional regulation. Differential display PCR, Northern blot, androgen stimulation, transcription inhibition assays The Prostate High 9537602
1999 Nkx3.1 null mutation (targeted gene disruption) results in defects in prostate ductal morphogenesis, secretory protein production, and progressive prostatic epithelial hyperplasia and dysplasia; haploinsufficiency is sufficient to cause these phenotypes, establishing Nkx3.1 as a prostate tumor suppressor with growth-suppressive roles in prostatic epithelium. Targeted gene disruption, histopathology, tissue recombinants Genes & development High 10215624
2000 NKX3.1 binds a novel TAAGTA consensus DNA sequence (distinct from other NK family members) with ~20 nM affinity, and functions as a transcriptional repressor from this site in reporter assays. Binding site selection assay, EMSA, luciferase reporter assay, competitive gel shift with mutated binding sites Nucleic acids research High 10871372
2000 Targeted disruption of Nkx3.1 causes defective branching morphogenesis and epithelial hyperplasia in prostate and palatine glands, with no effects on sclerotome, blood vessels, kidney, or brain, demonstrating organ-specific roles. Targeted gene disruption, histological analysis Developmental dynamics High 11002344
2002 Loss of Nkx3.1 cooperates with loss of Pten in prostate cancer progression, with cooperativity mediated by synergistic activation of Akt (PKB), establishing Nkx3.1 within the PTEN-AKT signaling pathway. Compound mutant mouse models, Western blot for phospho-Akt, histopathology PNAS High 11854455
2002 Conditional Cre/loxP-mediated deletion of Nkx3.1 in adult mouse prostate (one or both alleles) leads to PIN-like lesions; PIN foci in single-allele conditional knockouts lose expression of the wild-type allele, supporting haploinsufficiency and tumor suppressor role. Conditional Cre/loxP recombination, immunohistochemistry for Ki-67/E-cadherin/cytokeratins Molecular and cellular biology High 11839815
2002 Nkx3.1 displays growth-suppressing activities in cell culture and aged Nkx3.1 mutant mice develop PIN-like histopathological lesions that undergo progressively severe alterations after serial transplantation in nude mice. Cell culture growth assays, histopathology, tissue recombination/serial transplantation Cancer research High 12036903
2003 Nkx3.1 haploinsufficiency extends the proliferative stage of regenerating luminal cells; the number of Nkx3.1 alleles determines the probability of stochastic activation or inactivation of dosage-sensitive target genes, as revealed by microarray analysis. Mouse model analysis, microarray gene expression profiling, histopathology Cancer cell High 12676585
2005 Loss-of-function of Nkx3.1 leads to deregulated expression of antioxidant and prooxidant enzymes (GPx2, GPx3, Prdx6, Qscn6) and increased oxidative DNA damage (8-OHdG), linking Nkx3.1 to protection of prostatic epithelium against oxidative stress. Gene expression profiling, immunohistochemistry for 8-OHdG, Nkx3.1 null and compound mutant mice Cancer research High 16061659
2006 NKX3.1 associates with HDAC1, leading to increased p53 acetylation and p53 half-life via MDM2-dependent mechanisms; NKX3.1 also negatively modulates AR transcription and blocks AKT activation in PTEN-null prostate epithelium. Co-immunoprecipitation, in vivo restoration of Nkx3.1 in Pten-null mice, proliferation/apoptosis assays Cancer cell High 16697957
2006 NKX3.1 is regulated by protein kinase CK2: CK2 phosphorylates NKX3.1 on Thr89 and Thr93 in vitro, and CK2 activity is required for NKX3.1 stability in cells; specifically, free CK2α' (not holoenzyme) phosphorylates NKX3.1, establishing CK2α' as a regulator of NKX3.1 stability. In vitro kinase assay with mass spectrometry, CK2 inhibitors, siRNA knockdown, in-gel kinase assay, mutational analysis (T89A/T93A) Molecular and cellular biology High 16581776
2006 A germline T164A mutation in the NKX3.1 homeodomain (found in a hereditary prostate cancer family) alters homeodomain stability and decreases DNA-binding activity, as determined by NMR solution structure and circular dichroism. NMR spectroscopy, circular dichroism, DNA binding assays, family genetic analysis Cancer research High 16397218
2006 NKX3.1 physically interacts with serum response factor (SRF) via three N-terminal motifs (TN/EH-1 motif residues 29–35, SI motif residues 99–105, and acidic domain residues 88–96) and acts as a transcriptional co-activator of the smooth muscle gamma-actin promoter. NMR spectroscopy, targeted mutagenesis, SMGA reporter assays Journal of molecular biology High 16814806
2007 NKX3.1 directly binds topoisomerase I (Topo I) via its homeodomain (with Topo I core-linker domain junction), enhances Topo I-DNA complex formation and Topo I DNA cleavage activity; endogenous NKX3.1 and Topo I co-immunoprecipitate and co-localize in the nucleus, co-migrating to DNA damage sites after genotoxic stress. Topo I activity in prostates of Nkx3.1 null mice is reduced compared to wild-type. Affinity column pulldown, co-IP from LNCaP cells, in vitro Topo I activity assays, co-localization by immunofluorescence, genetically engineered mice Cancer research High 17234752
2007 The NKX3.1 haploinsufficiency phenotype is linked to differential histone H3/H4 acetylation states of dosage-sensitive target genes; NKX3.1 associates with and recruits the histone acetyltransferase p300/PCAF (p300/CBP-associated factor) to chromatin to regulate target gene expression. ChIP for histone acetylation, HDAC inhibitor (TSA) rescue, co-immunoprecipitation for p300/PCAF Journal of biological chemistry High 17602165
2007 TOPORS, an E3 ubiquitin ligase, interacts with NKX3.1, ubiquitinates it in vitro and in vivo, and overexpression of TOPORS leads to NKX3.1 proteasomal degradation; siRNA knockdown of TOPORS increases NKX3.1 steady-state level and half-life. Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown, protein half-life assay Journal of biological chemistry High 18077445
2008 Inflammatory cytokines TNF-α and IL-1β accelerate NKX3.1 protein loss by inducing rapid ubiquitination and proteasomal degradation; TNF-α acts via phosphorylation of C-terminal serine 196 (mutation S196A abrogates this); steady-state NKX3.1 turnover is controlled by serine 185; serine 195 has a modulating role on both pathways. Site-directed mutagenesis (S196A, S185A, S195A), cytokine treatment, ubiquitination assays, protein half-life measurements Cancer research High 18757402
2008 NKX3.1 physically interacts with MYOCD (myocardin) and is required for full MYOCD-dependent transactivation of the ACTG2 promoter through an NKX3.1 binding site adjacent to CArG2; functional association demonstrated by co-IP, GST pulldown, and luciferase assays. Co-immunoprecipitation, GST pulldown, luciferase reporter assay, gel shift assay Journal of biological chemistry High 19797053
2009 NKX3.1 activates expression of IGFBP-3 mRNA and protein ~10-fold; this activation attenuates IGF-I-induced phosphorylation of IGF-IR, IRS-1, PI3K, and AKT; siRNA knockdown of IGFBP-3 partially reverses NKX3.1's growth-suppressive effects, establishing IGFBP-3 as a downstream mediator of NKX3.1 tumor suppression. Expression microarray, stable transfection, siRNA knockdown, Western blot for signaling intermediates, proliferation assays, Nkx3.1 gene-targeted mice Cancer research High 19258508
2010 NKX3.1 localizes to sites of DNA damage, enhances ATM autophosphorylation at Ser1981, activates ATR (via CHK1 phosphorylation), and affects recruitment of phospho-ATM and H2AX phosphorylation at DNA damage foci; an inherited DNA-binding mutant is devoid of ATM activation and γH2AX co-localization. Immunofluorescence co-localization, siRNA knockdown of NKX3.1 in LNCaP, overexpression in PC-3, colony formation after DNA damage, ATM kinase activation assay Cancer research High 20395202
2010 NKX3.1 co-localizes genome-wide with the androgen receptor (AR) as shown by ChIP-seq; NKX3.1 and AR directly regulate each other in a feed-forward loop; NKX3.1 collaborates with AR and FoxA1 to regulate a gene network including RAB3B, a RAB GTPase that promotes prostate cancer cell survival. ChIP-seq, luciferase reporter assay, siRNA knockdown, gene expression profiling Molecular and cellular biology High 22083957
2010 NKX3.1 is a direct transcriptional target of the TAL1-LMO-Ldb1 complex (recruited by GATA-3 to the NKX3.1 promoter) in T-ALL cells; NKX3.1 activation is associated with suppression of HP1-α and chromatin opening at its promoter; NKX3.1 is required for T-ALL proliferation and directly regulates miR-17-92. ChIP, siRNA/shRNA knockdown, reporter assays, in vivo leukemia engraftment Journal of experimental medicine High 20855495
2010 ERG and ESE3 ETS factors control Nkx3.1 expression both directly (binding to NKX3.1 gene regulatory elements) and indirectly through regulation of EZH2 (Polycomb Group protein), which epigenetically silences Nkx3.1. ChIP, reporter assay, siRNA knockdown, gene expression profiling PLoS One High 20479932
2012 Nkx3.1 and Myc directly bind and crossregulate shared target genes in prostate epithelial cells; Nkx3.1 can oppose Myc transcriptional activity; loss of Nkx3.1 cooperates with Myc overexpression to promote prostate cancer in transgenic mice. ChIP-seq, gene expression profiling, reporter assays, transgenic mice with compound mutations Journal of clinical investigation High 22484818
2013 NKX3.1 undergoes phosphorylation at tyrosine 222 within minutes of DNA damage, which is required for functional interaction with ATM kinase N-terminal domain; NKX3.1 binding to ATM accelerates ATM activation, hastens γH2AX formation, and enhances ATM kinase activity in a DNA-damage-independent manner; ATM then phosphorylates NKX3.1, leading to its ubiquitination and degradation. Co-immunoprecipitation, in vitro ATM kinase assay, phospho-mutant analysis, γH2AX kinetics assay Cell reports High 23890999
2013 NKX3.1 homeodomain binds the topoisomerase I core-linker domain junction; NKX3.1 inhibits the DNA-resolving activity of reconstituted Topo I in vitro while enhancing full-length Topo I activity; Topo I knockdown blocks NKX3.1's effect on clonogenicity after DNA damage. In vitro Topo I activity assay with reconstituted enzyme fragments, domain mapping, siRNA knockdown, clonogenic survival assay Biochemical journal High 23557481
2013 NKX3.1 represses TWIST1 expression by directly binding to the TWIST1 promoter; NKX3.1 overexpression reduces TWIST1 promoter reporter activity, and NKX3.1 siRNA upregulates endogenous TWIST1, establishing TWIST1 as a direct NKX3.1 target gene involved in EMT. ChIP, luciferase reporter assay, siRNA knockdown, RT-PCR Cancer cell international High 23368843
2013 NKX3.1 represses RAMP1 expression by directly binding multiple sites in the RAMP1 locus; loss of NKX3.1 in knockout mice elevates RAMP1, and knockdown of RAMP1 in prostate cancer cells decreases proliferation, tumorigenicity, and MEK-ERK signaling. ChIP-seq, gene expression profiling, shRNA knockdown, xenograft tumor model American journal of pathology High 23867798
2013 Pim-1 kinase stabilizes NKX3.1 protein by phosphorylating it at Thr89, Ser185, Ser186, Ser195, and Ser196; Pim-1-mediated stabilization requires phosphorylation at Ser185, Ser186, and N-terminal PEST domain and Lys182, protecting NKX3.1 from proteasomal degradation. Mass spectrometry identification of phosphosites, Pim-1 inhibitor treatment, mutational analysis, protein half-life assay, proteasome inhibitor rescue Journal of cellular biochemistry High 23129228
2015 DYRK1B kinase directly phosphorylates NKX3.1 at serine 185 (the residue critical for steady-state turnover) via its kinase domain interaction with NKX3.1; DYRK1B inhibitors prolong NKX3.1 half-life. siRNA library screen, in vitro kinase assay, co-IP (DYRK1B kinase domain), protein half-life assay, small-molecule inhibition Molecular cancer research High 25777618
2015 NKX3.1 binds at the ERG gene breakpoint, inhibits juxtaposition of TMPRSS2 and ERG gene loci, suppresses their recombination, and promotes homology-directed DNA repair; loss of NKX3.1 favors error-prone non-homologous end-joining at the ERG breakpoint. ChIP at ERG breakpoint, FISH for loci juxtaposition, DNA repair pathway factor recruitment assays, human tissue correlation Cancer research High 25977336
2016 NKX3.1 gain-of-function in seminal vesicle epithelium is sufficient to respecify it toward a prostate fate in renal grafts; this activity requires interaction of NKX3.1 with the G9a histone methyltransferase via the homeodomain, and is mediated by activation of UTY (KDM6c), identifying an NKX3.1-G9a-UTY transcriptional regulatory network essential for prostate differentiation. In vivo renal graft respecification, Co-IP (NKX3.1-G9a interaction), gene expression profiling, loss-of-function mouse models Science High 27339988
2018 NKX3-1 functions downstream of the IL-6-STAT3 signaling pathway to activate endogenous OCT4 expression during reprogramming; NKX3-1 can substitute for exogenous OCT4 to generate fully pluripotent iPSCs from both mouse and human fibroblasts. Heterokaryon reprogramming system, siRNA knockdown, STAT3 pathway inhibition, iPSC generation and characterization Nature cell biology High 30013107
2019 PTEN functions as a phosphatase of NKX3.1, opposing DYRK1B-mediated phosphorylation at Ser185 and prolonging NKX3.1 half-life; PTEN and NKX3.1 interact primarily in the nucleus (nuclear PTEN localization is required); loss of PTEN in gene-targeted mice leads to rapid decrease in Nkx3.1 protein without affecting Nkx3.1 mRNA. Co-IP (PTEN-NKX3.1), mutational analysis (nuclear localization signal of PTEN), protein half-life assay, gene-targeted mice, Western blot, qRT-PCR Cancer research High 31213464
2021 In response to oxidative stress, NKX3.1 is imported to mitochondria via the chaperone protein HSPA9, where it regulates transcription of mitochondrial-encoded electron transport chain (ETC) genes, restoring oxidative phosphorylation and preventing cancer initiation; germline polymorphisms of NKX3.1 associated with increased cancer risk fail to protect from oxidative stress. Mitochondrial fractionation, HSPA9 Co-IP, mitochondrial transcription assay, genetically engineered mouse models, human organotypic cultures, mutant NKX3.1 functional assays Cancer discovery High 33893149
2021 LIMK2 directly phosphorylates NKX3.1, promoting its degradation in castration-resistant prostate cancer cells; NKX3.1 in turn promotes LIMK2 ubiquitylation; this negative crosstalk regulates AR, ARv7, and AKT signaling. In vitro kinase assay, Co-IP, ubiquitylation assay, siRNA knockdown, in vivo xenograft Cancers High 34066036
2006 Nkx3.1 binds Sp-family transcription factors via their respective DNA-binding domains and an N-terminal segment of Nkx3.1, and negatively regulates Sp-mediated transcription of PSA via TSA-sensitive (histone deacetylase-dependent) and TSA-insensitive mechanisms without requiring Nkx3.1's own DNA-binding activity. Co-immunoprecipitation, reporter assay, HDAC inhibitor (TSA) treatment, domain mutagenesis Biochemical journal High 16201967
2008 Nkx3-1 and LEF-1 bind to ER (estrogen receptor) cis-regulatory elements in vivo, function as transcriptional repressors of estrogen signaling, and can inhibit ER binding to chromatin, demonstrating competition for common chromatin-binding regions. ChIP, reporter assay, ER chromatin binding assay Cancer research High 18794125
2010 Androgen receptor binds canonical AREs in the NKX3.1 3'UTR (at positions +2378–2392 and +3098–3112) to mediate androgen-dependent upregulation of NKX3.1; AR recruitment confirmed by ChIP and mutational analysis. Reporter deletion analysis, EMSA, ChIP, site-directed mutagenesis Biochemical journal High 19886863
2009 NKX3.1 directly activates VEGF-C-repressing transcriptional activity with HDAC1 as corepressor; loss of NKX3.1 leads to increased VEGF-C expression; RalA acts in synergy with NKX3.1 loss to increase VEGF-C transcription. Reporter assay, Co-IP (NKX3.1-HDAC1), siRNA knockdown, ChIP Cancer research Medium 18974119
2013 Canonical Wnt signaling regulates Nkx3.1 expression during prostate organogenesis; Nkx3.1 in turn maintains canonical Wnt signaling activity in developing prostate bud tips (positive feedback loop), as shown in urogenital sinus explant cultures and TCF/Lef reporter mice. Wnt inhibitor treatment of urogenital sinus explants, TCF/Lef:H2B-GFP transgenic reporter mice, Nkx3.1 null neonatal prostates Developmental dynamics Medium 23813564

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Roles for Nkx3.1 in prostate development and cancer. Genes & development 511 10215624
2000 Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer research 294 11085535
1997 A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer. Genomics 289 9226374
2002 Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America 258 11854455
2010 NKX3.1 as a marker of prostatic origin in metastatic tumors. The American journal of surgical pathology 221 20588175
2002 Nkx3.1 mutant mice recapitulate early stages of prostate carcinogenesis. Cancer research 201 12036903
2002 Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia. Molecular and cellular biology 190 11839815
2011 Integration of regulatory networks by NKX3-1 promotes androgen-dependent prostate cancer survival. Molecular and cellular biology 148 22083957
1997 Tissue-specific expression of murine Nkx3.1 in the male urogenital system. Developmental dynamics : an official publication of the American Association of Anatomists 145 9142502
2006 NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss. Cancer cell 143 16697957
2005 Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer. Cancer research 132 15734999
2005 Loss-of-function of Nkx3.1 promotes increased oxidative damage in prostate carcinogenesis. Cancer research 124 16061659
1997 Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers. Cancer research 119 9377551
2010 ETS transcription factors control transcription of EZH2 and epigenetic silencing of the tumor suppressor gene Nkx3.1 in prostate cancer. PloS one 118 20479932
2003 Haploinsufficiency at the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation. Cancer cell 111 12676585
1998 Isolation and androgen regulation of the human homeobox cDNA, NKX3.1. The Prostate 107 9537602
2010 MYC overexpression induces prostatic intraepithelial neoplasia and loss of Nkx3.1 in mouse luminal epithelial cells. PloS one 103 20195545
2008 Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Differentiation; research in biological diversity 99 18557759
2000 Targeted disruption of the Nkx3.1 gene in mice results in morphogenetic defects of minor salivary glands: parallels to glandular duct morphogenesis in prostate. Mechanisms of development 89 10906459
2003 Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 85 14648854
2009 Loss of Nkx3.1 leads to the activation of discrete downstream target genes during prostate tumorigenesis. Oncogene 81 19597465
2000 Nkx3.1, a murine homolog of Ddrosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands. Developmental dynamics : an official publication of the American Association of Anatomists 81 11002344
2016 Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation. Science (New York, N.Y.) 76 27339988
2003 Expression of NKX3.1 in normal and malignant tissues. The Prostate 74 12661036
2010 Loss of Nkx3.1 expression in bacterial prostatitis: a potential link between inflammation and neoplasia. The American journal of pathology 68 20363913
2006 Vitamin D inhibits the formation of prostatic intraepithelial neoplasia in Nkx3.1;Pten mutant mice. Clinical cancer research : an official journal of the American Association for Cancer Research 66 17020998
2007 Prolonged exposure to reduced levels of androgen accelerates prostate cancer progression in Nkx3.1; Pten mutant mice. Cancer research 65 17909013
2020 NKX3-1 Is a Useful Immunohistochemical Marker of EWSR1-NFATC2 Sarcoma and Mesenchymal Chondrosarcoma. The American journal of surgical pathology 61 31972596
2001 Expression studies and mutational analysis of the androgen regulated homeobox gene NKX3.1 in benign and malignant prostate epithelium. The Journal of urology 60 11257711
2010 NKX3.1 activates cellular response to DNA damage. Cancer research 57 20395202
2010 NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia. The Journal of experimental medicine 57 20855495
2008 Inflammatory cytokines induce phosphorylation and ubiquitination of prostate suppressor protein NKX3.1. Cancer research 53 18757402
2012 Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis. The Journal of clinical investigation 52 22484818
2000 DNA-binding sequence of the human prostate-specific homeodomain protein NKX3.1. Nucleic acids research 52 10871372
2018 NKX3-1 is required for induced pluripotent stem cell reprogramming and can replace OCT4 in mouse and human iPSC induction. Nature cell biology 43 30013107
1999 Expression of the Nkx3.1 homobox gene during pre and postnatal development. Mechanisms of development 43 10415359
2007 NKX3.1 homeodomain protein binds to topoisomerase I and enhances its activity. Cancer research 42 17234752
2002 Transcription factors Nkx3.1 and Nkx3.2 (Bapx1) play an overlapping role in sclerotomal development of the mouse. Mechanisms of development 41 12204261
2000 Full-length cDNA sequence and genomic organization of human NKX3A - alternative forms and regulation by both androgens and estrogens. Gene 41 11137288
2007 Ubiquitination by TOPORS regulates the prostate tumor suppressor NKX3.1. The Journal of biological chemistry 39 18077445
2005 Mechanisms of prostate tumorigenesis: roles for transcription factors Nkx3.1 and Egr1. Annals of the New York Academy of Sciences 37 16382041
2013 Canonical Wnt signaling regulates Nkx3.1 expression and luminal epithelial differentiation during prostate organogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 36 23813564
2009 Myocardin-dependent activation of the CArG box-rich smooth muscle gamma-actin gene: preferential utilization of a single CArG element through functional association with the NKX3.1 homeodomain protein. The Journal of biological chemistry 36 19797053
2008 Nkx3-1 and LEF-1 function as transcriptional inhibitors of estrogen receptor activity. Cancer research 36 18794125
2006 NKX3.1 is regulated by protein kinase CK2 in prostate tumor cells. Molecular and cellular biology 36 16581776
2021 NKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation. Cancer discovery 35 33893149
2017 Sensitivity of HOXB13 as a Diagnostic Immunohistochemical Marker of Prostatic Origin in Prostate Cancer Metastases: Comparison to PSA, Prostein, Androgen Receptor, ERG, NKX3.1, PSAP, and PSMA. International journal of molecular sciences 35 28555048
2015 NKX3.1 Suppresses TMPRSS2-ERG Gene Rearrangement and Mediates Repair of Androgen Receptor-Induced DNA Damage. Cancer research 35 25977336
2007 Curcumin downregulates homeobox gene NKX3.1 in prostate cancer cell LNCaP. Acta pharmacologica Sinica 35 17303007
2006 Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function. Cancer research 35 16397218
2013 Functional activation of ATM by the prostate cancer suppressor NKX3.1. Cell reports 34 23890999
2018 Cooperation of loss of NKX3.1 and inflammation in prostate cancer initiation. Disease models & mechanisms 33 30266798
2013 Alterations of C-MYC, NKX3.1, and E-cadherin expression in canine prostate carcinogenesis. Microscopy research and technique 33 24030851
2013 TWIST1, A novel androgen-regulated gene, is a target for NKX3-1 in prostate cancer cells. Cancer cell international 32 23368843
2013 Targeted induction of endogenous NKX3-1 by small activating RNA inhibits prostate tumor growth. The Prostate 32 23836514
2010 A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression. Human molecular genetics 32 20716579
2004 Analysis of androgen regulated homeobox gene NKX3.1 during prostate carcinogenesis. The Journal of urology 32 15311057
2002 Occurrence of NKX3.1 C154T polymorphism in men with and without prostate cancer and studies of its effect on protein function. Cancer research 32 11980664
2008 Loss of NKX3.1 favors vascular endothelial growth factor-C expression in prostate cancer. Cancer research 30 18974119
2007 Overexpression HERG K(+) channel gene mediates cell-growth signals on activation of oncoproteins SP1 and NF-kappaB and inactivation of tumor suppressor Nkx3.1. Journal of cellular physiology 29 17311278
2015 MiR-378b Promotes Differentiation of Keratinocytes through NKX3.1. PloS one 28 26313654
2014 TNFα-mediated loss of β-catenin/E-cadherin association and subsequent increase in cell migration is partially restored by NKX3.1 expression in prostate cells. PloS one 28 25360740
2019 Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression. Cancer research 27 31213464
2007 Haploinsufficient prostate tumor suppression by Nkx3.1: a role for chromatin accessibility in dosage-sensitive gene regulation. The Journal of biological chemistry 27 17602165
2006 Analysis of NKX3.1 expression in prostate cancer tissues and correlation with clinicopathologic features. Pathology, research and practice 26 16413692
2005 Distinct regulatory elements mediate the dynamic expression pattern of Nkx3.1. Developmental dynamics : an official publication of the American Association of Anatomists 26 16245334
2010 Chromosome 8 markers of metastatic prostate cancer in African American men: gain of the MIR151 gene and loss of the NKX3-1 gene. The Prostate 25 21456068
2006 Nkx3.1 binds and negatively regulates the transcriptional activity of Sp-family members in prostate-derived cells. The Biochemical journal 25 16201967
2022 NKX3.1 Expression in Salivary Gland "Intraductal" Papillary Mucinous Neoplasm: A Low-Grade Subtype of Salivary Gland Mucinous Adenocarcinoma. Head and neck pathology 24 35834096
2010 Androgen regulation of the prostatic tumour suppressor NKX3.1 is mediated by its 3' untranslated region. The Biochemical journal 24 19886863
2014 NKX3.1 is expressed in ER-positive and AR-positive primary breast carcinomas. Journal of clinical pathology 23 24996432
2004 Interaction of Nkx3.1 and p27kip1 in prostate tumor initiation. The American journal of pathology 23 15111307
2013 RAMP1 is a direct NKX3.1 target gene up-regulated in prostate cancer that promotes tumorigenesis. The American journal of pathology 22 23867798
2017 Transcriptional regulation of the Nkx3.1 gene in prostate luminal stem cell specification and cancer initiation via its 3' genomic region. The Journal of biological chemistry 20 28679531
2015 The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase. Molecular cancer research : MCR 20 25777618
2014 A functional variant in NKX3.1 associated with prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Cancer prevention research (Philadelphia, Pa.) 20 24894197
2021 The Role of Nkx3.1 in Cancers and Stemness. International journal of stem cells 19 33632988
2013 Id4 deficiency attenuates prostate development and promotes PIN-like lesions by regulating androgen receptor activity and expression of NKX3.1 and PTEN. Molecular cancer 19 23786676
2012 Antioxidant treatment promotes prostate epithelial proliferation in Nkx3.1 mutant mice. PloS one 19 23077524
2021 LIMK2-NKX3.1 Engagement Promotes Castration-Resistant Prostate Cancer. Cancers 18 34066036
2016 Regulating NKX3.1 stability and function: Post-translational modifications and structural determinants. The Prostate 18 26841725
2013 Stabilization of the prostate-specific tumor suppressor NKX3.1 by the oncogenic protein kinase Pim-1 in prostate cancer cells. Journal of cellular biochemistry 18 23129228
2006 Physical and functional interactions between the prostate suppressor homeoprotein NKX3.1 and serum response factor. Journal of molecular biology 18 16814806
2018 Evaluation of NKX3.1 and C-MYC expression in canine prostatic cancer. Research in veterinary science 17 29665565
2009 NKX3.1 activates expression of insulin-like growth factor binding protein-3 to mediate insulin-like growth factor-I signaling and cell proliferation. Cancer research 17 19258508
2003 NKX3.1 expression is lost in testicular germ cell tumors. The American journal of pathology 17 14633588
2020 NKX3.1 and Prostein Expression in Testicular Tissue and Sex Cord-stromal Tumors. The American journal of surgical pathology 16 31498176
2020 NKX3.1 a useful marker for mesenchymal chondrosarcoma: An immunohistochemical study. Annals of diagnostic pathology 16 33302222
2019 Utility of NKX3.1 Immunostaining in the Detection of Metastatic Prostatic Carcinoma on Fine-Needle Aspiration Smears. American journal of clinical pathology 16 31175351
2017 NK3 homeobox 1 (NKX3.1) up-regulates forkhead box O1 expression in hepatocellular carcinoma and thereby suppresses tumor proliferation and invasion. The Journal of biological chemistry 16 28972178
2015 Inflammation contributes to NKX3.1 loss and augments DNA damage but does not alter the DNA damage response via increased SIRT1 expression. Journal of inflammation (London, England) 16 25705129
2014 DNA damage response (DDR) via NKX3.1 expression in prostate cells. The Journal of steroid biochemistry and molecular biology 16 24434284
2013 Structural and functional interactions of the prostate cancer suppressor protein NKX3.1 with topoisomerase I. The Biochemical journal 16 23557481
2007 Loss of Nkx3.1 expression in the transgenic adenocarcinoma of mouse prostate model. The Prostate 16 17929276
2017 Co-clinical Analysis of a Genetically Engineered Mouse Model and Human Prostate Cancer Reveals Significance of NKX3.1 Expression for Response to 5α-reductase Inhibition. European urology 15 28385453
2006 Expression of an Nkx3.1-CRE gene using ROSA26 reporter mice. Genesis (New York, N.Y. : 2000) 15 17078065
2021 Skene's Gland Derivatives in the Female Genital Tract and Cervical Adenoid Basal Carcinoma are Consistently Positive With Prostatic Marker NKX3.1. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 14 33021555
2020 Roles of CCNB2 and NKX3-1 in Nasopharyngeal Carcinoma. Cancer biotherapy & radiopharmaceuticals 14 32202926
2015 An EG-VEGF-Dependent Decrease in Homeobox Gene NKX3.1 Contributes to Cytotrophoblast Dysfunction: A Possible Mechanism in Human Fetal Growth Restriction. Molecular medicine (Cambridge, Mass.) 14 26208047
2009 Nkx3.1 and p27(KIP1) cooperate in proliferation inhibition and apoptosis induction in human androgen-independent prostate cancer cells. Cancer investigation 14 19266349