Affinage

SIX2

Homeobox protein SIX2 · UniProt Q9NPC8

Length
291 aa
Mass
32.3 kDa
Annotated
2026-06-10
85 papers in source corpus 37 papers cited in narrative 37 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

SIX2 is a homeodomain transcription factor that cell-autonomously maintains multipotent nephron progenitor cells in a self-renewing, undifferentiated state by opposing the inductive Wnt9b/Wnt signal that drives mesenchymal-to-epithelial differentiation (PMID:18682239, PMID:17036046). It enforces this balance by co-occupying cis-regulatory modules at differentiation genes (Wnt4, Fgf8) together with Lef/Tcf factors, forming a maintenance complex that is converted to a pro-differentiation complex when β-catenin enters it (PMID:22902740); Osr1 acts synergistically downstream of SIX2 to reinforce this antagonism of Wnt-directed nephrogenesis (PMID:24598167). SIX2 activity depends on its partner Eya1, which it translocates to the nucleus to control Myc, with loss of Eya1 collapsing SIX2 expression and the progenitor pool (PMID:25458011), and on the Brg1/SWI/SNF chromatin-remodeling complex, which SIX2 directs to enhancers of progenitor regulators such as Pbx1 and Mycn (PMID:34716243). SIX2 binds DNA through its homeodomain and activates transcription via a C-terminal activation domain (PMID:15327782, PMID:19716816), directly activating target genes including its own promoter and Gdnf (PMID:15327782), and is positioned within developmental regulatory hierarchies as an output of Hox proteins (activated by Hox11, repressed by Hoxa2) (PMID:19716816, PMID:18321982) and a target whose downregulation by Notch signaling licenses differentiation (PMID:27633993). SIX2 function is essential beyond the kidney, controlling pyloric sphincter and craniofacial/palate gene networks (PMID:19660448, PMID:29218017) and second heart field progenitor allocation (PMID:28122228). SIX2 protein level is set post-translationally by competing ubiquitin-proteasome activities, with TRIM21 catalyzing K48-linked ubiquitination at K82/K89/K97 to drive degradation (PMID:40954199). In cancer and disease contexts SIX2 promotes a stem-like state and metastasis, repressing E-cadherin and engaging a SIX2/SOX2 axis (PMID:25348955, PMID:30606720) and sustaining Wnt/β-catenin signaling (PMID:38554106). A human SIX2 missense variant (p.Gly264Glu) destabilizes the protein and reduces activation of its target PAX9 (PMID:31765609).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2004 Medium

    Established that SIX2 is a sequence-specific transcriptional activator with defined functional domains, answering how it acts on DNA.

    Evidence Promoter-reporter and DNA-binding assays plus domain mapping, identifying Gdnf and autoregulatory promoter sites and a C-terminal activation domain

    PMID:15327782

    Open questions at the time
    • Genome-wide target repertoire not defined
    • Cofactor requirements for activation not established
  2. 2006 High

    Defined the core developmental function: SIX2 keeps metanephric mesenchyme progenitors undifferentiated against ureteric bud induction.

    Evidence Loss- and gain-of-function mouse genetics with organ culture showing premature/ectopic epithelial differentiation upon loss and blocked differentiation upon gain

    PMID:17036046

    Open questions at the time
    • Molecular mechanism of differentiation suppression not yet defined
    • Direct target genes mediating maintenance unknown
  3. 2008 High

    Resolved that SIX2 acts cell-autonomously to self-renew a multipotent nephron progenitor population, and placed it in epistasis with the Wnt9b inductive signal.

    Evidence Genetic lineage tracing, clonal analysis, and conditional loss-of-function showing Six2-null cells ectopically join tubules via Wnt9b; separately, Hoxa2 control identified

    PMID:18321982 PMID:18682239

    Open questions at the time
    • Direct transcriptional mechanism opposing Wnt not defined
    • Hox-to-Six2 regulatory element not yet mapped
  4. 2009 High

    Showed a single upstream enhancer integrates opposing Hox inputs and that SIX2 regulates non-renal organogenesis, broadening its developmental scope.

    Evidence In vivo enhancer dissection with Hox domain mutagenesis (Hox11 activation / Hoxa2 repression) and Six2-null analysis of pyloric sphincter gene networks

    PMID:19660448 PMID:19716816

    Open questions at the time
    • How a shared site is read as activation vs repression in different tissues not fully resolved
  5. 2012 High

    Defined the molecular switch for self-renewal vs commitment: SIX2/Lef-Tcf maintenance complexes versus β-catenin-driven differentiation.

    Evidence ChIP, transcriptional profiling, and cis-regulatory mutagenesis showing SIX2 and β-catenin co-occupy Wnt4/Fgf8 modules

    PMID:22902740

    Open questions at the time
    • Stoichiometry/structure of the SIX2-Lef/Tcf-β-catenin complex unknown
    • How β-catenin entry is triggered not defined
  6. 2014 High

    Identified the Eya1 and Osr1 partnerships that empower SIX2 activity and reinforce Wnt antagonism.

    Evidence Co-IP, conditional knockouts, phosphatase assays (Eya1/Myc), and TCF-Groucho interaction analysis (Osr1) with in vivo Wnt4 reporters

    PMID:24598167 PMID:25458011

    Open questions at the time
    • How SIX2 mediates Eya1 nuclear import mechanistically unclear
    • Direct biochemical link between SIX2 and the Osr1-TCF-Groucho arm not established
  7. 2016 High

    Placed Notch upstream of SIX2 as the trigger that licenses differentiation, and identified LIF/STAT as a positive input sustaining SIX2.

    Evidence Notch conditional gain/loss-of-function with Six2 expression readout; STAT consensus-site reporter assays in metanephric mesenchyme

    PMID:26321142 PMID:27633993

    Open questions at the time
    • Direct vs indirect Notch repression of Six2 not distinguished
    • STAT finding is Medium-confidence single-lab promoter assay
  8. 2017 Medium

    Refined dosage-dependent SIX2 control of progenitor proliferation vs self-renewal and extended its progenitor role to the second heart field and palate.

    Evidence Quantitative morphometry/EdU in Six2 heterozygotes; lineage tracing/Shh KO in cardiac progenitors; Hoxa2-Six2 epistasis with siRNA rescue in palate

    PMID:28122228 PMID:29217079 PMID:29218017

    Open questions at the time
    • Mechanism coupling SIX2 dosage to MYC levels not resolved
    • Whether cardiac/palate roles share the kidney transcriptional mechanism unknown
  9. 2019 Medium

    Linked SIX2 to specific direct targets and to a human disease variant, and established a DNMT1-dependent epigenetic requirement in SIX2+ progenitors.

    Evidence ChIP/reporter assays mapping PAX9 and Gdnf/Smurf1 targets, p.Gly264Glu stability assay, and Six2-Cre conditional DNMT1 KO with WGBS/RNA-seq

    PMID:27148690 PMID:30850438 PMID:31720997 PMID:31765609

    Open questions at the time
    • DNMT1 finding shows requirement in SIX2+ cells, not direct SIX2-DNMT1 interaction
    • Neuronal Gdnf/Smurf1 targets validated in single labs only
  10. 2014 Medium

    Established a pro-metastatic, stemness-promoting role for SIX2 in cancer via E-cadherin repression and a SIX2/SOX2 axis.

    Evidence Knockdown/overexpression, in vivo metastasis assays, promoter methylation analysis (Cdh1) and ChIP at the Sox2 Srr2 enhancer in breast cancer

    PMID:25348955 PMID:30606720

    Open questions at the time
    • Mechanism by which SIX2 directs Cdh1 promoter methylation unresolved
    • Cancer findings from single labs
  11. 2021 High

    Defined SIX2's reliance on Brg1/SWI/SNF chromatin remodeling, its non-redundancy with the paralog Six1, and a conserved role in human β-cell maturation.

    Evidence Tagged-knock-in Co-IP and ChIP-seq (Brg1); Six1-for-Six2 knock-in rescue with comparative ChIP-seq; shRNA/ATAC-seq in human islets and SC-β cells

    PMID:32460030 PMID:33446570 PMID:34716243 PMID:35178390

    Open questions at the time
    • How SIX2 selects loci that Six1 cannot occupy not defined
    • β-cell target gene mechanisms are Medium-confidence single-lab studies
  12. 2024 Medium

    Identified post-translational control of SIX2 abundance and new cancer/disease effector targets.

    Evidence TRIM25/TRIM21 Co-IP and site-mapped ubiquitination assays, NIK stabilization assays, and ChIP/CUT&Tag mapping of SPRED2, LGSN, PFN2, and METTL9 targets across cancer and neuronal models

    PMID:37461228 PMID:38554106 PMID:39256760 PMID:40523929 PMID:40954199 PMID:42105075

    Open questions at the time
    • Whether these ubiquitin ligases regulate SIX2 in the developmental kidney context unknown
    • Most effector targets validated in single labs
  13. 2024 High

    Clarified a confounder in the widely used Six2TGC transgene by showing ectopic Six3 (not Six2) interferes with progenitor renewal.

    Evidence Targeted locus amplification, Hi-C, and CRISPR disruption with genetic rescue of the transgene

    PMID:38447671

    Open questions at the time
    • Implications for reinterpreting prior Six2TGC-based data not systematically addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the SIX2 maintenance complex is structurally organized and how upstream signals (Notch, Wnt, growth factor inputs) are integrated to flip SIX2 between self-renewal and differentiation outputs remains unresolved.
  • No structural model of SIX2-Lef/Tcf-β-catenin complex
  • Direct molecular link between Notch signaling and Six2 promoter repression unmapped
  • Whether cancer/neuronal SIX2 mechanisms recapitulate the developmental transcriptional program untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4 GO:0140097 catalytic activity, acting on DNA 2
Localization
GO:0005634 nucleus 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3
Partners
CTNNB1EYA1LEF1OSR1SMARCA4TCFTRIM21TRIM25
Complex memberships
Brg1/SWI/SNF chromatin remodeling complexSIX2-Lef/Tcf maintenance complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Six2-expressing cap mesenchyme cells are a multipotent nephron progenitor population that self-renew throughout kidney development. Six2 functions cell-autonomously to maintain progenitor status: cap mesenchyme cells lacking Six2 activity ectopically contribute to nephron tubules via a Wnt9b inductive signal, demonstrating Six2's cell-autonomous role in suppressing differentiation. Genetic lineage tracing (pulse labeling), clonal analysis, conditional loss-of-function, organ culture Cell stem cell High 18682239
2006 Six2 is required to maintain the metanephric mesenchyme progenitor population in an undifferentiated state by opposing inductive signals from the ureteric bud. Functional inactivation of Six2 causes premature and ectopic mesenchymal-to-epithelial differentiation and depletion of progenitors. Gain of Six2 function in cortical mesenchymal cells is sufficient to prevent their epithelial differentiation. Loss-of-function mouse genetics (Six2 knockout), gain-of-function in organ culture assay The EMBO journal High 17036046
2012 Six2 and β-catenin (Wnt signaling) co-occupy shared cis-regulatory modules flanking Wnt4 and Fgf8 in nephron progenitors. Six2 and Lef/Tcf factors form a regulatory complex that promotes progenitor maintenance, while entry of β-catenin into this complex promotes nephrogenesis. This regulatory balance controls commitment vs. self-renewal. Chromatin immunoprecipitation (ChIP), transcriptional profiling, in vitro and in vivo reporter assays, mutagenesis of Lef/Tcf binding sites Developmental cell High 22902740
2014 Eya1 interacts with Six2 (and Myc) to control self-renewing nephron progenitor cell activity. Six2 mediates translocation of Eya1 to the nucleus, where Eya1 uses its threonine phosphatase activity to control Myc phosphorylation/dephosphorylation. Conditional inactivation of Eya1 leads to loss of Six2 expression and premature epithelialization of progenitors. Co-immunoprecipitation, conditional knockout, cell fate tracing, biochemical phosphatase assay Developmental cell High 25458011
2004 Six2 activates expression of the Gdnf gene by binding to two Six2 binding sites in the Gdnf promoter. Six2 also binds and activates its own promoter (autoregulation). Six2 possesses a transcriptional activation domain in the C-terminus and nuclear localization determinants in the Six domain. Promoter-reporter assay, DNA binding assay (identification of promoter binding sites), transgenic LacZ reporter mice, biochemical characterization of Six2 protein domains Mechanisms of development Medium 15327782
2014 Osr1 acts downstream of Six2 (Six2 is required to maintain Osr1 expression in undifferentiated cap mesenchyme) and both act synergistically to prevent premature nephron progenitor differentiation. Osr1, but not Six2, enhances TCF interaction with Groucho co-repressors to antagonize Wnt/β-catenin-directed nephrogenic differentiation. Conditional knockout (tissue-specific), epistasis analysis, protein interaction assay (TCF-Groucho complex), in vivo Wnt4 enhancer reporter Development (Cambridge, England) High 24598167
2009 A single enhancer site upstream of the Six2 coding sequence is responsible for both activation by Hox11 proteins in the kidney and repression by Hoxa2 in the branchial arch and facial mesenchyme. DNA-binding activity is required for both activation and repression, but protein domains N- and C-terminal to the homeodomain confer activation versus repression activity. In vivo enhancer analysis in transgenic mice, mutagenesis of Hox protein domains, loss-of-function genetics Developmental biology High 19716816
2008 Six2 is a direct downstream transcriptional target of Hoxa2 in vivo. Ectopic expression of Six2 in the absence of Hoxa2 contributes to the Hoxa2 mouse mutant phenotype, and Six2 acts to mediate Hoxa2 control over the insulin-like growth factor pathway during branchial arch development. Genetic epistasis, in vivo target gene identification, loss-of-function (Hoxa2 knockout) Development (Cambridge, England) High 18321982
2016 Notch signaling is necessary and sufficient for downregulation of Six2 during nephrogenesis. Loss of Notch signaling in nephron progenitors prevents Six2 downregulation and blocks differentiation into any nephron segment, placing Notch upstream of Six2 in the differentiation pathway. Conditional gain- and loss-of-function of Notch signaling in mice, analysis of Six2 expression Development (Cambridge, England) High 27633993
2014 Six2 promotes breast cancer metastasis by transcriptionally and epigenetically repressing E-cadherin. Mechanistically, Six2 upregulates Zeb2 (in part through a microRNA-mediated mechanism) and stimulates promoter methylation of the E-cadherin gene (Cdh1). E-cadherin downregulation is necessary for Six2's ability to increase soft agar growth and in vivo metastasis. Loss-of-function (knockdown), gain-of-function (overexpression), in vivo metastasis assay, promoter methylation analysis, epistasis rescue Cancer research Medium 25348955
2019 Six2 directly binds the Sox2 Srr2 enhancer, promoting Sox2 expression and downstream expression of Nanog in breast cancer cells, thereby enhancing cancer stem cell properties and metastatic colonization. ChIP (direct enhancer binding), knockdown/overexpression functional assays, in vivo metastasis models Cancer research Medium 30606720
2021 Eya1 and Six2 interact with the Brg1-based SWI/SNF chromatin remodeling complex during kidney development. Brg1 occupies a distal enhancer of Eya1 driving nephron progenitor-specific expression. Brg1 enrichment to distal intronic enhancers of Pbx1 and a proximal promoter of Mycn requires Six2 activity. Co-immunoprecipitation (tagged knock-in), conditional knockout, genome-wide ChIP-seq, transcriptome profiling, in vivo enhancer reporter assay Journal of the American Society of Nephrology : JASN High 34716243
2020 SIX2 regulates functional maturation of human SC-β cells; knockdown or knockout of SIX2 drastically limits glucose-stimulated insulin secretion, cytoplasmic calcium flux, and mitochondrial respiration, and regulates expression of genes associated with these β cell processes. Knockdown (KD) and knockout (KO) in hESC-derived β cells, static and dynamic insulin secretion assays, calcium imaging, mitochondrial respiration assay, transcriptome analysis Cell reports Medium 32460030
2021 SIX2 and SIX3 regulate distinct gene targets in human β cells: SIX2 loss markedly impairs expression of genes governing β-cell insulin processing, glucose sensing, and electrophysiology. Chromatin accessibility studies identified genes directly regulated by SIX2. shRNA knockdown in human adult islets, transcriptome analysis, chromatin accessibility (ATAC-seq) Genes & development Medium 33446570
2019 Six2 mediates the neuroprotective effect of GDNF on dopaminergic neurons by directly binding to the CAGCTG sequence of the Smurf1 promoter and promoting Smurf1 expression, which in turn decreases p53 expression to reduce apoptosis. ChIP-seq, ChIP-qPCR, knockdown/overexpression, in vitro and in vivo apoptosis assays Cell death & disease Medium 27148690
2019 Six2 activates the GDNF promoter by directly binding to it in dopaminergic cells, and this activation is regulated by the Akt1/Eya1/Six2 signaling axis: Akt1 phosphorylates Eya1, activated Eya1 decreases Six2 phosphorylation, and dephosphorylated Six2 promotes GDNF transcription. ChIP-qPCR (direct promoter binding), phosphorylation analysis, knockdown/overexpression Journal of molecular neuroscience : MN Medium 31720997
2015 LIF activates STAT, which binds to a STAT consensus sequence in the Six2 proximal promoter to sustain SIX2 levels in metanephric mesenchyme cells, maintaining the SIX2+ progenitor pool. Promoter-reporter assay, STAT binding site identification, LIF stimulation experiments, in vitro culture model Stem cell reports Medium 26321142
2019 Six2 directly binds to the PAX9 5' upstream regulatory element and activates PAX9 expression; a human SIX2 coding missense variant (p.Gly264Glu) affects SIX2 protein stability and leads to decreased PAX9 expression. ChIP (SIX2 binding to PAX9 enhancer), luciferase reporter assay, mutagenesis (variant functional analysis), protein stability assay Developmental biology Medium 31765609
2017 In the developing kidney, Six2-dependent progenitor proliferation and self-renewal are separable by gene dosage: Six2 heterozygotes show increased nephron progenitor proliferation with increased MYC protein and MYC target gene upregulation, despite reduced SIX2 levels. Quantitative morphometry, EdU labeling (proliferation), immunostaining (MYC protein), transcriptional profiling Kidney international Medium 29217079
2009 Six2 activity is required for the formation of the pyloric sphincter, regulating a gene network including Bmp4, Bmpr1b, Nkx2.5, Sox9, and Gremlin in mice. Loss-of-function genetics (Six2 null mice), expression analysis of target genes Developmental biology Medium 19660448
2021 Smarcd1 (a SWI/SNF chromatin-remodeling complex member) forms a transcription complex with Six2 in dopaminergic neurons and is recruited to the GDNF promoter (specifically the 2840–2933 bp region) by Six2 to enhance Six2-driven GDNF expression and protect against apoptosis. Co-immunoprecipitation, ChIP (Smarcd1 binding to GDNF promoter region), knockdown/overexpression functional assays, LC-ESI-MS (interactome screen) Neuroscience letters Medium 34233203
2017 Six2 functions downstream of Hoxa2 in palate development: Six2 mRNA and protein are upregulated in Hoxa2-null palatal shelves, and siRNA-mediated Six2 knockdown restores proliferation and Cyclin D1 expression in Hoxa2-null palatal mesenchyme cells to near wild-type levels. Conditional loss-of-function (Hoxa2 KO), siRNA knockdown, cell proliferation assay (Ki-67 immunostaining, in vitro proliferation), western blot Frontiers in physiology Medium 29218017
2018 In Lowe syndrome (OCRL1 mutation), the transcription factor Six2 is substantially retained in the Golgi complex in kidney-differentiated cells, with reduced nuclear-localized fraction; OCRL1 knockout reproduces both ciliogenesis defects and Six2 retention at the Golgi. iPSC differentiation to kidney cells, immunofluorescence (subcellular fractionation/localization), OCRL1 KO in HK2 cells PloS one Medium 29444177
2024 SIX2 depletion in androgen-independent prostate cancer cells induces a switch from stem-like to epithelial state, reducing proliferation, colony formation, and metastasis both in vitro and in vivo. These effects are mediated through downregulation of the Wnt/β-catenin signaling pathway and reduction of nuclear β-catenin. Knockdown (siRNA/shRNA), chromatin accessibility analysis, in vitro and in vivo functional assays, immunostaining for nuclear β-catenin Nucleic acids research Medium 38554106
2024 SIX2 directly regulates METTL9 expression (shown by CUT&Tag analysis). METTL9 binds to SLC7A11 (confirmed by Co-IP), enhancing SLC7A11 stability and reducing degradation, thereby regulating ferroptosis independently of the GPX4 pathway. CUT&Tag (direct binding), Co-immunoprecipitation (METTL9-SLC7A11 interaction), RNA sequencing, overexpression/knockdown functional assays NPJ precision oncology Medium 40523929
2025 TRIM21 acts as an E3 ubiquitin ligase for SIX2: TRIM21 binds to SIX2 via its PRY-SPRY domain and catalyzes K48-type ubiquitination at lysine residues K82, K89, and K97 of SIX2, promoting its degradation via the ubiquitin-proteasome pathway. SIX2 transcriptionally activates LGSN expression through direct binding to its promoter. Co-immunoprecipitation, ubiquitination assay (K48-type), site-directed mutagenesis (K82/K89/K97), ChIP (SIX2 binding to LGSN promoter), proteasome inhibition (MG132) Oncogene High 40954199
2023 NIK (NF-κB Inducing Kinase) promotes SIX2 protein stability by suppressing its ubiquitination via the ubiquitin-proteasome system: NIK knockdown promotes SIX2 ubiquitination and decreases its protein stability (rescued by MG132 proteasome inhibitor), without affecting SIX2 mRNA levels. Knockdown, ubiquitination assay, MG132 proteasome inhibitor rescue, protein stability assay Environmental toxicology Medium 37461228
2024 SIX2 directly binds the PFN2 promoter to activate PFN2 expression. In turn, PFN2 promotes mRNA stability of SIX2 by recruiting the RNA binding protein YBX-1, activating the MAPK/JNK pathway downstream. ChIP (SIX2 binding to PFN2 promoter), RNA stability assay, Co-immunoprecipitation (PFN2-YBX-1), JNK pathway inhibition Journal of translational medicine Medium 39256760
2024 Aberrant enhancer-promoter interactions in the Six2TGC transgene drive ectopic expression of Six3 (not Six2), which interferes with SIX2 function in nephron progenitor cell renewal through its C-terminal domain, causing reduced nephron endowment. Targeted locus amplification (integration site mapping), Hi-C (chromatin conformation capture), CRISPR disruption of Six3 within transgene, genetic rescue experiments Journal of the American Society of Nephrology : JASN High 38447671
2019 DNMT1 is required in Six2-positive nephron progenitor cells for silencing of transposable elements and embryonic non-renal lineage genes; loss of DNMT1 (but not DNMT3a, DNMT3b, or TET2) in Six2-positive cells leads to severe kidney developmental defects with endogenous retroviral transcript activation and cell death. Conditional knockout (Six2-Cre driver), genome-wide methylation analysis (WGBS), RNA-seq, comparison with DNMT3a/3b/TET2 conditional KOs Journal of the American Society of Nephrology : JASN High 30850438
2017 Six2 marks a dynamic subset of second heart field progenitors whose descendants are allocated successively to regions of the heart. Six2 expression in cardiac progenitors depends in part on Shh signaling, and Shh deletion results in severe deficiency of Six2-positive progenitors. Genetic lineage tracing, progenitor ablation, conditional knockout of Shh, immunostaining Cell reports Medium 28122228
2022 Six1 cannot substitute for Six2 in mouse nephron progenitor renewal: forced Six1 expression mediated Eya1 nuclear translocation and inhibited premature epithelialization, but failed to rescue proliferation defects and cell death caused by Six2 knockout. Genome-wide binding showed Six1 occupied only a subset of Six2 target sites, with many Six2-bound loci crucial to progenitor renewal lacking Six1 occupancy. Conditional knock-in (Six1 replacing Six2), genome-wide ChIP-seq (Six1 vs. Six2 binding), phenotypic rescue analysis Frontiers in cell and developmental biology High 35178390
2017 Smad3 can transcriptionally target Six2 (identified by bioinformatics and validated by luciferase assay). TβRII promotes Six2 expression through Smad3-mediated transcriptional regulation; Six2 partially rescues proliferation defects caused by TβRII knockdown in metanephric mesenchyme cells. Luciferase reporter assay (Smad3 targeting Six2 promoter), knockdown/overexpression, EdU proliferation assay International journal of molecular sciences Low 28420207
2016 Zeb1 promotes Six2 promoter reporter activity (luciferase assay) and its expression in metanephric mesenchyme cells; knockdown of Zeb1 decreases Six2 expression and reduces cell proliferation and migration. Dual-luciferase reporter assay, knockdown, western blot, RT-PCR, EdU assay International journal of molecular sciences Low 27509493
2017 GATA1 directly binds the Six2 promoter and promotes its transcriptional activity; mutation of GATA1 binding sites in the mSix2 promoter decreases promoter activity. Knockdown of GATA1 reduces Six2 expression and increases apoptosis in metanephric mesenchyme cells, which is rescued by Six2 overexpression. Luciferase reporter assay with GATA1 binding site mutagenesis, knockdown, qPCR, apoptosis assay, rescue experiment In vitro cellular & developmental biology. Animal Low 28842839
2024 TRIM25 directly interacts with SIX2 and promotes its ubiquitination and degradation; TRIM25 reduces SPRED2 transcription (via SIX2 degradation), leading to ERK phosphorylation and suppression of neuronal autophagy under high-glucose conditions. SIX2 transcriptionally activates SPRED2 expression. Co-immunoprecipitation, cycloheximide chase assay, ubiquitination assay, ChIP, dual-luciferase reporter, western blot Journal of molecular neuroscience : MN Medium 42105075
2026 EYA4 interacts with SIX2 to promote p21 expression and accelerate cellular senescence. This regulatory function is independent of EYA4's phosphatase activity (shown by phosphatase-deficient mutant) and is p53-dependent. Co-immunoprecipitation (EYA4-SIX2 interaction), phosphatase-deficient mutant analysis, knockdown, luciferase reporter assay, p53 epistasis Advanced biotechnology Medium 41991886

Source papers

Stage 0 corpus · 85 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. Cell stem cell 763 18682239
2006 Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney. The EMBO journal 380 17036046
2012 Six2 and Wnt regulate self-renewal and commitment of nephron progenitors through shared gene regulatory networks. Developmental cell 214 22902740
2014 Eya1 interacts with Six2 and Myc to regulate expansion of the nephron progenitor pool during nephrogenesis. Developmental cell 99 25458011
2004 The transcription factor Six2 activates expression of the Gdnf gene as well as its own promoter. Mechanisms of development 87 15327782
2014 Osr1 acts downstream of and interacts synergistically with Six2 to maintain nephron progenitor cells during kidney organogenesis. Development (Cambridge, England) 70 24598167
2019 Transcriptional factor six2 promotes the competitive endogenous RNA network between CYP4Z1 and pseudogene CYP4Z2P responsible for maintaining the stemness of breast cancer cells. Journal of hematology & oncology 67 30832689
2016 Notch signaling promotes nephrogenesis by downregulating Six2. Development (Cambridge, England) 56 27633993
2014 Homeoprotein Six2 promotes breast cancer metastasis via transcriptional and epigenetic control of E-cadherin expression. Cancer research 55 25348955
2020 Circular RNA 0007255 regulates the progression of breast cancer through miR-335-5p/SIX2 axis. Thoracic cancer 49 31962380
2017 Temporally Distinct Six2-Positive Second Heart Field Progenitors Regulate Mammalian Heart Development and Disease. Cell reports 44 28122228
2017 The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer. Theranostics 44 28435452
2020 The FGF, TGFβ and WNT axis Modulate Self-renewal of Human SIX2+ Urine Derived Renal Progenitor Cells. Scientific reports 41 31959818
2019 Crucial and Overlapping Roles of Six1 and Six2 in Craniofacial Development. Journal of dental research 41 30905259
2008 Six2 functions redundantly immediately downstream of Hoxa2. Development (Cambridge, England) 41 18321982
2019 SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program. Cancer research 40 30606720
2020 SIX2 Regulates Human β Cell Differentiation from Stem Cells and Functional Maturation In Vitro. Cell reports 38 32460030
2012 SIX2 and CITED1, markers of nephronic progenitor self-renewal, remain active in primitive elements of Wilms' tumor. Journal of pediatric surgery 38 22703800
2021 SIX2 and SIX3 coordinately regulate functional maturity and fate of human pancreatic β cells. Genes & development 37 33446570
2019 DNMT1 in Six2 Progenitor Cells Is Essential for Transposable Element Silencing and Kidney Development. Journal of the American Society of Nephrology : JASN 36 30850438
2010 Inactivation of Six2 in mouse identifies a novel genetic mechanism controlling development and growth of the cranial base. Developmental biology 36 20515681
2015 Preferential Propagation of Competent SIX2+ Nephronic Progenitors by LIF/ROCKi Treatment of the Metanephric Mesenchyme. Stem cell reports 34 26321142
2013 Wnt and BMP signaling cooperate with Hox in the control of Six2 expression in limb tendon precursor. Developmental biology 33 23499659
2008 Misexpression of Six2 is associated with heritable frontonasal dysplasia and renal hypoplasia in 3H1 Br mice. Developmental dynamics : an official publication of the American Association of Anatomists 33 18570229
2017 Haploinsufficiency for the Six2 gene increases nephron progenitor proliferation promoting branching and nephron number. Kidney international 30 29217079
2009 Non-homeodomain regions of Hox proteins mediate activation versus repression of Six2 via a single enhancer site in vivo. Developmental biology 30 19716816
2000 Structure, mapping and expression of the human gene encoding the homeodomain protein, SIX2. Gene 30 10773454
2012 Conditional expression of Wnt9b in Six2-positive cells disrupts stomach and kidney function. PloS one 29 22912798
2017 Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6-TMC8 and SIX3-SIX2 loci associated with HbA1c. Scientific reports 28 29170429
2009 Deficiency in Six2 during prenatal development is associated with reduced nephron number, chronic renal failure, and hypertension in Br/+ adult mice. American journal of physiology. Renal physiology 28 19193724
2016 MicroRNA-185 inhibits cell proliferation and epithelial-mesenchymal transition in hepatocellular carcinoma by targeting Six2. European review for medical and pharmacological sciences 25 27212161
2015 A new frontonasal dysplasia syndrome associated with deletion of the SIX2 gene. American journal of medical genetics. Part A 25 26581443
2016 Transcription factor Six2 mediates the protection of GDNF on 6-OHDA lesioned dopaminergic neurons by regulating Smurf1 expression. Cell death & disease 24 27148690
2014 SIX2 Effects on Wilms Tumor Biology. Translational oncology 24 25500091
2012 The pluripotent renal stem cell regulator SIX2 is activated in renal neoplasms and influences cellular proliferation and migration. Human pathology 24 22995329
2009 Six2 activity is required for the formation of the mammalian pyloric sphincter. Developmental biology 24 19660448
2019 Six2 promotes non-small cell lung cancer cell stemness via transcriptionally and epigenetically regulating E-cadherin. Cell proliferation 22 31012173
2017 Derivation and characterization of integration-free iPSC line ISRM-UM51 derived from SIX2-positive renal cells isolated from urine of an African male expressing the CYP2D6 *4/*17 variant which confers intermediate drug metabolizing activity. Stem cell research 22 29035842
2013 MiR-181b targets Six2 and inhibits the proliferation of metanephric mesenchymal cells in vitro. Biochemical and biophysical research communications 22 24055707
2016 Zeb1 Is a Potential Regulator of Six2 in the Proliferation, Apoptosis and Migration of Metanephric Mesenchyme Cells. International journal of molecular sciences 21 27509493
2010 Mutational analysis of HOXA2 and SIX2 in a Bronx population with isolated microtia. International journal of pediatric otorhinolaryngology 21 20542577
2017 Six2 Plays an Intrinsic Role in Regulating Proliferation of Mesenchymal Cells in the Developing Palate. Frontiers in physiology 18 29218017
2024 SIX2 promotes cell plasticity via Wnt/β-catenin signalling in androgen receptor independent prostate cancer. Nucleic acids research 16 38554106
2016 SIX2 haploinsufficiency causes conductive hearing loss with ptosis in humans. Journal of human genetics 16 27383657
2021 Chromatin Remodelers Interact with Eya1 and Six2 to Target Enhancers to Control Nephron Progenitor Cell Maintenance. Journal of the American Society of Nephrology : JASN 15 34716243
2019 Six2 regulates Pax9 expression, palatogenesis and craniofacial bone formation. Developmental biology 14 31765609
2022 De novo SIX2 activation in human kidneys treated with neonatal kidney stem/progenitor cells. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 13 35913414
2016 Postembryonic Nephrogenesis and Persistence of Six2-Expressing Nephron Progenitor Cells in the Reptilian Kidney. PloS one 13 27144443
2014 miR181c promotes apoptosis and suppresses proliferation of metanephric mesenchyme cells by targeting Six2 in vitro. Cell biochemistry and function 13 25187057
2019 PPARG Negatively Modulates Six2 in Tumor Formation of Clear Cell Renal Cell Carcinoma. DNA and cell biology 12 31090452
2018 Kidney-differentiated cells derived from Lowe Syndrome patient's iPSCs show ciliogenesis defects and Six2 retention at the Golgi complex. PloS one 12 29444177
2015 Identification of distal enhancers for Six2 expression in pronephros. The International journal of developmental biology 11 26009236
2022 Six1 and Six2 of the Sine Oculis Homeobox Subfamily are Not Functionally Interchangeable in Mouse Nephron Formation. Frontiers in cell and developmental biology 9 35178390
2014 Down-regulated Six2 by knockdown of neurofibromin results in apoptosis of metanephric mesenchyme cells in vitro. Molecular and cellular biochemistry 9 24573885
2018 SIX2 gene haploinsufficiency leads to a recognizable phenotype with ptosis, frontonasal dysplasia, and conductive hearing loss. Clinical dysmorphology 8 29315086
2016 Six2 Is a Coordinator of LiCl-Induced Cell Proliferation and Apoptosis. International journal of molecular sciences 8 27618015
2024 Reduced Nephron Endowment in Six2-TGCtg Mice Is Due to Six3 Misexpression by Aberrant Enhancer-Promoter Interactions in the Transgene. Journal of the American Society of Nephrology : JASN 7 38447671
2022 Tet2- and Tet3- Mediated Cytosine Hydroxymethylation in Six2 Progenitor Cells in Mice Is Critical for Nephron Progenitor Differentiation and Nephron Endowment. Journal of the American Society of Nephrology : JASN 7 36522157
2019 MES23.5 DA Immortalized Neuroblastoma Cells Self-protect Against Early Injury by Overexpressing Glial Cell-derived Neurotrophic Factor via Akt1/Eya1/Six2 Signaling. Journal of molecular neuroscience : MN 7 31720997
2024 Microglial SIX2 suppresses lipopolysaccharide (LPS)-induced neuroinflammation by up-regulating FXYD2 expression. Brain research bulletin 6 38688414
2024 Six2 regulates the malignant progression and 5-FU resistance of hepatocellular carcinoma through the PI3K/AKT/mTOR pathway and DNMT1/E-cadherin methylation mechanism. Neoplasma 6 39556430
2024 The SIX2/PFN2 feedback loop promotes the stemness of gastric cancer cells. Journal of translational medicine 4 39256760
2023 NIK-mediated reactivation of SIX2 enhanced the CSC-like traits of hepatocellular carcinoma cells through suppressing ubiquitin-proteasome system. Environmental toxicology 4 37461228
2021 Smarcd1 antagonizes the apoptosis of injured MES23.5 DA cells by enhancing the effect of Six2 on GDNF expression. Neuroscience letters 4 34233203
2020 Generation and characterization of Six2 conditional mice. Genesis (New York, N.Y. : 2000) 4 32277572
2022 [Effects of transcription factor SIX2 gene on the proliferation of bovine skeletal muscle satellite cells]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 3 37308406
2019 Constructing an Isogenic 3D Human Nephrogenic Progenitor Cell Model Composed of Endothelial, Mesenchymal, and SIX2-Positive Renal Progenitor Cells. Stem cells international 3 31191670
2019 Transcription factor Six2 induces a stem cell-like phenotype in renal cell carcinoma cells. FEBS open bio 3 31420918
2017 TβRII Regulates the Proliferation of Metanephric Mesenchyme Cells through Six2 In Vitro. International journal of molecular sciences 3 28420207
2017 Six2 is involved in GATA1-mediated cell apoptosis in mouse embryonic kidney-derived cell lines. In vitro cellular & developmental biology. Animal 3 28842839
2018 Gulo regulates the proliferation, apoptosis and mesenchymal-to-epithelial transformation of metanephric mesenchyme cells via inhibiting Six2. Biochemical and biophysical research communications 2 30219227
2013 [Expression and promoter methylation of SIX2 gene in peripheral blood of pediatric patients with nephroblastoma]. Zhonghua yi xue za zhi 2 24124738
2011 Osmoregulatory defect in adult mice associated with deficient prenatal expression of six2. American journal of physiology. Regulatory, integrative and comparative physiology 2 21653879
2025 Targeting SIX2 as a novel sensitization strategy of sorafenib treatment on advanced hepatocellular carcinoma through modulating METTL9-SLC7A11 axis. NPJ precision oncology 1 40523929
2025 TRIM21-mediated ubiquitination of SIX2 attenuates breast cancer stemness via LGSN suppression. Oncogene 1 40954199
2025 Human Urine-Derived SIX2-Positive Renal Progenitor Cells Partially Improve Kidney Fibrosis by Paracrine Signaling. Stem cells and development 1 41168982
2023 Reduced nephron endowment in the common Six2-TGC mouse line is due to Six3 misexpression by aberrant enhancer-promoter interactions in the transgene. bioRxiv : the preprint server for biology 1 37873415
2021 MicroRNA-185 inhibits cell proliferation and epithelial-mesenchymal transition in hepatocellular carcinoma by targeting Six2. European review for medical and pharmacological sciences 1 34109599
2019 Correction to: Transcriptional factor six2 promotes the competitive endogenous RNA network between CYP4Z1 and pseudogene CYP4Z2P responsible for maintaining the stemness of breast cancer cells. Journal of hematology & oncology 1 31651345
2026 SIX2-Mediated Microglial M2 Polarization and Exosomal miR-3470b Delivery Protect Dopaminergic Neurons in Parkinson's Disease. CNS neuroscience & therapeutics 0 41700504
2026 EYA4 promotes cellular senescence by enhancing P21 transcription through interaction with SIX2. Advanced biotechnology 0 41991886
2026 TRIM25 Suppresses Hippocampal Neuronal Autophagy under High Glucose via Ubiquitination and Degradation of SIX2. Journal of molecular neuroscience : MN 0 42105075
2025 OSR1 and SIX2 drive divergent transcriptional programs in human kidney cells: implications for regeneration and tumorigenesis. Frontiers in bioengineering and biotechnology 0 41112069
2025 Modelling APOL1-mediated kidney inflammation and fibrosis using a partially reprogrammed urine-derived SIX2-positive renal progenitor cell line. Stem cell research & therapy 0 41225540
2024 RETRACTION: Six2 Promotes Non-Small Cell Lung Cancer Cell Stemness Via Transcriptionally and Epigenetically Regulating E-Cadherin. Cell proliferation 0 38804816

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