Affinage

MXD1

Max dimerization protein 1 · UniProt Q05195

Length
221 aa
Mass
25.3 kDa
Annotated
2026-06-10
25 papers in source corpus 18 papers cited in narrative 18 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

MXD1 is a bHLH-LZ transcriptional repressor that antagonizes MYC-driven gene programs by heterodimerizing with MAX and competing with MYC for the shared MAX partner (PMID:32681706, PMID:32053209). Heterodimerization with MAX is governed by defined leucine-zipper residues and must precede DNA binding, after which the MXD1/MAX complex engages E-box elements (PMID:18155722). Repression is executed through the MXD1 SIN3-interacting domain (SID), which recruits the Sin3A corepressor and HDAC-2 to increase histone deacetylase activity at target loci; the isolated SID is a potent portable repressor domain in synthetic CRISPRi contexts (PMID:25611699, PMID:32156728). Through MAX-dependent E-box binding, MXD1 directly represses specific promoters including hTERT, PTEN, BCR-ABL1, and CXCL10, with functional consequences for telomerase activity, PI3K/AKT signaling, and inflammatory and oncogenic outputs (PMID:25611699, PMID:28543796, PMID:30419548, PMID:32794336). Beyond E-box gene repression, MXD1 localizes to the nucleolus, interacts with UBF, binds rDNA chromatin, and suppresses pre-rRNA synthesis, coupling it to control of ribosome biogenesis (PMID:27588501, PMID:32053209). MXD1 abundance is heavily regulated post-translationally and post-transcriptionally: FBW7 controls its turnover in parallel with MYC under 1,25D/VDR signaling, USP36 deubiquitination stabilizes it, SIRT1/DNMT3B-mediated DNA methylation silences its locus, and m6A modification of MXD1 mRNA read by YTHDF2 tunes its expression (PMID:23112173, PMID:29383100, PMID:33647641, PMID:40303324, PMID:41632223). In context-specific settings MXD1 acts as a cofactor of the methyltransferase MLL1 to deposit H3K4me3 at transposable elements, linking it to chromatin accessibility and a viral-mimicry response (PMID:39819860).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2007 High

    Established the structural logic of MXD1 function by defining which leucine-zipper residues dictate MXD1/MAX heterodimer specificity and showing heterodimerization is obligatory before DNA binding.

    Evidence Mutagenesis of leucine-zipper residues with in vitro and in vivo DNA-binding readouts

    PMID:18155722

    Open questions at the time
    • Does not address how heterodimer choice is regulated in vivo
    • No structure of the full repressive complex on chromatin
  2. 2011 High

    Characterized the MXD1-type SID–Sin3 PAH2 interaction and revealed competitive regulation within Sin3-class corepressor assemblies, clarifying how SID engages the repressor machinery.

    Evidence NMR solution structure, mutagenesis, and competitive binding assays (Pf1/MRG15 system)

    PMID:21440557

    Open questions at the time
    • Structural work on a related SID-bearing protein rather than MXD1 directly
    • Does not quantify MXD1 SID affinity in cells
  3. 2012 High

    Showed that MXD1 and MYC share the FBW7 ubiquitin ligase and are reciprocally regulated by 1,25D/VDR, explaining how upstream signals reset the DNA-bound MYC:MXD1 ratio.

    Evidence Cell and mouse studies with VDR/FBW7 knockdown, protein stability assays, ChIP, and mathematical modeling

    PMID:23112173

    Open questions at the time
    • Does not define FBW7 phosphodegron on MXD1 directly
    • Tissue specificity of this regulation not mapped
  4. 2015 Medium

    Connected MXD1 corepressor recruitment to a defined target output by showing MXD1–Sin3A–HDAC-2 assembly represses hTERT via direct promoter binding in a MAX-dimerization-dependent manner.

    Evidence Reciprocal Co-IP, HDAC activity assay, ChIP at hTERT promoter, luciferase reporter

    PMID:25611699

    Open questions at the time
    • Single lab
    • Generality of HDAC-2 selectivity across MXD1 targets unknown
  5. 2016 High

    Defined a non-canonical nucleolar role: MXD1 binds UBF and rDNA chromatin to repress rRNA synthesis, extending its function beyond classic E-box gene repression to ribosome biogenesis.

    Evidence Co-IP, proximity ligation assay, ChIP at rDNA, siRNA knockdown, and overexpression in multiple cell types

    PMID:27588501

    Open questions at the time
    • Whether MAX is required for nucleolar localization is not resolved
    • Mechanism of UBF-directed recruitment to rDNA undefined
  6. 2016 Medium

    Linked MXD1 dosage to hematopoietic lineage decisions, showing its knockdown skews CD34+ progenitors toward granulocytes at the expense of megakaryocytes and identifying it as a miR-382-5p target.

    Evidence siRNA knockdown in CD34+ HSPCs, colony assays, luciferase reporter validation

    PMID:27520398

    Open questions at the time
    • Transcriptional targets driving lineage skew not defined
    • Single lab
  7. 2017 Medium

    Extended the MXD1 target repertoire to PTEN, showing HIF-1α-induced MXD1 binds PTEN E-boxes to derepress PI3K/AKT and drive chemoresistance.

    Evidence Luciferase reporter, ChIP, siRNA knockdown, cell viability assays in hypoxic osteosarcoma

    PMID:28543796

    Open questions at the time
    • MAX-dependence of PTEN binding not directly tested here
    • Single context
  8. 2017 Medium

    Identified an epigenetic silencing mechanism whereby SIRT1 acting with DNMT3B methylates the MXD1 locus to suppress its expression during melanoma progression.

    Evidence ChIP-seq, SIRT1–DNMT3B Co-IP, SIRT1 knockdown, 5AzaCdR pharmacological reversal, qPCR

    PMID:29383100

    Open questions at the time
    • Specific methylated CpGs not mapped
    • Generality beyond melanoma untested
  9. 2018 Low

    Proposed MXD1 repression of the BCR-ABL1 promoter as a route to imatinib re-sensitization in CML.

    Evidence Reporter gene assay, overexpression, qPCR, proliferation assays

    PMID:30419548

    Open questions at the time
    • No ChIP confirmation of direct promoter binding
    • Single lab, single assay class
  10. 2020 Low

    Demonstrated MXD1 competes with MYC for MAX and that this balance is tuned by a lncRNA/miRNA axis to suppress MYC-driven proliferation.

    Evidence RNA pull-down, luciferase reporter, rescue/overexpression in ovarian cancer cells

    PMID:32681706

    Open questions at the time
    • No direct structural evidence of MXD1–MAX competition in this context
    • Single lab
  11. 2020 Medium

    Validated the MXD1 SID as a portable, potent repressor domain, providing functional proof that SID drives transcriptional silencing in cells beyond KRAB.

    Evidence dCas9-SID CRISPRi library screen, RT-qPCR, competition assays, MYC ChIP at lncRNA promoters

    PMID:32156728

    Open questions at the time
    • Synthetic context; does not measure endogenous MXD1 occupancy
    • Corepressor recruitment by fused SID not directly mapped
  12. 2020 Medium

    Showed an MXD1-derived mini-protein engages both MAX and UBF and binds E-box promoters, recapitulating dual transcriptional and potentially nucleolar inhibition of MYC with high potency.

    Evidence Co-IP (Mad–MAX, Mad–UBF), E-box binding assay, proliferation and reporter assays

    PMID:32053209

    Open questions at the time
    • Engineered mini-protein, not full-length endogenous MXD1
    • Single lab
  13. 2020 Medium

    Established a physiological MYCL/MXD1 antagonism, where induced Mxd1 restrains the MYCL biosynthetic program during cDC1 dendritic cell maturation.

    Evidence Mxd1 knockout mice, expression profiling, epistasis with Mycl-deficient mice

    PMID:32071205

    Open questions at the time
    • Direct Mxd1 target genes in cDC1 not enumerated
    • Single lab
  14. 2020 Medium

    Implicated MXD1 in antiviral transcription by showing it binds the CXCL10 promoter and is required for influenza-induced CXCL10, with MEK1/2-dependent induction.

    Evidence EMSA, siRNA knockdown, qPCR, viral replication assay, MEK inhibitor treatment in macrophages

    PMID:32794336

    Open questions at the time
    • How a repressor drives CXCL10 induction mechanistically unresolved
    • Strain-specific replication effects unexplained
  15. 2021 Low

    Placed MXD1 in a regulatory feedback loop involving USP36 stabilization, c-JUN-driven transcription, and m6A-dependent lncRNA control affecting trophoblast proliferation.

    Evidence Western blot, Co-IP, luciferase reporter, m6A assay, siRNA knockdown

    PMID:33647641

    Open questions at the time
    • USP36 deubiquitination of MXD1 not reconstituted directly
    • Single lab, correlational mechanistic chain
  16. 2025 Medium

    Revealed a chromatin-activating role distinct from canonical repression: MXD1 partners with MLL1 to deposit H3K4me3 at transposable elements, triggering viral mimicry in drug-resistant PDAC.

    Evidence scRNA-seq, ATAC-seq, CUT&TAG, PDX models, MXD1 inhibition

    PMID:39819860

    Open questions at the time
    • How MXD1 switches from Sin3-repression to MLL1-coactivation unknown
    • Direct MXD1–MLL1 interaction not biochemically resolved
  17. 2025 Medium

    Defined m6A control of MXD1 mRNA via METTL14 writing and YTHDF2 reading, linking MXD1 dosage to VEGFA/VCAM1 and pathological retinal neovascularization.

    Evidence MeRIP-seq, RIP, dual-luciferase, ChIP-qPCR, METTL14 conditional KO mouse, angiogenesis co-culture

    PMID:40303324

    Open questions at the time
    • Direction of YTHDF2 effect on MXD1 stability not fully reconciled across studies
    • Single tissue context
  18. 2025 Medium

    Connected VitD/VDR signaling to an FTO/YTHDF2 m6A axis that stabilizes Mxd1, which then represses PTEN to activate PI3K/AKT and drive M2 microglial polarization.

    Evidence VDR ChIP at FTO, m6A assay, YTHDF2 knockdown, Mxd1 ChIP at PTEN, reporter and polarization assays in vitro and in vivo

    PMID:41632223

    Open questions at the time
    • Reconciliation of m6A removal (FTO) increasing stability with YTHDF2 dependence
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MXD1 is partitioned between its canonical MAX/Sin3-HDAC repressive function, its nucleolar UBF/rDNA role, and its MLL1-associated coactivator role at transposable elements remains mechanistically unresolved.
  • No model explains the repressor-to-coactivator switch
  • Determinants of nucleolar versus nucleoplasmic targeting unknown
  • Genome-wide endogenous MXD1 occupancy not integrated across contexts

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 4 GO:0060089 molecular transducer activity 2
Localization
GO:0005634 nucleus 3 GO:0005730 nucleolus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
FBW7HDAC2MAXMLL1SIN3AUBFUSP36YTHDF2
Complex memberships
MXD1/MAX heterodimerSin3A-HDAC corepressor complex

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 MXD1 localizes to the nucleolus in multiple cell lines and primary cells (neurons, Sertoli cells), interacts with UBF (confirmed by co-immunoprecipitation and proximity ligation assay), binds transcribed rDNA chromatin and ribosomal intergenic regions (ChIP), and represses rRNA synthesis: siRNA knockdown of MXD1 increases pre-rRNA synthesis while enforced MXD1 expression reduces it. Co-immunoprecipitation, proximity ligation assay, chromatin immunoprecipitation, siRNA knockdown, co-localization imaging Oncotarget High 27588501
2007 Structural determinants in the leucine zipper of Mxd1 (D112a) and Max (N78a, H81d) dictate specificity of Mxd1/Max heterodimerization and whether the Mxd1/Max/DNA complex forms; heterodimerization must precede DNA binding in vivo. Mutagenesis of leucine zipper residues, DNA-binding assays Journal of molecular biology High 18155722
2011 The PAH2 domain of mSin3A interacts with the SID1 motif of Pf1 in a manner structurally reminiscent of the Mad1/Mxd1–Sin3 interaction; MRG15 competes with Sin3 for the same Pf1 segment, implying competitive regulation within the Rpd3S/Sin3S complex. NMR solution structure, mutagenesis, competitive binding assays Journal of molecular biology High 21440557
2012 1,25-dihydroxyvitamin D (1,25D)/VDR signaling enhances MXD1 expression and protein stability while inhibiting c-MYC expression and accelerating its turnover; the E3-ubiquitin ligase FBW7 controls stability of both c-MYC and MXD1, and FBW7 ablation attenuates 1,25D-mediated regulation of their turnover, dramatically altering the ratio of DNA-bound c-MYC vs. MXD1. Cell- and animal-based studies, mathematical modeling, VDR/FBW7 knockdown, protein stability assays, ChIP Proceedings of the National Academy of Sciences of the United States of America High 23112173
2015 Increased Mxd1 recruits the Sin3A repressor complex via enhanced binding with HDAC-2, resulting in increased HDAC activity and transcriptional repression; Mxd1 represses hTERT mRNA expression through direct binding to the hTERT promoter (confirmed by ChIP), reducing telomerase activity; these effects require Mxd1 dimerization with Max. Co-immunoprecipitation (Mxd1–Sin3A–HDAC-2), HDAC activity assay, ChIP at hTERT promoter, luciferase reporter, western blot Cancer biology & therapy Medium 25611699
2017 HIF-1α-induced Mxd1 directly binds E-box sites within the PTEN promoter (confirmed by luciferase reporter and ChIP), repressing PTEN transcription; this suppression activates PI3K/AKT signaling and promotes cisplatin resistance in hypoxic osteosarcoma cells. Luciferase reporter assay, ChIP, siRNA knockdown, western blot, cell viability assay Molecular carcinogenesis Medium 28543796
2017 SIRT1 targets the Mxd1 locus in concert with DNMT3B; SIRT1 silencing increases Mxd1 mRNA expression, and DNMT inhibitor 5AzaCdR reverses Mxd1 silencing, indicating that SIRT1-DNMT3B-mediated DNA methylation suppresses Mxd1 expression during melanoma progression. ChIP-seq (SIRT1 binding at Mxd1 locus), Co-immunoprecipitation (SIRT1–DNMT3B), stable SIRT1 knockdown, 5AzaCdR treatment, qPCR Oncotarget Medium 29383100
2020 MXD1 competes with MYC for binding to MAX; the MAGI2-AS3 lncRNA sequesters miR-525-5p, relieving miR-525-5p-mediated repression of MXD1, thereby increasing MXD1 availability to compete with MYC for MAX binding and suppress MYC-driven proliferation in ovarian cancer cells. RNA pull-down, luciferase reporter, western blot, rescue/overexpression assays Cancer medicine Low 32681706
2020 The SIN3-interacting domain (SID) derived from MXD1 functions as a potent transcriptional repressor domain when fused to dCas9 (CRISPRi), outperforming the KRAB domain in lymphoid cell lines; the SID domain can be fused to the MS2 aptamer-binding protein MCP for doxycycline-regulated CRISPRi. CRISPRi library screen, RT-qPCR, competition assay with GFP-expressing sgRNA constructs, chromatin immunoprecipitation (MYC at lncRNA promoters) Proceedings of the National Academy of Sciences of the United States of America Medium 32156728
2020 A mini-protein (Mad) derived from MXD1 interacts with MAX and with the nucleolar upstream binding factor (UBF), binds E-box DNA in MYC target gene promoters, and represses MYC-mediated transcription; Mad is 10-fold more potent than the MYC inhibitor Omomyc in inhibiting MYC-driven cell proliferation. Co-immunoprecipitation (Mad–MAX, Mad–UBF), E-box DNA-binding assay, cell proliferation assay, transcriptional reporter assay FEBS letters Medium 32053209
2020 Mxd1 is induced during maturation of Batf3-dependent cDC1 dendritic cells; Mxd1-deficient mature cDC1s exhibit impaired ability to inhibit the MYCL-supported transcriptional program, establishing reciprocal MYCL/MXD1 regulation of biosynthetic gene expression during cDC1 maturation. Mxd1 knockout mice, gene expression profiling, epistasis analysis with Mycl-deficient mice Proceedings of the National Academy of Sciences of the United States of America Medium 32071205
2018 MXD1 directly inhibits the transcriptional activity of the BCR-ABL1 gene promoter (reporter gene assay), reducing BCR-ABL1 mRNA and protein, thereby suppressing proliferation and sensitizing imatinib-resistant CML cells to imatinib. Reporter gene assay, overexpression, western blot, qPCR, cell proliferation assay Leukemia research Low 30419548
2016 MXD1 knockdown in CD34+ hematopoietic stem/progenitor cells mimics miR-382-5p overexpression, promoting granulocyte expansion and impairing megakaryocyte commitment; MXD1 was validated as a direct target of miR-382-5p by luciferase reporter assay. siRNA knockdown of MXD1 in CD34+ HSPCs, luciferase reporter assay, colony assays Stem cells and development Medium 27520398
2020 MXD1 directly binds the CXCL10 promoter in influenza-infected human macrophages (EMSA), and MXD1 knockdown significantly attenuates H1N1- and H9N2/G1-induced CXCL10 expression; MXD1 knockdown also decreases H9N2 replication but not H1N1 replication; MXD1 induction is dependent on MEK1/2 activation. EMSA, siRNA knockdown, qPCR, viral replication assay, MEK1/2 inhibitor treatment Journal of leukocyte biology Medium 32794336
2021 MXD1 protein stability is enhanced by the deubiquitinase USP36, and MXD1 transcription is promoted by up-regulation of the transcription factor c-JUN; MXD1 in turn up-regulates lnc-HZ01 stability via increased m6A RNA methylation, forming a positive feedback loop that promotes EIF4E transcription and inhibits trophoblast cell proliferation. Western blot, co-immunoprecipitation, luciferase reporter, siRNA knockdown, m6A methylation assay The Science of the total environment Low 33647641
2025 In trametinib-resistant PDAC, MXD1 acts as a cofactor of the histone methyltransferase MLL1 to increase H3K4 trimethylation at transposable element loci, enhancing chromatin accessibility and transcription of transposable elements, which produces dsRNAs that activate viral mimicry response and downstream oncogenic interferon-stimulated genes. scRNA-seq, ATAC-seq, CUT&TAG, patient-derived xenograft models, MXD1 inhibition experiments Gut Medium 39819860
2025 METTL14-mediated m6A modification of MXD1 mRNA is recognized by the m6A reader YTHDF2; this modification alters MXD1 expression, and increased MXD1 modulates VEGFA and VCAM1 expression, promoting retinal neovascularization in an OIR model. MeRIP-seq, RIP assay, dual-luciferase reporter, ChIP-qPCR, METTL14 conditional KO mouse, co-culture angiogenesis assay Theranostics Medium 40303324
2025 In microglia, VitD/VDR transcriptionally activates FTO; upregulated FTO reduces m6A methylation on Mxd1 mRNA in a YTHDF2-dependent manner, enhancing Mxd1 mRNA stability and protein expression; increased Mxd1 then binds and represses the PTEN promoter, activating PI3K/AKT and facilitating nuclear translocation of PGC-1α to promote M2 microglial polarization. VDR ChIP at FTO promoter, m6A methylation assay, YTHDF2 knockdown, Mxd1 ChIP at PTEN promoter, luciferase reporter, in vitro and in vivo polarization assays Inflammation Medium 41632223

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 MiR-19a/b modulate the metastasis of gastric cancer cells by targeting the tumour suppressor MXD1. Cell death & disease 104 24675462
2012 Vitamin D receptor as a master regulator of the c-MYC/MXD1 network. Proceedings of the National Academy of Sciences of the United States of America 98 23112173
2021 Lnc-HZ01 with m6A RNA methylation inhibits human trophoblast cell proliferation and induces miscarriage by up-regulating BPDE-activated lnc-HZ01/MXD1 positive feedback loop. The Science of the total environment 54 33647641
2020 An MXD1-derived repressor peptide identifies noncoding mediators of MYC-driven cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 35 32156728
2015 Down regulation of miR-202 modulates Mxd1 and Sin3A repressor complexes to induce apoptosis of pancreatic cancer cells. Cancer biology & therapy 35 25611699
2011 Solution structure of the mSin3A PAH2-Pf1 SID1 complex: a Mad1/Mxd1-like interaction disrupted by MRG15 in the Rpd3S/Sin3S complex. Journal of molecular biology 28 21440557
2020 MAGI2-AS3 suppresses MYC signaling to inhibit cell proliferation and migration in ovarian cancer through targeting miR-525-5p/MXD1 axis. Cancer medicine 26 32681706
2020 The MYCL and MXD1 transcription factors regulate the fitness of murine dendritic cells. Proceedings of the National Academy of Sciences of the United States of America 23 32071205
2017 Mxd1 mediates hypoxia-induced cisplatin resistance in osteosarcoma cells by repression of the PTEN tumor suppressor gene. Molecular carcinogenesis 23 28543796
2016 miR-382-5p Controls Hematopoietic Stem Cell Differentiation Through the Downregulation of MXD1. Stem cells and development 22 27520398
2020 Inhibition of Myc transcriptional activity by a mini-protein based upon Mxd1. FEBS letters 21 32053209
2016 miR-19a/b modulates lung cancer cells metastasis through suppression of MXD1 expression. Oncology letters 19 27588137
2016 MXD1 localizes in the nucleolus, binds UBF and impairs rRNA synthesis. Oncotarget 18 27588501
2022 HOXA5 inhibits the proliferation of extrahepatic cholangiocarcinoma cells by enhancing MXD1 expression and activating the p53 pathway. Cell death & disease 17 36167790
2021 Targeting miR-21 with NL101 blocks c-Myc/Mxd1 loop and inhibits the growth of B cell lymphoma. Theranostics 16 33537096
2017 SIRT1 regulates Mxd1 during malignant melanoma progression. Oncotarget 16 29383100
2019 The MicroRNA-382-5p/MXD1 Axis Relates to Breast Cancer Progression and Promotes Cell Malignant Phenotypes. The Journal of surgical research 10 31635836
2007 Elucidation of the structural determinants responsible for the specific formation of heterodimeric Mxd1/Max b-HLH-LZ and its binding to E-box sequences. Journal of molecular biology 8 18155722
2020 MXD1 regulates the H9N2 and H1N1 influenza A virus-induced chemokine expression and their replications in human macrophage. Journal of leukocyte biology 7 32794336
2025 Targeting MXD1 sensitises pancreatic cancer to trametinib. Gut 4 39819860
2025 BARD1-mediated stabilization of METTL14 promotes retinal neovascularization by m6A-modifying MXD1 mRNA on a YTHDF2-dependent manner. Theranostics 4 40303324
2025 Study on the mechanism and clinical value of miR-210-3p and miR-582-5p in acute myocardial infarction by targeting MXD1. Journal of cardiothoracic surgery 4 40616070
2018 MXD1 regulates the imatinib resistance of chronic myeloid leukemia cells by repressing BCR-ABL1 expression. Leukemia research 1 30419548
2026 FTO-dependent m6A Demethylation Activates Mxd1 To Enhance Vitamin D-induced Suppression of Neuroinflammation Via PTEN/AKT/PGC-1α Signaling Pathways in Microglia. Inflammation 0 41632223
2025 Identifying aging-related biomarkers in adipose tissue using integrative bioinformatics and machine-learning approaches: discovery of ELN, MXD1, and FGF21 as key genes. Frontiers in endocrinology 0 40958908

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