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Showing ZBTB14 — ZFP161 is a alias.

ZBTB14

Zinc finger and BTB domain-containing protein 14 · UniProt O43829

Length
449 aa
Mass
51.0 kDa
Annotated
2026-06-11
10 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZBTB14 (ZFP161/ZF5) is a BTB/POZ–Krüppel-type C2H2 zinc finger protein that functions both as a sequence-specific transcription factor and as a scaffolding factor in the replication-stress response, coordinating gene expression and genome stability across diverse cell types (PMID:9244432, PMID:31757956, PMID:41789397). Through its zinc fingers it binds target promoters directly and can either repress or activate transcription depending on context: it activates c-MYC to promote proliferation and transformation (PMID:41789397), represses the TMEM208 promoter to suppress radiotherapy resistance in breast cancer (PMID:39692812), represses the myeloid master regulator pu.1 to restrain monocyte/macrophage expansion (PMID:36205309), and represses the cytokines IL6 and LIF in skeletal muscle downstream of AMPK (PMID:29688769). Its repressor activity requires SUMOylation on a conserved lysine, and a patient-derived mutation routes the protein to autophagic degradation (PMID:36205309). Independently of its transcriptional role, ZBTB14 acts at stalled replication forks, binding RPA and ATR/ATRIP through distinct regions to stabilize the RPA–ATR–ATRIP complex and activate ATR/Chk1 signaling (PMID:31757956). Beyond transcription, it modulates developmental and fibrotic signaling, suppressing BMP/Smad1/5/8 phosphorylation while promoting β-catenin accumulation to coordinate embryonic patterning (PMID:29664133) and driving hepatic stellate cell activation via β-catenin in NAFLD fibrosis (PMID:37796689). The protein partitions between nucleus and cytoplasm with diurnal oscillation (PMID:39870297).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1997 Medium

    Establishing the domain architecture defined ZBTB14 as a BTB/POZ–zinc finger protein and predicted a transcriptional-repressor, growth-suppressive function by homology to murine ZF5.

    Evidence cDNA cloning, ORF analysis, and chromosomal mapping

    PMID:9244432

    Open questions at the time
    • Function inferred from murine ortholog, not directly assayed in human cells
    • No direct target genes identified
    • DNA-binding specificity not defined
  2. 2005 Medium

    Identifying ZNF295 as a physical partner placed ZBTB14 in a BTB/POZ protein interaction network and confirmed it possesses both repressor and activator transcriptional activity.

    Evidence Co-immunoprecipitation and promoter-reporter assays

    PMID:15629158

    Open questions at the time
    • Functional consequence of the ZNF295 interaction on specific targets not resolved
    • Single-lab Co-IP
    • Endogenous complex not characterized
  3. 2018 Medium

    Loss-of-function in muscle and reciprocal manipulation in Xenopus showed ZBTB14 represses specific cytokine genes and modulates BMP and Wnt signaling, extending its role to physiological transcriptional control and developmental patterning.

    Evidence siRNA knockdown with mRNA quantification in myotubes; overexpression/morpholino in Xenopus embryos with phospho-Smad and β-catenin Western blots

    PMID:29664133 PMID:29688769

    Open questions at the time
    • Direct promoter binding to IL6/LIF not shown
    • Mechanism linking ZBTB14 to Smad1/5/8 and β-catenin levels not defined
    • Single-lab findings in distinct systems
  4. 2019 High

    Demonstrating direct binding to RPA and ATR/ATRIP revealed a transcription-independent scaffolding role: ZBTB14 stabilizes the RPA–ATR–ATRIP complex to activate ATR/Chk1 signaling under replication stress.

    Evidence Reciprocal Co-IP, domain-mapping pulldowns, and ZFP161 knockout mice with ATR signaling and genomic-instability readouts

    PMID:31757956

    Open questions at the time
    • Structural basis of RPA/ATRIP engagement not resolved
    • How transcriptional and replication-fork roles are coordinated unknown
    • Whether DNA-binding is required for fork recruitment unclear
  5. 2022 High

    Work in zebrafish established that SUMOylation on a conserved lysine is required for ZBTB14 repressor activity at the pu.1 promoter and that an AML-associated mutation triggers autophagic degradation, linking a post-translational switch to hematopoietic control and disease.

    Evidence Zbtb14-deficient zebrafish, pu.1 luciferase reporter assays, SUMOylation mutant analysis, and autophagic degradation assays

    PMID:36205309

    Open questions at the time
    • SUMO E3 ligase mediating modification not identified
    • Whether SUMOylation governs all repression targets unknown
    • Causal contribution of the mutation to human AML not established in patients
  6. 2023 Medium

    ZBTB14 was shown to promote hepatic stellate cell activation through β-catenin, implicating it in NAFLD-associated fibrosis.

    Evidence Gerbil NAFLD model, siRNA knockdown in HSCs, β-catenin readouts, and mRNA sequencing

    PMID:37796689

    Open questions at the time
    • Direct transcriptional targets in HSCs not defined
    • Mechanism connecting ZBTB14 to β-catenin not resolved
    • Single-lab study
  7. 2024 Medium

    ChIP and rescue epistasis demonstrated direct repression of the TMEM208 promoter, defining a ZBTB14–TMEM208 axis that suppresses radiotherapy resistance in breast cancer.

    Evidence ChIP-qPCR, luciferase reporter, and overexpression/rescue in breast cancer cells and xenografts

    PMID:39692812

    Open questions at the time
    • Binding motif within the promoter not mapped
    • Generality across tumor types unknown
    • Single-lab study
  8. 2026 Medium

    ChIP and functional assays showed human ZBTB14 directly binds and activates the c-MYC promoter to drive proliferation and transformation, reversing the repressor role attributed to its murine ortholog and underscoring context-dependent regulatory output.

    Evidence ChIP, gene expression, and proliferation/transformation assays in RPE-1 cells

    PMID:41789397

    Open questions at the time
    • Determinants of activator-versus-repressor switching not defined
    • Cofactors at the c-MYC promoter not identified
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • What dictates whether ZBTB14 activates or represses a given promoter, and how its transcriptional and replication-fork scaffolding roles are integrated, remain unresolved.
  • No unifying model for activator/repressor switching
  • Genome-wide direct target map lacking
  • Interplay between SUMOylation, localization oscillation, and function unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 2 R-HSA-73894 DNA Repair 1
Partners
ATRATRIPRPAZNF295
Complex memberships
RPA-ATR-ATRIP complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 ZFP161 (ZBTB14) encodes a protein with five C2H2 Krüppel-type zinc finger motifs near the C-terminus and a BTB/POZ domain in the N-terminal region, and is 98% homologous to murine ZF5, a putative transcriptional repressor of c-myc with growth-suppressive activity in mouse cell lines. cDNA cloning, sequencing, and open reading frame analysis; chromosomal mapping via somatic cell hybrid panels Genomics Medium 9244432
2005 ZFP161 (ZBTB14) physically interacts with ZNF295 (both isoforms ZNF295L and ZNF295S), another BTB/POZ zinc finger protein; ZFP161 is itself a transcriptional repressor and activator, and ZNF295 acts as a transcription repressor through both its BTB/POZ domain and a central region. Co-immunoprecipitation (interaction assay), promoter-reporter transcription activity assays Biochemical and biophysical research communications Medium 15629158
2018 ZBTB14 knockdown in skeletal muscle (rat L6 myotubes and primary human muscle cells) increases constitutive mRNA levels of IL6 and LIF, identifying ZBTB14 as a transcriptional repressor of these cytokines in skeletal muscle; this regulation is downstream of AMPK activation. siRNA knockdown, mRNA quantification, transcriptional blocker (actinomycin D) experiments, cross-species bioinformatics American journal of physiology. Endocrinology and metabolism Medium 29688769
2018 Xenopus Zbtb14 overexpression reduces levels of phosphorylated Smad1/5/8 to suppress BMP signaling and induces accumulation of β-Catenin to promote Wnt signaling, thereby coordinating dorsal-ventral and anterior-posterior patterning of early embryos. Overexpression and knockdown (morpholino) in Xenopus embryos; Western blot for phospho-Smad1/5/8 and β-Catenin levels Development, growth & differentiation Medium 29664133
2019 ZFP161 (ZBTB14) acts as a scaffolding protein at stalled replication forks, binding directly to RPA and to ATR/ATRIP through distinct regions, thereby stabilizing the RPA-ATR-ATRIP complex and facilitating ATR/Chk1 pathway activation in response to replication stress. Co-immunoprecipitation, domain-mapping pulldown assays, ZFP161 knockout mice with ATR signaling readouts, genomic instability assays Nature communications High 31757956
2022 Zebrafish Zbtb14 functions as a transcriptional repressor of pu.1, restraining monocyte/macrophage expansion; SUMOylation on a conserved lysine residue is required for its repression activity; a serine-to-phenylalanine mutation found in an AML patient targets ZBTB14 protein for autophagic degradation. Zbtb14-deficient zebrafish, luciferase reporter assays for pu.1 promoter repression, SUMOylation mutant analysis, autophagic degradation assays eLife High 36205309
2023 Zbtb14 regulates activation of hepatic stellate cells (HSCs) via the β-catenin pathway, promoting NAFLD-associated fibrosis; Zbtb14 was upregulated in liver fibrosis tissues and in activated HSCs. Gerbil NAFLD fibrosis model, siRNA knockdown in HSCs, β-catenin pathway readouts, mRNA sequencing Frontiers in bioscience (Landmark edition) Medium 37796689
2024 ZBTB14 directly binds the TMEM208 promoter and represses its transcription, suppressing radiotherapy resistance in breast cancer cells; overexpression of TMEM208 reverses the inhibitory effects of ZBTB14 overexpression. Chromatin immunoprecipitation (ChIP)-qPCR, luciferase reporter assays, overexpression and rescue experiments in breast cancer cells and xenograft models Journal of mammary gland biology and neoplasia Medium 39692812
2025 ZFP161 (ZBTB14) protein localizes to both cytoplasm and cell nuclei in hippocampal neurons, with cytoplasmic and nuclear levels showing diurnal (phase-shifted) oscillations; this oscillation is disrupted in a pilocarpine model of temporal lobe epilepsy. Immunostaining, Western blot of cytoplasmic and nuclear fractions across diurnal time points, pilocarpine epilepsy mouse model Neuroscience Medium 39870297
2026 Human ZFP161 (ZBTB14) directly binds the promoter region of c-MYC and transcriptionally activates c-MYC expression, promoting cell proliferation and tumorigenesis; this is the opposite of the repressor activity described for murine ZF5. Chromatin immunoprecipitation (ChIP), gene expression assays, cell proliferation and transformation assays in RPE-1 cells Frontiers in oncology Medium 41789397

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 The human gene ZFP161 on 18p11.21-pter encodes a putative c-myc repressor and is homologous to murine Zfp161 (Chr 17) and Zfp161-rs1 (X Chr). Genomics 32 9244432
2019 ZFP161 regulates replication fork stability and maintenance of genomic stability by recruiting the ATR/ATRIP complex. Nature communications 25 31757956
2018 IL6 and LIF mRNA expression in skeletal muscle is regulated by AMPK and the transcription factors NFYC, ZBTB14, and SP1. American journal of physiology. Endocrinology and metabolism 23 29688769
2018 Coordinated regulation of the dorsal-ventral and anterior-posterior patterning of Xenopus embryos by the BTB/POZ zinc finger protein Zbtb14. Development, growth & differentiation 16 29664133
2005 Novel human BTB/POZ domain-containing zinc finger protein ZNF295 is directly associated with ZFP161. Biochemical and biophysical research communications 16 15629158
2022 Zbtb14 regulates monocyte and macrophage development through inhibiting pu.1 expression in zebrafish. eLife 15 36205309
2024 Transcription Impairment of TMEM208 by ZBTB14 Suppresses Breast cancer Radiotherapy Resistance. Journal of mammary gland biology and neoplasia 2 39692812
2023 Zbtb14 Promotes Non-Alcoholic Fatty Liver Disease-Associated Fibrosis in Gerbils via the β-Catenin Pathway. Frontiers in bioscience (Landmark edition) 2 37796689
2025 Diurnal dynamics of the Zbtb14 protein in the ventral hippocampus are disrupted in epileptic mice. Neuroscience 1 39870297
2026 ZFP161 promotes colorectal cancer progression by transcriptionally activating c-MYC. Frontiers in oncology 0 41789397

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