Affinage

BTG2

Protein BTG2 · UniProt P78543

Length
158 aa
Mass
17.4 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BTG2 (TIS21/PC3) is an antiproliferative protein that enforces cell-cycle exit and quiescence through two convergent activities: activation of mRNA deadenylation and regulation of arginine methylation, both deployed downstream of stress and damage signals (PMID:18337750, PMID:23089312, PMID:32165587). As a deadenylation activator, BTG2 binds the CAF1/CCR4-NOT complex via its conserved Box B/APRO domain and stimulates poly(A) tail shortening of transcripts, a function dissected biochemically and structurally: the BTG2 APRO domain bridges the first RRM domain of PABPC1 to CAF1, and these minimal components are sufficient to stimulate deadenylation and are required for BTG2 to control proliferation (PMID:9712883, PMID:18337750, PMID:18974182, PMID:26912148). Genetic loss of BTG1/2 in T cells globally lengthens poly(A) tails and stabilizes mRNAs, lowering the activation threshold and establishing deadenylation as the basis of BTG2-dependent quiescence (PMID:32165587). In parallel, BTG2 is a regulatory partner of the arginine methyltransferase PRMT1, modulating its activity to direct histone H4 arginine methylation at the RARβ promoter, to methylate Mre11 in support of double-strand break repair, and to methylate CDK4 and thereby block CDK4-Cyclin D3 assembly and cell-cycle progression (PMID:8663146, PMID:16782888, PMID:23089312, PMID:28628091). BTG2 is transcriptionally induced by p53 after DNA damage and by NF-κB, and it imposes G1 arrest by suppressing cyclin E, CDK4, and cyclin D1 and G2/M arrest by inhibiting cyclin B1-CDK1 and disrupting the FoxM1-cyclin B1 loop (PMID:8944033, PMID:9766435, PMID:15378000, PMID:15302583, PMID:18393292). It additionally couples to differentiation and tissue patterning by enhancing BMP/Smad signaling, regulating adult neurogenesis through Id3 and Cxcl3, and modulating antioxidant responses via NFE2L2; in cancer it suppresses invasion through an Akt1-Sp1-Nox4-ROS axis (PMID:15542835, PMID:20020054, PMID:22493435, PMID:25798836, PMID:23115191). BTG2 protein stability is set by ubiquitin ligases SKP2 and TRIM6 (the latter targeting Lys5) and by Erk1/2 phosphorylation at Ser147 that recruits Pin1 to drive mitochondrial depolarization and senescence (PMID:15788397, PMID:20569234, PMID:19615363, PMID:31992359).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1994 Medium

    Establishing BTG2/TIS21 as a rapidly synthesized, rapidly turned-over soluble intracellular protein framed it as an immediate-response factor rather than a secreted or membrane signaling molecule.

    Evidence Pulse-chase metabolic labeling, subcellular fractionation, and immunohistochemistry

    PMID:8263025

    Open questions at the time
    • Does not define molecular function
    • Reported as non-nuclear, later studies place it on chromatin and in deadenylation complexes
  2. 1996 High

    Identification of BTG2 as a p53-induced gene that arrests proliferation, and as a physical modulator of PRMT1 methyltransferase activity, defined its two foundational axes: the DNA-damage response and arginine methylation.

    Evidence p53-inducible gene identification with overexpression readouts; yeast two-hybrid, GST pulldown, and in vitro methyltransferase assays

    PMID:8663146 PMID:8944033

    Open questions at the time
    • How PRMT1 modulation connects to antiproliferation not yet defined
    • Substrate specificity of the BTG2-PRMT1 module unknown
  3. 1998 High

    Mapping the conserved Box B domain interaction with mCaf1 placed BTG2 in the CCR4 deadenylase complex, while overexpression linked it to downregulation of cyclin E and CDK4 during G1 arrest.

    Evidence Yeast two-hybrid, GST pulldown, Co-IP, Box B deletion mutagenesis; stable transfection with FACS and cyclin/CDK kinase assays

    PMID:9712883 PMID:9766435

    Open questions at the time
    • Functional consequence of Caf1 binding not yet tested
    • Whether cyclin/CDK loss is direct or via mRNA decay unresolved
  4. 2001 High

    Demonstrating BTG2 binding to hCAF1/hPOP2 and to PICK1, with LXXLL-dependent modulation of ERα transcription, expanded its role to nuclear-receptor transcriptional control and PKC signaling.

    Evidence Co-IP, GST pulldown, domain mapping, ERα reporter assays; PICK1 PDZ-domain mapping and in vitro PKC phosphorylation

    PMID:11136725 PMID:11237868

    Open questions at the time
    • Physiological relevance of PICK1 interaction not established
    • Link between deadenylation complex binding and transcriptional output unclear
  5. 2003 Medium

    Showing BTG2 resides in multiple CCR4-NOT complexes of distinct sizes that vary with cell-cycle stage suggested complex composition tunes BTG2 function across the cycle.

    Evidence Immunoprecipitation, gel filtration chromatography, and cell-cycle fractionation

    PMID:12771185

    Open questions at the time
    • Functional difference between complex sizes not demonstrated
    • Mechanism linking hCAF1 relocalization to function unknown
  6. 2004 High

    Three studies extended BTG2 to developmental and stress signaling: it binds BMP-Smad1/8 to enhance BMP signaling (with a vertebral phenotype in knockouts), is induced by NF-κB to suppress cyclin D1, and inhibits cyclin B1-Cdc2 via a PKCδ pathway independent of p53.

    Evidence Btg2-null mice with Co-IP and BMP reporters; NF-κB stimulation with cyclin D1 rescue; PKC pharmacology, nocodazole synchronization, and in vivo kinase assays

    PMID:15302583 PMID:15378000 PMID:15542835

    Open questions at the time
    • Whether Smad and cyclin effects share a common biochemical mechanism unresolved
    • Direct versus indirect control of cyclin levels not separated from mRNA decay activity
  7. 2005 High

    Discovery that Erk1/2 phosphorylates BTG2 at Ser147 to recruit Pin1 and trigger mitochondrial depolarization defined a post-translational switch converting BTG2 toward cell death.

    Evidence In vitro kinase assay, P148A mutagenesis, Co-IP, shRNA, confocal Pin1 imaging, and JC-1 flow cytometry

    PMID:15788397

    Open questions at the time
    • How cytoplasmic Pin1 relocalization causes depolarization not detailed
    • Relationship to deadenylation function unknown
  8. 2006 High

    ChIP evidence that BTG2 brings PRMT1 to the RARα complex and deposits H4 arginine methylation at the RARβ promoter, reversed by retinoic acid, gave a concrete chromatin mechanism for BTG2 in differentiation priming.

    Evidence Co-IP of RARα complex, ChIP for H4 methylation/acetylation, and differentiation assays in myeloid progenitors

    PMID:16782888

    Open questions at the time
    • Genome-wide scope of BTG2-directed H4 methylation unknown
    • How retinoic acid triggers BTG2/PRMT1 dissociation unresolved
  9. 2008 High

    A cluster of studies cemented BTG2 as a general deadenylation activator and stability-regulated cell-cycle brake: it stimulates CAF1/CCR4-dependent poly(A) shortening of all transcripts, its crystal structure reveals the CAF1-binding interface, it inhibits FoxM1 by reducing cyclin B1-CDK1 activity, SKP2 targets it for degradation, and its PRMT1 partnership drives neurite outgrowth.

    Evidence In vitro deadenylation with CAF1 nuclease-dead mutants; X-ray crystallography with interface mutagenesis; in vitro kinase/FoxM1 mutant analysis with KO MEFs; Co-IP, ubiquitination and CHX-chase; PRMT1/Btg2 knockdown in Neuro2a

    PMID:18337750 PMID:18393292 PMID:18556508 PMID:18773938 PMID:18974182 PMID:19615363

    Open questions at the time
    • Whether deadenylation accounts for all antiproliferative phenotypes not fully separated from methylation activity
    • In vivo target transcripts of BTG2-driven decay not enumerated at this stage
  10. 2009 High

    BTG2 was shown to promote DSB repair via PRMT1-dependent Mre11 methylation while damping ATM-Chk2-p53(S20) signaling, to drive p53-independent senescence through Pin1, and to control adult neurogenesis through direct repression of Id3.

    Evidence γH2AX/Comet assays with Mre11 methylation and phospho-signaling; senescence assays with Pin1 Co-IP and rescue; PC3/Tis21-null mice with ChIP at Id3 and behavioral readouts

    PMID:20020054 PMID:20569234 PMID:23089312

    Open questions at the time
    • How BTG2 simultaneously promotes repair and limits damage signaling mechanistically unresolved
    • Pin1-dependent senescence versus DNA-repair roles not reconciled
  11. 2012 High

    BTG2 was linked to oxidative-stress defense through direct NFE2L2/Nrf2 interaction and antioxidant gene induction, to EMT suppression via miR-21-regulated prostate phenotype, and to Cxcl3-dependent cerebellar precursor migration and tumor suppression.

    Evidence Co-IP, ChIP at ARE, H2O2 viability with Box B mutagenesis; 3'-UTR decoy with orthotopic model; Tis21/Ptch1 double-KO with Cxcl3 rescue

    PMID:22493435 PMID:22614007 PMID:23115191

    Open questions at the time
    • Whether antioxidant and decay functions are coupled unknown
    • Direct versus indirect nature of Cxcl3 regulation not fully resolved
  12. 2016 High

    Structural-functional reconstitution showed the BTG2 APRO domain bridges PABPC1 RRM1 to CAF1 sufficiently to stimulate deadenylation and to control proliferation, and BTG2 was shown to restrain cardiomyocyte hypertrophy by lowering cytosolic RNA via deadenylation-complex binding.

    Evidence In vitro reconstitution with purified domains and interface mutagenesis plus proliferation assays; cardiomyocyte shRNA with single-cell RNA imaging and mass spectrometry of partners

    PMID:26912148 PMID:27346836

    Open questions at the time
    • Identity of the proliferation-relevant decay substrates not defined
    • How PABPC1 bridging selects target mRNAs unknown
  13. 2017 High

    Identification of PRMT1-mediated CDK4 methylation as the mechanism by which the BTG2-PRMT1 module blocks CDK4-Cyclin D3 assembly provided a direct biochemical link from arginine methylation to cell-cycle arrest in pre-B cells.

    Evidence Co-IP, in vitro CDK4 methylation assay, CDK4-Cyclin D3 pulldown, conditional KO pre-B cells, and BCR-ABL1 transformation model in vivo

    PMID:28628091

    Open questions at the time
    • Whether CDK4 methylation contributes to BTG2 function outside pre-B cells unknown
    • Relationship to deadenylation-driven cyclin loss not integrated
  14. 2020 High

    Genetic dissection in T cells established that BTG1/2-driven mRNA deadenylation maintains lymphocyte quiescence, and TRIM6 was identified as an E3 ligase ubiquitinating BTG2 at Lys5 to control its stability.

    Evidence Conditional double-KO mice with mRNA-seq, poly(A) tail and half-life measurements; IP/proteomics with TRIM6 C15A mutant, Lys5 mutagenesis, and CHX-chase

    PMID:31992359 PMID:32165587

    Open questions at the time
    • Specific quiescence-determining transcripts not enumerated
    • Signals regulating TRIM6-BTG2 turnover unknown
  15. 2022 Medium

    BTG2 mRNA was shown to be controlled by m6A modification: VIRMA/KIAA1429-deposited m6A reduces BTG2 mRNA via YTHDF2-dependent decay, defining an upstream layer of BTG2 regulation.

    Evidence MeRIP-seq, RNA stability assay, KIAA1429 knockdown, and m6A dot blot

    PMID:35730068

    Open questions at the time
    • Single-lab correlation; direct YTHDF2 binding to BTG2 m6A sites not fully mapped
    • Physiological contexts where this regulation operates limited
  16. 2023 Medium

    BTG2 was shown to bind Smad3 specifically and drive podocyte EMT in a TGF-β/Smad3-BTG2 feedback circuit, with podocyte-specific deletion protecting against glomerulosclerosis, extending BTG2's Smad-modulating role to disease.

    Evidence Podocyte-specific conditional KO, Co-IP discriminating Smad2 versus Smad3, SIS3 rescue, and ADR-induced FSGS model

    PMID:37749872

    Open questions at the time
    • How BTG2 distinguishes Smad3 from Smad2 mechanistically unknown
    • Reconciliation with earlier BMP-Smad1/8 enhancement not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How BTG2 selects specific mRNAs for deadenylation versus broadly activating decay, and how its deadenylation and PRMT1-methylation activities are coordinated within a single antiproliferative program, remain unresolved.
  • No defined transcript-selection rule for BTG2-driven decay
  • No unified model linking deadenylation, arginine methylation, and transcriptional co-regulation
  • Structural basis of context-specific Smad and nuclear-receptor partnering not solved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0003723 RNA binding 3 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-1640170 Cell Cycle 5 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-73894 DNA Repair 2
Partners
CNOT7NFE2L2PABPC1PIN1PRMT1SKP2SMAD1SMAD3
Complex memberships
CCR4-NOT deadenylase complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 BTG2/TIS21 interacts physically with PRMT1 (protein-arginine N-methyltransferase 1), and GST-TIS21 fusion protein modulates endogenous PRMT1 methyltransferase activity on protein substrates, suggesting BTG2 acts as a regulatory subunit of PRMT1. Yeast two-hybrid screening, GST pulldown, in vitro methyltransferase activity assay with cell extracts The Journal of biological chemistry High 8663146
1996 BTG2 expression is induced by p53 in response to DNA damage and its overexpression inhibits cell proliferation, placing BTG2 as a p53-dependent component of the DNA damage cellular response pathway. p53-inducible gene identification, transfection overexpression with proliferation/cell-cycle readouts Nature genetics High 8944033
1998 BTG1 and BTG2 physically interact with mCaf1 (mouse CCR4-associated factor 1) in vitro and in vivo, and the conserved Box B domain of BTG proteins is essential for the BTG–mCaf1 interaction, suggesting BTG2 participates in transcriptional regulation via the CCR4 complex. Yeast two-hybrid screening, GST pulldown (in vitro binding assay), co-immunoprecipitation in HeLa cells, transient transfection, Box B deletion mutagenesis The Journal of biological chemistry High 9712883
1998 Overexpression of TIS21 in 293 cells reduces synthesis of cyclin E and CDK4 proteins and decreases cyclin E-associated CDK kinase activity, causing G1 accumulation, identifying cyclin E and CDK4 downregulation as a mechanism of TIS21-induced G1 arrest. Stable transfection, FACS cell-cycle analysis (double thymidine block), western blot for cyclin E and CDK4, cyclin E-associated kinase activity assay Molecular carcinogenesis Medium 9766435
2001 BTG1 and BTG2 interact with both hCAF1 and hPOP2 (human paralogs of the yeast CCR4-associated factors) in vitro and in vivo, and LXXLL nuclear receptor box motifs in BTG1/BTG2 are involved in regulating estrogen receptor alpha (ERα)-mediated transcription, demonstrating that BTG2 can modulate ERα function through the CCR4-like complex. Co-immunoprecipitation, GST pulldown, interaction domain mapping, transient transfection reporter assays for ERα transcriptional activity The Journal of biological chemistry High 11136725
2001 TIS21/BTG2 protein interacts physically with rPICK1 (a PKCα-binding protein) via PICK1's PDZ domain, and this interaction modulates PKC-mediated phosphorylation of TIS21, suggesting a role for BTG2 in PKC signal transduction. Yeast two-hybrid, GST pulldown with in vitro translated TIS21, co-immunoprecipitation from NIH 3T3 cells, PDZ domain deletion mutagenesis, in vitro PKC phosphorylation assay The Biochemical journal Medium 11237868
2003 BTG2 interacts in vivo with hCCR4 protein via hCAF1 and hPOP2 within mammalian CCR4-NOT complexes of ~650 kDa, ~1 MDa, and ~1.9 MDa; hCAF1 cellular localization changes as cells progress from quiescence to S phase, suggesting distinct CCR4 complexes mediate different BTG2 functions at different cell-cycle stages. Immunoprecipitation, gel filtration chromatography, cell-cycle fractionation, transient transfection reporter assays for ERα activity Journal of cell science Medium 12771185
2004 BTG2 physically interacts with BMP-activated Smad proteins (Smad1/Smad8) and enhances BMP transcriptional signaling, as demonstrated biochemically and by the vertebral patterning phenotype in Btg2-null mice which phenocopies reduced BMP signaling. Btg2-knockout mouse generation, vertebral phenotype analysis, co-immunoprecipitation/pulldown of Btg2 with Smad1/Smad8, transcriptional reporter assays for BMP signaling Molecular and cellular biology High 15542835
2004 BTG2 expression is induced by NF-κB activation in breast cancer cells, and BTG2 inhibits breast cancer cell growth by arresting cells in G1 through suppression of cyclin D1 expression; this effect is reversed by cyclin D1 re-expression. NF-κB stimulation assays, BTG2 ectopic expression in breast cancer cells, growth arrest assays, rescue experiment with cyclin D1 overexpression Oncogene Medium 15378000
2004 TIS21/BTG2 is expressed through a PKC-delta signaling pathway and inhibits cyclin B1-Cdc2 binding and kinase activity in vivo (G2/M inhibition), independent of p53; TIS21 also stabilizes cyclin A and cyclin B1 by preventing their degradation. PKC inhibitor pharmacology, dnPKC-delta transfection, nocodazole synchronization, co-immunoprecipitation of cyclin B1-Cdc2, in vivo kinase assay, FACS analysis Experimental cell research Medium 15302583
2005 p-Erk1/2 phosphorylates TIS21 at Ser147; this phosphorylation promotes binding of TIS21 to Pin1 (prolyl isomerase), which causes Pin1 relocalization to the cytoplasm and subsequent mitochondrial depolarization and cell death. The P148A mutation abolishes Pin1 binding. In vitro kinase assay with p-Erk1/2 and p-p38, site-directed mutagenesis (P148A), co-immunoprecipitation, shRNAi knockdown of TIS21, confocal microscopy of Pin1 localization, flow cytometry (JC-1 mitochondrial membrane potential) The Journal of biological chemistry High 15788397
2006 BTG2 enhances PRMT1 participation in the RARα transcriptional complex on the RARβ promoter, increases histone H4 arginine methylation at this gene in the absence of retinoic acid, and upon retinoic acid treatment BTG2 and PRMT1 dissociate from RARα, enabling histone H4 demethylation and acetylation that prime differentiation. Co-immunoprecipitation of RARα complex, chromatin immunoprecipitation (ChIP) for H4 arginine methylation and acetylation at RARβ promoter, overexpression in myeloid leukemia cells and CD34+ progenitors, differentiation assays Molecular and cellular biology High 16782888
2008 BTG2 is a general activator of mRNA deadenylation: it stimulates poly(A) tail shortening of all transcripts tested through its interaction with the CAF1/CCR4 deadenylase complex; CAF1 nuclease activity is required for efficient deadenylation, and both CAF1 and CCR4 deadenylase activities are required for BTG2-induced poly(A) degradation. In vitro deadenylation assays with reporter mRNAs, CAF1 nuclease-dead mutants, BTG2 overexpression in mammalian cells, mRNA half-life measurements The EMBO journal High 18337750
2008 Crystal structures of human BTG2 and mouse TIS21 were solved to 2.3 Å and 2.2 Å resolution, respectively; the structures reveal a putative CAF1 binding site; structure-guided mutagenesis of BTG2 at this site reduces CAF1 deadenylase activity, demonstrating that BTG2 suppresses CAF1 deadenylase activity through direct structural interaction. X-ray crystallography, in vitro CAF1 deadenylase activity assay with wild-type and interface mutant BTG2 Nucleic acids research High 18974182
2008 TIS21 inhibits FoxM1 phosphorylation (required for FoxM1 activation) by reducing cyclin B1-CDK1 kinase activity, thereby disrupting the FoxM1-cyclin B1 regulatory loop; this was confirmed by in vitro kinase assay, FoxM1 mutant analyses, and in vivo reciprocal expression studies. In vitro kinase assay, FoxM1 phosphorylation mutant analysis, TIS21 forced expression in Huh7 cells, TIS21-null mouse embryonic fibroblasts, DEN-induced hepatocarcinoma model Hepatology High 18393292
2008 PRMT1 plays a pivotal role in neurite outgrowth of Neuro2a cells, and BTG2 (a PRMT1 binding partner) depletion downregulates nuclear arginine methylation and inhibits neurite outgrowth, indicating the BTG2-PRMT1 interaction is functionally required for arginine methylation-dependent neuronal differentiation. shRNA knockdown of PRMT1 and Btg2 in Neuro2a cells, immunofluorescence for neurite morphology, western blot for methylarginine marks Neuroscience letters Medium 18773938
2009 TIS21 promotes repair of DNA double-strand breaks by increasing PRMT1-dependent arginine methylation of Mre11, activating Mre11 nuclease activity; TIS21 also blocks the ATM→Chk2(T68)→p53(S20) damage signal cascade while not affecting p53(S15) phosphorylation, thereby reducing apoptosis after etoposide treatment. Adenoviral TIS21 transduction of Huh7 cells, γH2AX foci clearance assay, Comet assay, immunoprecipitation and radiolabeling for Mre11 methylation, PRMT1 in vitro activity assay, western blot for Chk2 and p53 phosphorylation, TIS21-null MEFs DNA repair High 23089312
2009 BTG2 depletion in human fibroblasts extends cellular lifespan, and ectopic BTG2 induces senescence independently of p53; BTG2 is stabilized by telomere dysfunction and serum-dependently binds and relocalizes Pin1 (prolyl isomerase), and Pin1 inhibition leads to senescence while ectopic Pin1 rescues BTG2-induced senescence. siRNA depletion, ectopic overexpression, co-immunoprecipitation of BTG2-Pin1, cellular lifespan/senescence assays, Pin1 overexpression rescue experiment in late-passage fibroblasts Aging cell Medium 20569234
2009 PC3/Tis21 deletion causes increased proliferation of adult dentate gyrus progenitor cells and arrest of their terminal differentiation, with accumulation of undifferentiated postmitotic neurons and reduced terminally differentiated neurons; PC3/Tis21 associates with the Id3 promoter and negatively regulates Id3 expression, placing Tis21 upstream of Id3 in the differentiation cascade. PC3/Tis21-null mouse analysis, BrdU/NeuN neurogenesis markers, ChIP for Tis21 at Id3 promoter, immunofluorescence, Morris water maze behavioral assay PloS one High 20020054
2009 SKP2 (SCF ubiquitin ligase subunit) binds to the C-terminus of TIS21 via its leucine-rich repeat (LRR) domain and promotes polyubiquitination and proteasomal degradation of TIS21; FoxM1 regulates Skp2 expression and thereby controls TIS21 protein stability. Co-immunoprecipitation, deletion mutagenesis of Skp2 (ΔLRR) and TIS21 (ΔC), ubiquitination assays, cycloheximide chase (protein half-life), siRNA knockdown of Skp2, FoxM1 co-expression Experimental cell research Medium 19615363
2010 TIS21/BTG2 inhibits invadopodia formation in MDA-MB-231 breast cancer cells by downregulating intracellular reactive oxygen species (ROS) levels, with consequent F-actin remodeling; this was confirmed in TIS21-null MEFs which show enhanced invadopodia. Adenoviral TIS21 transduction, invadopodia/gelatin degradation assay, Matrigel invasion assay, FACS-based ROS measurement (DCFH-DA), TIS21-null MEF controls Journal of cancer research and clinical oncology Medium 23907596
2012 BTG2 stimulates antioxidant gene expression (catalase, SOD1, SOD2) through direct interaction with the transcription factor NFE2L2 (Nrf2); BTG2 is detectable at the antioxidant response element (ARE) of NFE2L2-responsive genes by ChIP; the conserved Box B domain is required for BTG2-NFE2L2 interaction, protection against oxidative stress, and antioxidant gene upregulation. Co-immunoprecipitation for BTG2-NFE2L2 interaction, ChIP at ARE elements, cell viability assays under H2O2 stress, siRNA knockdown of NFE2L2, Box B deletion mutagenesis The Journal of biological chemistry High 22493435
2012 BTG2 loss shifts normal prostate basal cells toward luminal marker expression and induces EMT traits; miR-21 overexpression suppresses BTG2 levels and promotes luminal/EMT phenotype; derepression of BTG2 via a decoy 3'-UTR construct reduces luminal and EMT markers in prostate tumor cells and abrogates orthotopic tumor growth. BTG2 knockdown/lentiviral 3'-UTR decoy in prostate cell lines, immunofluorescence for luminal/EMT markers, miR-21 overexpression, orthotopic murine model Oncogene Medium 22614007
2013 TIS21/BTG2 inhibits breast cancer cell invasion through a TIS21-Akt1-Sp1-Nox4 pathway: TIS21 activates Akt1, which reduces Sp1-mediated Nox4 transcription, decreasing Nox4-derived ROS and thereby inhibiting mDia (diaphanous-related formin) expression and F-actin remodeling required for invasion. RNA interference knockdown of Akt1, adenoviral TIS21 transduction, Nox4 promoter reporter assays, ROS measurement, Matrigel invasion assay, western blot for mDia/actin regulators Oncogene Medium 25798836
2016 BTG2 APRO domain directly interacts with the first RRM domain of PABPC1 (cytoplasmic poly(A)-binding protein); PABPC1 RRM1 and BTG2 APRO domains together are sufficient to stimulate CAF1 deadenylase activity in vitro without other CCR4-NOT subunits; this BTG2-PABPC1 interaction is required for BTG2 to control cell proliferation. In vitro reconstitution of deadenylation assay with purified domains, pulldown/binding assays for APRO-RRM1 interaction, mutagenesis of interaction interface, cell proliferation assays Nature communications High 26912148
2017 BTG2 and PRMT1 form a module in pre-B cells that induces cell-cycle arrest by enabling PRMT1 to methylate CDK4, thereby preventing CDK4-Cyclin D3 complex formation and blocking cell cycle progression; BTG2-PRMT1 also blocks proliferation of BCR-ABL1-transformed pre-B cells in vitro and in vivo. Co-immunoprecipitation, in vitro methylation assay for CDK4 by PRMT1, CDK4-Cyclin D3 complex pulldown, BTG2/PRMT1 conditional knockout pre-B cells, BCR-ABL1 transformation model in vivo Nature immunology High 28628091
2020 BTG1 and BTG2 (BTG1/2) promote mRNA deadenylation and degradation to maintain T cell quiescence; BTG1/2-deficient T cells show increased global mRNA abundance with longer poly(A) tails and greater mRNA half-lives, reducing the activation threshold; this establishes mRNA deadenylation as the mechanism underlying BTG2-dependent T cell quiescence. Conditional BTG1/2 double-knockout mice, global mRNA-seq, poly(A) tail length measurement, mRNA half-life assays, T cell proliferation and spontaneous activation assays Science High 32165587
2020 TRIM6 E3 ubiquitin ligase interacts with TIS21/BTG2, promotes its polyubiquitination at Lys5, and decreases TIS21 protein stability; a TRIM6 catalytic mutant (C15A) fails to ubiquitinate TIS21; TIS21 overexpression reverses TRIM6-driven cell proliferation and suppresses FoxM1/cyclin B1 signaling. Immunoprecipitation, proteomics, ubiquitination assay with TRIM6 WT and C15A mutant, cycloheximide chase, site-directed mutagenesis of TIS21 (Lys5), TIS21 overexpression rescue assays Journal of experimental & clinical cancer research Medium 31992359
2022 KIAA1429 (VIRMA, an m6A RNA methyltransferase) mediates m6A modification of BTG2 mRNA; knockdown of KIAA1429 decreases BTG2 mRNA m6A levels, leading to increased YTHDF2 (m6A reader)-dependent BTG2 mRNA stability and elevated BTG2 expression, placing BTG2 regulation downstream of m6A mRNA modification. MeRIP-seq (methylated RNA immunoprecipitation sequencing), RNA stability assay, KIAA1429 knockdown, transcriptome-seq, m6A dot blot Cancer communications Medium 35730068
2016 Btg2 negatively regulates cardiomyocyte hypertrophy by reducing cytosolic (but not nuclear) RNA levels; Btg2 binds components of mRNA deadenylation complexes as shown by mass spectrometry; Btg2 knockdown enhances cytosolic RNA accumulation under adrenergic stimulation. Btg2 shRNA knockdown in cardiomyocytes, Myc-mediated hypermetabolic model, single-cell RNA imaging with nascent RNA labeling, ChIP-seq, mass spectrometry of Btg2-associated proteins, cardiomyocyte surface area measurement Scientific reports Medium 27346836
2023 BTG2 promotes podocyte-to-mesenchymal transition (EMT) and FSGS by binding specifically to Smad3 (not Smad2) and enhancing Smad3 signaling; podocyte-specific deletion of Btg2 protects against proteinuria and glomerulosclerosis; a TGF-β/Smad3–Btg2 positive feedback circuit was identified. Podocyte-specific Btg2 conditional knockout mice, co-immunoprecipitation of Btg2 with Smad2 vs Smad3, Smad3 inhibitor (SIS3) rescue, Btg2 overexpression in cultured MPC5 podocytes, ADR-induced FSGS model Advanced science Medium 37749872
1994 The TIS21/PC3 protein is a non-nuclear, soluble intracellular protein (not secreted and not membrane-associated), as established by immunohistochemistry and subcellular fractionation experiments; the protein is synthesized rapidly after stimulation and is degraded much more rapidly than the related TIS7/PC4 protein. Pulse-chase metabolic labeling, subcellular fractionation, immunohistochemistry with anti-TIS21 antiserum Journal of cellular physiology Medium 8263025
2012 Tis21 deletion in Patched1 heterozygous mice increases medulloblastoma frequency; genome-wide analysis identified Cxcl3 as a transcriptional target of Tis21; Tis21-null cerebellar granule neuron precursors show downregulated Cxcl3 and defective migration; addition of exogenous Cxcl3 rescues migration defect and reduces hyperplastic lesion area, placing Tis21 upstream of Cxcl3-dependent GCP migration. Double-KO mouse cross (Tis21-/-; Ptch1+/-), genome-wide gene expression analysis, cerebellar slice migration assay, Cxcl3 protein addition rescue experiment The Journal of neuroscience High 23115191
2008 In TIS21-null mice, p-Erk1/2 preferentially binds Akt (preventing Akt activation), and mTOR is constitutively active; reconstitution of TIS21 inhibits p-Erk1/2-Akt interaction; TIS21 thereby negatively regulates estradiol-stimulated hematopoietic stem cell expansion through this Akt/mTOR axis. TIS21 knockout mice, co-immunoprecipitation of p-Erk1/2 with Akt, TIS21 reconstitution in MEFs, Erk1 siRNA knockdown, rapamycin treatment, LSK flow cytometry of bone marrow Stem cells Medium 18556508

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase. The Journal of biological chemistry 418 8663146
1996 Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway. Nature genetics 381 8944033
2001 In search of a function for the TIS21/PC3/BTG1/TOB family. FEBS letters 216 11377414
2001 The gene PC3(TIS21/BTG2), prototype member of the PC3/BTG/TOB family: regulator in control of cell growth, differentiation, and DNA repair? Journal of cellular physiology 197 11267995
2012 Androgen-regulated miR-32 targets BTG2 and is overexpressed in castration-resistant prostate cancer. Oncogene 178 22266859
1999 Expression of the antiproliferative gene TIS21 at the onset of neurogenesis identifies single neuroepithelial cells that switch from proliferative to neuron-generating division. Proceedings of the National Academy of Sciences of the United States of America 170 10200315
2018 Tumor suppressors BTG1 and BTG2: Beyond growth control. Journal of cellular physiology 167 30350856
2009 Regulation of the cell cycle gene, BTG2, by miR-21 in human laryngeal carcinoma. Cell research 154 19546886
1991 Structure and expression of TIS21, a primary response gene induced by growth factors and tumor promoters. The Journal of biological chemistry 150 1713584
2020 mRNA destabilization by BTG1 and BTG2 maintains T cell quiescence. Science (New York, N.Y.) 146 32165587
1998 Interaction of BTG1 and p53-regulated BTG2 gene products with mCaf1, the murine homolog of a component of the yeast CCR4 transcriptional regulatory complex. The Journal of biological chemistry 126 9712883
2014 BTG2: a rising star of tumor suppressors (review). International journal of oncology 121 25405282
2016 MiR-27a-3p functions as an oncogene in gastric cancer by targeting BTG2. Oncotarget 118 27409164
2018 MiR-25-3p promotes the proliferation of triple negative breast cancer by targeting BTG2. Molecular cancer 113 29310680
2001 Relationships of the antiproliferative proteins BTG1 and BTG2 with CAF1, the human homolog of a component of the yeast CCR4 transcriptional complex: involvement in estrogen receptor alpha signaling pathway. The Journal of biological chemistry 109 11136725
2008 The BTG2 protein is a general activator of mRNA deadenylation. The EMBO journal 108 18337750
2020 Up-regulated LINC01234 promotes non-small-cell lung cancer cell metastasis by activating VAV3 and repressing BTG2 expression. Journal of hematology & oncology 93 31959200
2012 BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial-mesenchymal transition. Oncogene 91 22614007
2006 TIS21 (/BTG2/PC3) as a link between ageing and cancer: cell cycle regulator and endogenous cell death molecule. Journal of cancer research and clinical oncology 90 16456675
2015 MiR-21 Protected Cardiomyocytes against Doxorubicin-Induced Apoptosis by Targeting BTG2. International journal of molecular sciences 85 26132560
2004 Impaired expression of the cell cycle regulator BTG2 is common in clear cell renal cell carcinoma. Cancer research 82 14996721
2009 Impaired terminal differentiation of hippocampal granule neurons and defective contextual memory in PC3/Tis21 knockout mice. PloS one 73 20020054
2008 TIS21 negatively regulates hepatocarcinogenesis by disruption of cyclin B1-Forkhead box M1 regulation loop. Hepatology (Baltimore, Md.) 70 18393292
2016 BTG2 bridges PABPC1 RNA-binding domains and CAF1 deadenylase to control cell proliferation. Nature communications 69 26912148
1998 Induction of growth inhibition of 293 cells by downregulation of the cyclin E and cyclin-dependent kinase 4 proteins due to overexpression of TIS21. Molecular carcinogenesis 68 9766435
2004 Expression of the NF-kappaB-responsive gene BTG2 is aberrantly regulated in breast cancer. Oncogene 66 15378000
2002 BTG2(TIS21/PC3) induces neuronal differentiation and prevents apoptosis of terminally differentiated PC12 cells. Oncogene 65 12360398
2004 B-cell translocation gene 2 (Btg2) regulates vertebral patterning by modulating bone morphogenetic protein/smad signaling. Molecular and cellular biology 63 15542835
2022 Gene amplification-driven RNA methyltransferase KIAA1429 promotes tumorigenesis by regulating BTG2 via m6A-YTHDF2-dependent in lung adenocarcinoma. Cancer communications (London, England) 62 35730068
2002 The human BTG2/TIS21/PC3 gene: genomic structure, transcriptional regulation and evaluation as a candidate tumor suppressor gene. Gene 60 11814693
2018 PRMT5 promotes cell proliferation by inhibiting BTG2 expression via the ERK signaling pathway in hepatocellular carcinoma. Cancer medicine 59 29441724
2003 BTG2 antiproliferative protein interacts with the human CCR4 complex existing in vivo in three cell-cycle-regulated forms. Journal of cell science 59 12771185
2006 Btg2 enhances retinoic acid-induced differentiation by modulating histone H4 methylation and acetylation. Molecular and cellular biology 58 16782888
2021 m6A-Induced LncRNA MEG3 Suppresses the Proliferation, Migration and Invasion of Hepatocellular Carcinoma Cell Through miR-544b/BTG2 Signaling. OncoTargets and therapy 53 34163177
2004 TIS21/BTG2/PC3 is expressed through PKC-delta pathway and inhibits binding of cyclin B1-Cdc2 and its activity, independent of p53 expression. Experimental cell research 52 15302583
2020 Genistein inhibits high fat diet-induced obesity through miR-222 by targeting BTG2 and adipor1. Food & function 51 32129363
2009 Impact of BTG2 expression on proliferation and invasion of gastric cancer cells in vitro. Molecular biology reports 50 19728149
2005 Phosphorylation of serine 147 of tis21/BTG2/pc3 by p-Erk1/2 induces Pin-1 binding in cytoplasm and cell death. The Journal of biological chemistry 48 15788397
2012 Tis21 knock-out enhances the frequency of medulloblastoma in Patched1 heterozygous mice by inhibiting the Cxcl3-dependent migration of cerebellar neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 23115191
2019 MiR-6875-3p promotes the proliferation, invasion and metastasis of hepatocellular carcinoma via BTG2/FAK/Akt pathway. Journal of experimental & clinical cancer research : CR 46 30621734
2017 The BTG2-PRMT1 module limits pre-B cell expansion by regulating the CDK4-Cyclin-D3 complex. Nature immunology 46 28628091
2019 NUSAP1 knockdown inhibits cell growth and metastasis of non-small-cell lung cancer through regulating BTG2/PI3K/Akt signaling. Journal of cellular physiology 44 31603257
2008 Crystal structures of human BTG2 and mouse TIS21 involved in suppression of CAF1 deadenylase activity. Nucleic acids research 42 18974182
2022 Exosomal circRNA BTG2 derived from RBP-J overexpressed-macrophages inhibits glioma progression via miR-25-3p/PTEN. Cell death & disease 41 35643814
1994 Synthesis, degradation, and subcellular localization of proteins encoded by the primary response genes TIS7/PC4 and TIS21/PC3. Journal of cellular physiology 40 8263025
2020 SRXN1 stimulates hepatocellular carcinoma tumorigenesis and metastasis through modulating ROS/p65/BTG2 signalling. Journal of cellular and molecular medicine 39 32746503
2017 BTG2 is a tumor suppressor gene upregulated by p53 and PTEN in human bladder carcinoma cells. Cancer medicine 39 29239139
2014 3' UTR-dependent, miR-92-mediated restriction of Tis21 expression maintains asymmetric neural stem cell division to ensure proper neocortex size. Cell reports 39 24726360
2013 Regulation of Btg2(/TIS21/PC3) expression via reactive oxygen species-protein kinase C-ΝFκΒ pathway under stress conditions. Cellular signalling 39 23876794
2010 BTG2 antagonizes Pin1 in response to mitogens and telomere disruption during replicative senescence. Aging cell 39 20569234
2004 BTG2, its family and its tutor. Bulletin du cancer 39 15381462
1995 Differential expression of TIS21 and TIS1 genes in the various organs of Balb/c mice, thymic carcinoma tissues and human cancer cell lines. Journal of cancer research and clinical oncology 38 7768965
2020 miR-15a-5p and miR-21-5p contribute to chemoresistance in cytogenetically normal acute myeloid leukaemia by targeting PDCD4, ARL2 and BTG2. Journal of cellular and molecular medicine 37 33270982
2022 Emerging role of anti-proliferative protein BTG1 and BTG2. BMB reports 36 35880434
2020 TRIM6 promotes colorectal cancer cells proliferation and response to thiostrepton by TIS21/FoxM1. Journal of experimental & clinical cancer research : CR 35 31992359
2015 miR-25 modulates NSCLC cell radio-sensitivity through directly inhibiting BTG2 expression. Biochemical and biophysical research communications 34 25576360
2015 Inhibition of breast cancer invasion by TIS21/BTG2/Pc3-Akt1-Sp1-Nox4 pathway targeting actin nucleators, mDia genes. Oncogene 34 25798836
2012 Effects of BTG2 on proliferation inhibition and anti-invasion in human lung cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 34 22392501
2009 Tis21 expression marks not only populations of neurogenic precursor cells but also new postmitotic neurons in adult hippocampal neurogenesis. Cerebral cortex (New York, N.Y. : 1991) 34 19482889
2023 Btg2 Promotes Focal Segmental Glomerulosclerosis via Smad3-Dependent Podocyte-Mesenchymal Transition. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 33 37749872
2021 MicroRNA miR-92a-3p regulates breast cancer cell proliferation and metastasis via regulating B-cell translocation gene 2 (BTG2). Bioengineered 33 34082648
2015 MicroRNA‑21 regulates the expression of BTG2 in HepG2 liver cancer cells. Molecular medicine reports 32 26151427
2015 BTG2 inhibits the proliferation and metastasis of osteosarcoma cells by suppressing the PI3K/AKT pathway. International journal of clinical and experimental pathology 30 26722427
2013 BTG2 inhibits the proliferation, invasion, and apoptosis of MDA-MB-231 triple-negative breast cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 30 23420441
2018 miR-663 sustains NSCLC by inhibiting mitochondrial outer membrane permeabilization (MOMP) through PUMA/BBC3 and BTG2. Cell death & disease 28 29352138
2012 TIS21(/BTG2/PC3) accelerates the repair of DNA double strand breaks by enhancing Mre11 methylation and blocking damage signal transfer to the Chk2(T68)-p53(S20) pathway. DNA repair 28 23089312
2008 Disruption of GM2/GD2 synthase gene resulted in overt expression of 9-O-acetyl GD3 irrespective of Tis21. Journal of neurochemistry 28 18194438
2012 B-cell translocation gene 2 (BTG2) stimulates cellular antioxidant defenses through the antioxidant transcription factor NFE2L2 in human mammary epithelial cells. The Journal of biological chemistry 27 22493435
2009 TIS21/BTG2/PC3 and cyclin D1 are key determinants of nuclear diacylglycerol kinase-zeta-dependent cell cycle arrest. Cellular signalling 27 19263516
2021 Elevation of miR-146a Inhibits BTG2/BAX Expression to Ameliorate Postoperative Cognitive Dysfunction Following Probiotics (VSL#3) Treatment. Molecular neurobiology 26 33725320
2014 Inhibition of bladder cancer invasion by Sp1-mediated BTG2 expression via inhibition of DNA methyltransferase 1. The FEBS journal 26 25284287
2018 Estradiol Prevents High Glucose-Induced β-cell Apoptosis by Decreased BTG2 Expression. Scientific reports 25 30115961
2011 Aberrant expression of the p53-inducible antiproliferative gene BTG2 in hepatocellular carcinoma is associated with overexpression of the cell cycle-related proteins. Cell biochemistry and biophysics 25 21327578
2001 Mitogen-stimulated TIS21 protein interacts with a protein-kinase-Calpha-binding protein rPICK1. The Biochemical journal 25 11237868
2021 Deletion of B-cell translocation gene 2 (BTG2) alters the responses of glial cells in white matter to chronic cerebral hypoperfusion. Journal of neuroinflammation 24 33812385
2015 Control of the Normal and Pathological Development of Neural Stem and Progenitor Cells by the PC3/Tis21/Btg2 and Btg1 Genes. Journal of cellular physiology 24 25967096
2008 PRMT1 and Btg2 regulates neurite outgrowth of Neuro2a cells. Neuroscience letters 24 18773938
2007 Molecular characterization of the BTG2 and BTG3 genes in fetal muscle development of pigs. Gene 24 17890019
2017 BTG2 Is Down-Regulated and Inhibits Cancer Stem Cell-Like Features of Side Population Cells in Hepatocellular Carcinoma. Digestive diseases and sciences 23 29098552
2016 Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA. Scientific reports 23 27346836
2012 TIS21/BTG2/PC3 enhances downregulation of c-Myc during differentiation of HL-60 cells by activating Erk1/2 and inhibiting Akt in response to all-trans-retinoic acid. European journal of cancer (Oxford, England : 1990) 23 22341854
2008 TIS21/(BTG2) negatively regulates estradiol-stimulated expansion of hematopoietic stem cells by derepressing Akt phosphorylation and inhibiting mTOR signal transduction. Stem cells (Dayton, Ohio) 23 18556508
2005 The BTG/TOB family protein TIS21 regulates stage-specific proliferation of developing thymocytes. European journal of immunology 23 16163674
2021 Exosomal microRNA-15a from ACHN cells aggravates clear cell renal cell carcinoma via the BTG2/PI3K/AKT axis. The Kaohsiung journal of medical sciences 22 34337864
2014 Tis21 is required for adult neurogenesis in the subventricular zone and for olfactory behavior regulating cyclins, BMP4, Hes1/5 and Ids. Frontiers in cellular neuroscience 22 24744701
2022 DSCR9/miR-21-5p axis inhibits pancreatic cancer proliferation and resistance to gemcitabine via BTG2 signaling. Acta biochimica et biophysica Sinica 21 36789695
2020 LINC01089 inhibits the progression of cervical cancer via inhibiting miR-27a-3p and increasing BTG2. The journal of gene medicine 21 33025678
2013 Expression and significance of miRNA-21 and BTG2 in lung cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 21 23857284
2009 Estradiol downregulation of the tumor suppressor gene BTG2 requires estrogen receptor-alpha and the REA corepressor. International journal of cancer 21 19117054
2014 Association of BTG2, CYR61, ZFP36, and SCD gene polymorphisms with Graves' disease and ophthalmopathy. Thyroid : official journal of the American Thyroid Association 20 24780075
1998 Overexpression of the PC3/TIS21/BTG2 mRNA is part of the stress response induced by acute pancreatitis in rats. Biochemical and biophysical research communications 20 9712737
2023 miR-21-5p prevents doxorubicin-induced cardiomyopathy by downregulating BTG2. Heliyon 19 37131441
2025 Predicting the molecular mechanism of ginger targeting PRMT1/BTG2 axis to inhibit gastric cancer based on WGCNA and machine algorithms. Phytomedicine : international journal of phytotherapy and phytopharmacology 18 40446574
2021 Circular RNA circ_0014717 Suppresses Hepatocellular Carcinoma Tumorigenesis Through Regulating miR-668-3p/BTG2 Axis. Frontiers in oncology 18 33598424
2019 The effect of decitabine on the expression and methylation of the PPP1CA, BTG2, and PTEN in association with changes in miR-125b, miR-17, and miR-181b in NALM6 cell line. Journal of cellular biochemistry 18 30912184
2019 lncRNA SNHG5 Modulates Endometrial Cancer Progression via the miR-25-3p/BTG2 Axis. Journal of oncology 18 31885582
2013 TIS21/BTG2 inhibits invadopodia formation by downregulating reactive oxygen species level in MDA-MB-231 cells. Journal of cancer research and clinical oncology 18 23907596
2009 Skp2 enhances polyubiquitination and degradation of TIS21/BTG2/PC3, tumor suppressor protein, at the downstream of FoxM1. Experimental cell research 18 19615363
2017 Terminal Differentiation of Adult Hippocampal Progenitor Cells Is a Step Functionally Dissociable from Proliferation and Is Controlled by Tis21, Id3 and NeuroD2. Frontiers in cellular neuroscience 17 28740463
2013 BTG2 overexpression increases the radiosensitivity of breast cancer cells in vitro and in vivo. Oncology research 17 24308156

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