Affinage

MLX

Max-like protein X · UniProt Q9UH92

Length
298 aa
Mass
33.3 kDa
Annotated
2026-06-10
51 papers in source corpus 24 papers cited in narrative 24 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

MLX is a bHLH-Zip transcription factor that serves as the obligate dimerization hub of a network controlling glucose-responsive and metabolic gene expression (PMID:10593926, PMID:14742444). It heterodimerizes with the Mad/Mnt repressor proteins Mad1, Mad4, and Mnt to recruit the mSin3A-HDAC corepressor and silence CACGTG E-box transcription, and with the glucose-sensing factors ChREBP and MondoA to drive activation (PMID:10593926, PMID:10918583, PMID:11230181, PMID:16782875). As the obligate partner of ChREBP, MLX is strictly required for binding to tandem-E-box carbohydrate response elements (ChoRE): ChREBP cannot bind alone, and two ChREBP-MLX heterodimers cooperate through inter-dimer contacts made by the MLX loop region to occupy the ChoRE and confer glucose responsiveness (PMID:14742444, PMID:15664996, PMID:17148476). This heterotetramer assembly is gated by CK2/GSK3-dependent phosphorylation of a conserved MLX motif, which high glucose-6-phosphate inhibits (PMID:40073115). With MondoA, MLX forms a complex retained in the cytoplasm — associated with the outer mitochondrial membrane and held by CRM1-dependent export and 14-3-3 — that shuttles to the nucleus upon glucose elevation to activate glycolytic genes through three sequential steps: nuclear accumulation, promoter occupancy, and histone acetyltransferase recruitment (PMID:12446771, PMID:16782875, PMID:20385767). Through these complexes MLX governs hepatic de novo lipogenesis versus catabolism (PMID:37088121), is required for liver tumorigenesis driven by lipid synthesis (PMID:37684408), supports Myc-driven cancer metabolism (PMID:25640402), drives myoblast fusion via glucose-induced IGF2/Akt myokine signaling (PMID:26584623), and is essential in vivo for male fertility and for dietary sugar tolerance in Drosophila (PMID:23593032, PMID:34669700). MLX also functions outside carbohydrate sensing: it translocates to the nucleus under Golgi stress to repress GASE-driven Golgi stress genes (PMID:27251850), and its levels are controlled by SRSF5-directed alternative splicing that targets it for ubiquitin-mediated degradation (PMID:40586738).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1996 Low

    Established the molecular identity of MLX (TCFL4) as a conserved, widely expressed bHLH-Zip transcription factor, providing the gene and predicted domain architecture later studies would dissect.

    Evidence cDNA cloning, sequencing, and chromosomal mapping to 17q21.1

    PMID:8973301

    Open questions at the time
    • No functional or mechanistic role assigned
    • No interacting partners identified
    • bHLH-Zip activity only predicted from sequence
  2. 1999 High

    Defined MLX's first biochemical function — a Max-like partner that dimerizes selectively with Mad1/Mad4 to repress E-box transcription via mSin3A-HDAC, placing MLX in the Myc/Max/Mad transcriptional network.

    Evidence Yeast two-hybrid, in vitro binding, Co-IP, reporter assays, mutagenesis

    PMID:10593926

    Open questions at the time
    • Did not identify glucose-sensing activator partners
    • Physiological repression targets not defined
    • No in vivo validation
  3. 2000 Medium

    Extended the MLX interaction repertoire to Mnt/Rox and demonstrated low-concentration homodimerization, broadening the network of repressor complexes MLX can nucleate.

    Evidence Yeast two-hybrid, in vitro binding, reporter assays

    PMID:10918583

    Open questions at the time
    • Physiological relevance of homodimers unclear
    • No structural basis for partner selectivity
    • No endogenous validation
  4. 2001 High

    Identified ChREBP (WBSCR14) as an MLX partner forming CACGTG-binding heterodimers, first connecting MLX to a factor that would prove central to glucose-responsive transcription.

    Evidence Yeast two-hybrid, Co-IP, EMSA, reporter assays

    PMID:11230181

    Open questions at the time
    • Glucose responsiveness not yet established
    • Functional readout limited to E-box repression in this context
    • No endogenous target genes
  5. 2002 High

    Resolved how MLX-MondoA complexes are spatially controlled, showing a novel C-terminal dimerization interface and CRM1/14-3-3-dependent cytoplasmic retention as the gatekeeping step before nuclear function.

    Evidence Subcellular fractionation, imaging, leptomycin B, 14-3-3 Co-IP, domain mutagenesis

    PMID:12446771

    Open questions at the time
    • Signal triggering nuclear entry not defined
    • Target genes downstream not characterized
    • Mechanism shown for MondoA-MLX, not ChREBP-MLX
  6. 2004 High

    Established MLX as the obligate ChREBP partner for ChoRE binding, explaining why ChREBP alone is inert and how the heterodimer discriminates glucose-responsive elements.

    Evidence Yeast two-hybrid, EMSA with purified proteins, reporter assays, rat hepatocytes

    PMID:14742444

    Open questions at the time
    • Structural basis of glucose discrimination not resolved
    • Endogenous chromatin context not tested here
    • Upstream glucose signal not defined
  7. 2005 High

    Demonstrated the obligate requirement for MLX at endogenous lipogenic genes using dominant-negative interference and partner-specific rescue, confirming the ChREBP-MLX axis controls glucose-induced transcription in native chromatin.

    Evidence Dominant-negative MLX, hepatocyte transfection, endogenous gene analysis, rescue

    PMID:15664996

    Open questions at the time
    • Did not address MondoA-specific targets
    • Mechanism of glucose sensing unresolved
    • No whole-animal validation
  8. 2006 High

    Localized the cooperative-binding determinant to the MLX loop region, showing two ChREBP-MLX dimers contact each other to occupy tandem ChoRE E-boxes — the structural basis for glucose responsiveness.

    Evidence Computational model, loop mutagenesis, EMSA, hepatocyte reporter assays

    PMID:17148476

    Open questions at the time
    • Atomic structure not solved
    • How glucose modulates this contact not yet known
    • Loop role in MondoA complexes untested
  9. 2006 High

    Defined the MondoA-MLX complex as the necessary and sufficient driver of glycolytic gene expression, revealing its outer-mitochondrial-membrane association and nuclear shuttling.

    Evidence Fractionation, salt/protease assays, imaging, ChIP, loss/gain-of-function, metabolic assays

    PMID:16782875

    Open questions at the time
    • Functional role of mitochondrial association unclear
    • Glucose-sensing signal upstream undefined
    • HAT recruitment step not yet shown
  10. 2010 High

    Dissected glucose control of MondoA-MLX into three sequential regulatory steps (nuclear accumulation, promoter occupancy, HAT recruitment), accounting for the majority of glucose-induced transcription.

    Evidence ChIP, nuclear fractionation, transcriptomics, histone modification assays, glucose titration

    PMID:20385767

    Open questions at the time
    • Identity of recruited HAT not pinned
    • Direct glucose-sensing metabolite not defined here
    • Step-specific molecular triggers incomplete
  11. 2013 High

    Established the in vivo physiological necessity of Mlx for dietary sugar tolerance and metabolic homeostasis using Drosophila genetics, separating circulating-glucose control from sugar tolerance.

    Evidence Drosophila null mutants/RNAi, lipidomics, metabolomics, target-gene dissection

    PMID:23593032

    Open questions at the time
    • Mammalian organismal phenotype not addressed here
    • Specific effector genes not all identified
    • Glucose-sensing mechanism not resolved
  12. 2014 High

    Revealed a reciprocal mTOR-MondoA regulatory loop, in which mTOR sequesters MondoA to block MLX complex formation and TXNIP induction, integrating nutrient signaling with MondoA-MLX output.

    Evidence Co-IP, nuclear fractionation, mTOR inhibitors, ROS manipulation, TXNIP/glucose-uptake assays

    PMID:25332233

    Open questions at the time
    • Direct MLX role in mTOR binding unclear (shown for MondoA)
    • Structural basis of mTOR-MondoA contact unknown
    • In vivo relevance of the loop untested here
  13. 2015 High

    Connected MLX/MondoA to oncogenic metabolism, showing they are required for Myc-driven metabolic reprogramming and lipid biosynthesis, with knockdown triggering apoptosis in Myc-driven cancers.

    Evidence shRNA knockdown, metabolomics, expression profiling, xenograft assays

    PMID:25640402

    Open questions at the time
    • Direct MLX-bound loci in this context not mapped
    • Which complex (ChREBP vs MondoA) dominates unclear
    • Therapeutic targetability not established
  14. 2015 High

    Mapped the downstream effector hierarchy of Mondo-Mlx in Drosophila, identifying Dawdle and Sugarbabe as mediators that partition sugar metabolism and de novo lipogenesis.

    Evidence Drosophila genetics, genome-wide transcriptomics, epistasis, metabolic assays

    PMID:26440885

    Open questions at the time
    • Mammalian effector orthologs not validated
    • Direct vs indirect target distinction incomplete
    • No biochemical reconstitution
  15. 2015 High

    Demonstrated a glucose-driven MLX function in muscle, where MLX induces IGF2 to activate Akt and promote myoblast fusion, with MLX-null mice showing impaired regeneration.

    Evidence RNAi, dominant-negative MLX, conditioned-medium/IGF2 rescue, Akt assays, MLX-null mouse injury model

    PMID:26584623

    Open questions at the time
    • Direct MLX binding at IGF2 not mapped
    • Which heterodimer partner mediates this unclear
    • Link to systemic metabolism not addressed
  16. 2016 Medium

    Identified a carbohydrate-independent role for MLX as a Golgi-stress-induced repressor that translocates to the nucleus, binds GASE, and antagonizes TFE3-driven Golgi stress genes.

    Evidence GASE affinity purification, fractionation/imaging, knockdown/overexpression reporters, GASE binding assays

    PMID:27251850

    Open questions at the time
    • Dimerization partner for GASE binding not defined
    • Stress signal triggering translocation unknown
    • Single-lab finding without reciprocal validation
  17. 2018 Medium

    Showed a disease-associated MLX missense variant (Q139R) enhances MondoA heterodimerization and TXNIP/inflammasome output, linking altered MLX dimerization to oxidative stress and macrophage pathology.

    Evidence Genotyping, structural modeling, TXNIP/inflammasome/ROS/autophagy assays, MondoA-translocation inhibitor rescue

    PMID:30354298

    Open questions at the time
    • Causality at organismal level not established
    • Structural mechanism only modeled
    • Single-lab cell-based assays
  18. 2021 High

    Established MLX as essential for mammalian male fertility, mapping direct MLX-bound loci controlling germ-cell metabolism and survival in conditional knockout mice.

    Evidence Mlx conditional knockout, ChIP-seq, metabolomics, transcriptomics, apoptosis assays, histology

    PMID:34669700

    Open questions at the time
    • Which partner (ChREBP/MondoA) operates in germ cells unclear
    • Metabolic vs direct transcriptional contributions not separated
    • Stress-pathway activation mechanism not fully resolved
  19. 2023 High

    Defined MLX as a master switch for hepatic anabolic-catabolic balance in human cells, with knockdown shifting metabolism from lipogenesis toward oxidation, glycolysis, and improved insulin signaling.

    Evidence siRNA in primary human hepatocytes, transcriptomics, stable isotope tracing, FAO/insulin assays

    PMID:37088121

    Open questions at the time
    • Direct vs indirect targets not separated
    • In vivo human relevance inferred
    • Partner contribution not dissected
  20. 2023 High

    Demonstrated MLX is required for liver tumorigenesis through its control of lipid synthesis, with high-fat diet partially rescuing tumors in Mlx-deficient livers.

    Evidence Liver-specific Mlx knockout, multiple HCC models, high-fat-diet rescue, dominant-negative AAV

    PMID:37684408

    Open questions at the time
    • Lipid species driving tumorigenesis not pinpointed
    • Other metabolic outputs not excluded
    • Translation to human HCC untested
  21. 2023 Medium

    Linked MLX to redox/ferroptosis control by showing it positively regulates SLC7A11 to sustain cystine uptake and GSH, with knockdown driving ferroptosis in osteosarcoma.

    Evidence MLX knockdown in vitro/in vivo, transcriptomics, ferroptosis/ROS/iron assays, SLC7A11 reporters

    PMID:37460542

    Open questions at the time
    • Direct MLX binding at SLC7A11 not confirmed
    • Partner dependence unclear
    • Single-lab study
  22. 2025 High

    Identified phosphorylation as the molecular switch coupling glucose metabolism to MLX function, showing CK2/GSK3 phosphorylation of a conserved motif drives ChREBP-MLX heterotetramer formation and is inhibited by glucose-6-phosphate.

    Evidence Phospho-site mapping, kinase identification, mutagenesis, EMSA, reporters, Drosophila genetics

    PMID:40073115

    Open questions at the time
    • Atomic structure of the tetramer unsolved
    • Whether the same applies to MondoA-MLX unclear
    • Spatial regulation of kinase activity undefined
  23. 2025 Medium

    Revealed post-transcriptional control of MLX, where SRSF5-directed alternative splicing promotes MLX ubiquitination/degradation, modulating NR2F2 activity and trophoblast survival.

    Evidence RT-PCR, RIP, Co-IP, in vivo ubiquitination, SRSF5 knockdown, NR2F2 reporters

    PMID:40586738

    Open questions at the time
    • Identity of the ubiquitin ligase not defined
    • Generalizability beyond trophoblasts unknown
    • Single-lab evidence
  24. 2026 Low

    Proposed a lipid-droplet-targeting role for the MLX C-terminal hairpin that recognizes packing defects on TG-rich droplets and competes with active dimerization, adding a lipid-sensing layer to MLX regulation.

    Evidence Molecular dynamics simulations with biophysical validation

    PMID:41902402

    Open questions at the time
    • Computational only — no in vitro reconstitution or cell-based validation
    • Physiological consequence of LD binding unmeasured
    • Competition with dimerization not demonstrated in cells

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the distinct MLX complexes (ChREBP-MLX, MondoA-MLX, Mad/Mnt-MLX) are selected and spatially partitioned in a given cell, and what atomic-resolution structure underlies cooperative ChoRE binding and phosphorylation control.
  • No high-resolution structure of the ChREBP-MLX heterotetramer on ChoRE
  • Rules governing partner choice in vivo undefined
  • Integration of phosphorylation, localization, splicing, and lipid sensing into one model incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953897 Cellular responses to stimuli 1
Partners
MLXIPMLXIPLMNTMXD1MXD4SRSF5TFE3YWHAZ
Complex memberships
ChREBP-MLX heterodimer/heterotetramerMad/Mnt-MLX repressor complex (mSin3A-HDAC)MondoA-MLX heterodimer

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 MLX is a novel bHLH-Zip protein structurally related to Max that forms heterodimers with Mad1 and Mad4 (but not other Mad family members), binds CACGTG E-box sequences, and represses transcription through recruitment of the mSin3A-HDAC corepressor complex in a dimerization- and DNA-binding-dependent manner. Yeast two-hybrid identification, in vitro binding assays, co-immunoprecipitation, transcriptional reporter assays, mutagenesis The Journal of biological chemistry High 10593926
1996 TCFL4 (now MLX) encodes a widely expressed putative bHLH-Zip transcription factor located at 17q21.1, with high conservation between mouse and human. cDNA cloning, sequencing, chromosomal mapping Gene Low 8973301
2000 MLX interacts with Rox/Mnt in addition to Mad1 and Mad4, and MLX can homodimerize and bind E-box sequences at low concentrations. Yeast two-hybrid, in vitro binding assays, reporter assays Oncogene Medium 10918583
2001 WBSCR14 (ChREBP) forms heterodimers with MLX to bind CACGTG E-box sequences; MLX association with WBSCR14 results in repression of E-box-dependent transcription, similar to its association with Mad/Mnt proteins. Yeast two-hybrid, co-immunoprecipitation, EMSA, transcriptional reporter assays Human molecular genetics High 11230181
2002 MLX and MondoA both possess a C-terminal domain with cytoplasmic localization activity; heterodimerization between MondoA and MLX via this C-terminal domain (a novel dimerization interface independent of the leucine zipper) inactivates the cytoplasmic retention signal and enables nuclear entry. CRM1-dependent nuclear export and 14-3-3 binding to MondoA MCR domains further retain the MondoA-Mlx heterocomplex in the cytoplasm. Subcellular fractionation, fluorescence microscopy, CRM1 inhibitor (leptomycin B), 14-3-3 co-immunoprecipitation, mutagenesis of localization domains Molecular and cellular biology High 12446771
2004 MLX is the obligate heterodimeric partner of ChREBP required for binding to carbohydrate response elements (ChoRE) and transcriptional activation of glucose-responsive lipogenic enzyme genes; ChREBP alone cannot bind ChoRE sequences in vitro, but ChREBP-Mlx heterodimers bind ChoRE and discriminate glucose-responsive from non-glucose-responsive E-box elements. Yeast two-hybrid screen, co-transfection reporter assays in HEK293 cells, in vitro EMSA with purified proteins, primary rat hepatocyte overexpression The Journal of biological chemistry High 14742444
2005 MLX is an obligatory partner of ChREBP for glucose-responsive gene regulation in hepatocytes; dominant-negative Mlx forms (that dimerize with ChREBP but block DNA binding) inhibit glucose-induced transcription of endogenous lipogenic genes from their chromosomal context; the response is rescued by wild-type Mlx or ChREBP but not MondoA. Dominant-negative Mlx constructs, primary hepatocyte transfection, endogenous gene expression analysis, rescue experiments The Journal of biological chemistry High 15664996
2006 The loop region of MLX is critical for DNA binding to ChoRE and glucose-responsive transcription: two ChREBP-Mlx heterodimers interact via their Mlx loop regions to stabilize binding to tandem E-box motifs in the ChoRE; Mlx loop variants that cannot mediate this interaction retain single E-box binding but lose ChoRE binding and glucose responsiveness. Computational model structure, site-directed mutagenesis of Mlx loop region, EMSA, transcriptional reporter assays in hepatocytes Nucleic acids research High 17148476
2006 Endogenous MondoA and Mlx associate with the outer mitochondrial membrane in primary skeletal muscle cells and K562 erythroblasts (interaction is salt- and protease-sensitive); MondoA shuttles between mitochondria and nucleus to activate glycolytic target genes (LDHA, HKII, PFKFB3) via direct binding to CACGTG promoter elements; MondoA-Mlx is necessary and sufficient for glycolysis. Subcellular fractionation, salt/protease sensitivity assays, fluorescence microscopy, ChIP, loss-of-function and gain-of-function experiments, metabolic assays Molecular and cellular biology High 16782875
2010 Glucose controls MondoA-Mlx function at three sequential steps: (1) nuclear accumulation, (2) promoter occupancy of target genes, and (3) recruitment of a histone H3 acetyltransferase to promoter-bound MondoA-Mlx to activate transcription; MondoA-Mlx is required for ~75% of glucose-induced transcription. ChIP, nuclear fractionation, transcriptome analysis, histone modification assays, glucose titration experiments Molecular and cellular biology High 20385767
2013 In Drosophila, Mlx and its partner Mondo are essential for dietary sugar tolerance; mlx null mutants show widespread changes in lipid and phospholipid profiles, elevated circulating glucose, and signs of amino acid catabolism; genetic dissection of Mlx target genes separates circulating glucose regulation from dietary sugar tolerance. Drosophila genetics (null mutants, RNAi), lipidomics, metabolomics, dietary manipulation, systematic loss-of-function analysis of target genes PLoS genetics High 23593032
2014 mTOR binds MondoA in the cytoplasm and prevents MondoA-Mlx complex formation, restricting MondoA nuclear entry and reducing TXNIP expression; conversely, mTOR inhibition induces MondoA-dependent TXNIP expression and reduces glucose uptake; MondoA can also suppress mTORC1 activity via transcriptional upregulation of TXNIP, creating a reciprocal regulatory loop. Co-immunoprecipitation, nuclear fractionation, mTOR inhibitor treatment, ROS manipulation, TXNIP reporter/expression assays, glucose uptake assays Molecular and cellular biology High 25332233
2015 Knockdown of Mlx (or MondoA) blocks Myc-induced reprogramming of multiple metabolic pathways and results in apoptosis in Myc-driven cancer cells; MondoA and Mlx co-regulate a set of metabolic genes with Myc, with lipid biosynthesis identified as a critical function for deregulated Myc-driven cancer survival. shRNA knockdown, metabolomics, gene expression profiling, in vivo xenograft tumorigenesis assays Cancer cell High 25640402
2015 In Drosophila, Mondo-Mlx controls the majority of sugar-regulated genes involved in nutrient digestion, transport, and metabolism; Mlx acts through downstream effectors including the Activin ligand Dawdle and the Gli-like transcription factor Sugarbabe, with Sugarbabe controlling de novo lipogenesis and fatty acid desaturation as a subset of Mondo-Mlx-dependent processes. Drosophila genetics, genome-wide transcriptomics, epistasis analysis (double mutants), in vivo metabolic assays Cell reports High 26440885
2015 MLX promotes myoblast fusion and myogenesis by inducing expression of myokines including IGF2 in response to glucose; MLX-driven IGF2 activates Akt kinase signaling; MLX-null mice display decreased IGF2 induction and diminished muscle regeneration after injury. RNAi knockdown, dominant-negative MLX, conditioned medium rescue, recombinant IGF2 rescue, Akt phosphorylation assays, MLX-null mouse model with muscle injury Genes & development High 26584623
2016 MLX acts as a transcriptional repressor of the Golgi stress response: in normal conditions MLX resides in the cytoplasm and does not bind the Golgi apparatus stress response element (GASE); upon Golgi stress, MLX translocates to the nucleus and binds GASE, reducing TFE3 binding and suppressing transcriptional induction of Golgi-related genes. GASE-binding protein identification (affinity purification), subcellular fractionation/imaging, MLX knockdown and overexpression with reporter assays, ChIP or EMSA for GASE binding Cell structure and function Medium 27251850
2018 The MLX Q139R missense mutation (rs665268, in the DNA-binding site) causes structural changes in MLX that enhance heterodimer formation with MondoA, upregulate TXNIP expression, increase NLRP3 inflammasome activity and cellular oxidative stress, suppress autophagy, and induce macrophage proliferation and macrophage-endothelium interaction; these effects are abolished by an inhibitor of MondoA nuclear translocation. Clinical genotyping, structural modeling, cell-based functional assays (TXNIP expression, inflammasome activity, ROS measurement, autophagy assay), macrophage proliferation/adhesion assays, pharmacological inhibition Circulation. Genomic and precision medicine Medium 30354298
2021 MLX and its binding partner MondoA are both required for male fertility in the mouse; loss of Mlx results in altered metabolism, activation of multiple stress pathways, germ cell apoptosis, and dysregulation of male-specific germ cell transcripts; genomic analysis identified direct MLX-bound loci involved in metabolic targets, male germ cell development, and apoptotic effectors. Mlx conditional knockout mice, genomic binding analysis (ChIP-seq), metabolomics, transcriptomics, apoptosis assays, histology PLoS biology High 34669700
2023 MLX positively regulates SLC7A11 (xCT glutamate/cystine antiporter) transcription to promote cystine uptake and GSH biosynthesis, thereby detoxifying ROS and maintaining redox balance in osteosarcoma cells; MLX knockdown leads to ferrous iron accumulation and ferroptosis. MLX knockdown in vivo and in vitro, transcriptomic sequencing, ferroptosis assays, ROS measurement, iron assays, SLC7A11 reporter/expression assays Cell death & disease Medium 37460542
2023 MLX knockdown in primary human hepatocytes decreases de novo lipogenesis, increases fatty acid oxidation and ketogenesis, reduces lipid accumulation, increases glycolysis and glucose production, and increases insulin-stimulated pAKT levels, demonstrating MLX's role in controlling the balance between lipid anabolism and catabolism in human liver. siRNA knockdown in primary human hepatocytes, transcriptomics, stable isotope tracing (DNL, gluconeogenesis), fatty acid oxidation assays, insulin signaling (pAKT) Metabolism: clinical and experimental High 37088121
2023 Liver-specific knockout of Mlx dramatically decreases lipogenic gene expression and circulating lipid levels; in multiple HCC models (DEN treatment, hydrodynamic oncogene injection), Mlx loss robustly blocks tumor development; high-fat diet can partially restore tumorigenesis in Mlx-deficient livers, indicating that lipid synthesis is a critical downstream mechanism. Liver-specific Mlx knockout mice, multiple HCC induction models, high-fat diet rescue, dominant-negative MLX via AAV, gene expression analysis Oncogene High 37684408
2025 MLX phosphorylation on an evolutionarily conserved motif (by CK2 and GSK3 kinases) is necessary for ChREBP-MLX heterotetramer formation on ChoRE tandem E-boxes and for transcriptional activity; high intracellular glucose-6-phosphate accumulation inhibits MLX phosphorylation and heterotetramer formation, thereby impairing ChREBP-MLX activity; in Drosophila, MLX phosphorylation is required for sugar tolerance and lipid homeostasis. Phosphorylation site mapping, kinase identification (CK2, GSK3), mutagenesis of phosphorylation sites, EMSA, transcriptional reporter assays, Drosophila in vivo genetics Science advances High 40073115
2025 SRSF5-mediated alternative splicing of MLX pre-mRNA promotes ubiquitination and proteasomal degradation of MLX protein; MLX degradation in trophoblast cells enhances NR2F2 transcriptional activity and inhibits trophoblast apoptosis. RT-PCR, RIP assay, Co-IP, in vivo ubiquitination assay, SRSF5 knockdown, NR2F2 reporter assays FASEB journal Medium 40586738
2026 MLX's C-terminal dimerization/cytoplasmic localization domain contains an amphipathic helix-loop-helix hairpin that specifically targets triacylglycerol-rich lipid droplets over sterol ester-rich LDs through packing defect recognition (not direct TG interaction); LD association competes with active MLX dimerization and modulates MLX nuclear activity. Molecular dynamics simulations with biophysical validation of LD association mechanisms Biophysical journal Low 41902402

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Mlx is the functional heteromeric partner of the carbohydrate response element-binding protein in glucose regulation of lipogenic enzyme genes. The Journal of biological chemistry 180 14742444
2015 Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis. Cancer cell 176 25640402
2005 Direct role of ChREBP.Mlx in regulating hepatic glucose-responsive genes. The Journal of biological chemistry 152 15664996
2006 MondoA-Mlx heterodimers are candidate sensors of cellular energy status: mitochondrial localization and direct regulation of glycolysis. Molecular and cellular biology 97 16782875
2014 Functional interactions among members of the MAX and MLX transcriptional network during oncogenesis. Biochimica et biophysica acta 95 24857747
2001 WBSCR14, a gene mapping to the Williams--Beuren syndrome deleted region, is a new member of the Mlx transcription factor network. Human molecular genetics 93 11230181
2013 Mondo/ChREBP-Mlx-regulated transcriptional network is essential for dietary sugar tolerance in Drosophila. PLoS genetics 91 23593032
2015 Mondo-Mlx Mediates Organismal Sugar Sensing through the Gli-Similar Transcription Factor Sugarbabe. Cell reports 88 26440885
1999 Mlx, a novel Max-like BHLHZip protein that interacts with the Max network of transcription factors. The Journal of biological chemistry 88 10593926
2010 Glucose controls nuclear accumulation, promoter binding, and transcriptional activity of the MondoA-Mlx heterodimer. Molecular and cellular biology 79 20385767
2000 Mlx, a new Max-like bHLHZip family member: the center stage of a novel transcription factors regulatory pathway? Oncogene 67 10918583
2006 A critical role for the loop region of the basic helix-loop-helix/leucine zipper protein Mlx in DNA binding and glucose-regulated transcription. Nucleic acids research 61 17148476
2006 The Mlx network: evidence for a parallel Max-like transcriptional network that regulates energy metabolism. Current topics in microbiology and immunology 58 16620032
2013 Coordination of nutrient availability and utilization by MAX- and MLX-centered transcription networks. Cold Spring Harbor perspectives in medicine 45 24003245
2002 A novel heterodimerization domain, CRM1, and 14-3-3 control subcellular localization of the MondoA-Mlx heterocomplex. Molecular and cellular biology 45 12446771
2015 The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling. Genes & development 44 26584623
2020 ErCas12a CRISPR-MAD7 for Model Generation in Human Cells, Mice, and Rats. The CRISPR journal 42 32315227
2014 MondoA-Mlx transcriptional activity is limited by mTOR-MondoA interaction. Molecular and cellular biology 33 25332233
2008 Hepatic overexpression of dominant negative Mlx improves metabolic profile in diabetes-prone C57BL/6J mice. Biochemical and biophysical research communications 32 19121288
2011 Evolution of the Max and Mlx networks in animals. Genome biology and evolution 31 21859806
2021 Genome editing in plants with MAD7 nuclease. Journal of genetics and genomics = Yi chuan xue bao 29 34120856
2020 Expanding and understanding the CRISPR toolbox for Bacillus subtilis with MAD7 and dMAD7. Biotechnology and bioengineering 26 32077487
2014 Association between the MLX interacting protein-like, BUD13 homolog and zinc finger protein 259 gene polymorphisms and serum lipid levels. Scientific reports 25 24989072
2023 Super-enhancer-driven MLX mediates redox balance maintenance via SLC7A11 in osteosarcoma. Cell death & disease 24 37460542
2021 The glucose-sensing transcription factor MLX balances metabolism and stress to suppress apoptosis and maintain spermatogenesis. PLoS biology 24 34669700
2016 MLX Is a Transcriptional Repressor of the Mammalian Golgi Stress Response. Cell structure and function 19 27251850
2022 Coordinated Cross-Talk Between the Myc and Mlx Networks in Liver Regeneration and Neoplasia. Cellular and molecular gastroenterology and hepatology 18 35259493
2022 A Mad7 System for Genetic Engineering of Filamentous Fungi. Journal of fungi (Basel, Switzerland) 14 36675838
2018 Single-Nucleotide Polymorphism of the MLX Gene Is Associated With Takayasu Arteritis. Circulation. Genomic and precision medicine 14 30354298
2023 Glucose-induced and ChREBP: MLX-mediated lipogenic program promotes hepatocellular carcinoma development. Oncogene 13 37684408
2023 Expanding the CRISPR toolbox for Chinese hamster ovary cells with comprehensive tools for Mad7 genome editing. Biotechnology and bioengineering 12 36864663
2023 MLX plays a key role in lipid and glucose metabolism in humans: Evidence from in vitro and in vivo studies. Metabolism: clinical and experimental 11 37088121
2008 Template synthesis and physico-chemical characterization of 14-membered tetraimine macrocyclic complexes, [MLX(2)] [M=Co(II), Ni(II), Cu(II) and Zn(II)]. DNA binding study on [CoLCl(2)] complex. Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy 11 19119063
2023 A MAD7-based genome editing system for Escherichia coli. Microbial biotechnology 10 36929689
2024 Comparison of CRISPR-MAD7 and CRISPR-Cas9 for Gene Disruptions in Komagataella phaffii. Journal of fungi (Basel, Switzerland) 7 38535206
2016 Contrasting Patterns in the Evolution of Vertebrate MLX Interacting Protein (MLXIP) and MLX Interacting Protein-Like (MLXIPL) Genes. PloS one 7 26910886
2022 β-micrustoxin (Mlx-9), a PLA2 from Micrurus lemniscatus snake venom: biochemical characterization and anti-proliferative effect mediated by p53. The journal of venomous animals and toxins including tropical diseases 5 35432496
2014 Is C771G polymorphism of MLX interacting protein-like (MLXIPL) gene a novel genetic risk factor for non-alcoholic fatty liver disease? Cellular and molecular biology (Noisy-le-Grand, France) 5 26177557
1996 TCFL4: a gene at 17q21.1 encoding a putative basic helix-loop-helix leucine-zipper transcription factor. Gene 5 8973301
2024 Body-Wide Inactivation of the Myc-Like Mlx Transcription Factor Network Accelerates Aging and Increases the Lifetime Cancer Incidence. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 4 38976573
2020 Effects of Mlx-8, a phospholipase A2 from Brazilian coralsnake Micrurus lemniscatus venom, on muscarinic acetylcholine receptors in rat hippocampus. The journal of venomous animals and toxins including tropical diseases 4 32063920
1986 Natural killer-like cells produce the cell-directed inhibitor of monocyte leukotaxis, CDI-MLx, in vitro. Cellular immunology 3 3742609
2025 Multiplex Genome Editing and Regulation in Bacillus subtilis with CRISPR-MAD7. ACS synthetic biology 2 40729556
2024 Cas12a and MAD7, genome editing tools for breeding. Breeding science 2 39246434
2025 SRSF5 Regulates Trophoblast Apoptosis by Inhibiting NR2F2 Transcriptional Activity Through MLX Ubiquitin Degradation Mediated by Alternative Splicing in Preeclampsia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1 40586738
2024 Domestication Gene Mlx and Its Partner Mondo Are Involved in Controlling the Larval Body Size and Cocoon Shell Weight of Bombyx mori. International journal of molecular sciences 1 38542400
2026 Mechanistic insights into the selective targeting of MLX to triacylglycerol-rich lipid droplets. Biophysical journal 0 41902402
2025 MLX phosphorylation stabilizes the ChREBP-MLX heterotetramer on tandem E-boxes to control carbohydrate and lipid metabolism. Science advances 0 40073115
2025 Engineering a High-Fidelity MAD7 Variant with Enhanced Specificity for Precision Genome Editing via CcdB-Based Bacterial Screening. Biomolecules 0 41154642
2024 MLX phosphorylation stabilizes the ChREBP-MLX heterotetramer on tandem E-boxes to control carbohydrate and lipid metabolism. bioRxiv : the preprint server for biology 0 39282306
2023 The Myc-Like Mlx Network Impacts Aging and Metabolism. bioRxiv : the preprint server for biology 0 38076995

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