Affinage

Showing MTDH — AEG-1 is a alias.

MTDH

Protein LYRIC · UniProt Q86UE4

Length
582 aa
Mass
63.8 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 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

MTDH (AEG-1/LYRIC/3D3) is a single-pass membrane-associated oncogenic scaffold protein, predominantly resident in the endoplasmic reticulum and perinuclear/nuclear-envelope regions, that drives transformation, metastasis, angiogenesis, chemoresistance, and immune evasion by coupling membrane and nuclear signaling to multiple transcriptional and post-transcriptional programs (PMID:15927426, PMID:14980505, PMID:19940250). Its activity is gated by post-translational modification: IKKβ phosphorylates MTDH at Ser298 to license IκBα degradation and NF-κB-dependent gene expression (PMID:25849741), and zDHHC6-mediated palmitoylation at Cys75 (reversed by PPT1/2) destabilizes MTDH and weakens its interaction with SND1 (PMID:36276642). The MTDH–SND1 complex is a central effector that sustains RISC-directed gene silencing and tumor progression, and destabilizes Tap1/Tap2 mRNAs to suppress antigen presentation and antitumor T-cell responses; pharmacological disruption of this interaction suppresses tumor growth and enhances anti-PD-1 sensitivity (PMID:35121987, PMID:35121988, PMID:23889990). MTDH is a required driver of NF-κB activation in hepatocarcinogenesis and TLR signaling, recruiting TRAF6 to TAK1 to enable K63-ubiquitination and downstream NF-κB/MAPK output (PMID:25193383, PMID:33987665), and it activates Wnt/β-catenin signaling through direct interaction with GSK-3β (PMID:34462446, PMID:25880337). In the nucleus it represses retinoid signaling by sequestering and inactivating RXR, blocking coactivator recruitment, with consequences for lipid homeostasis and DIO1 expression (PMID:25125681, PMID:26070567, PMID:25944909), represses EAAT2 via YY1/CBP (PMID:21852380), and relieves PLZF-mediated transcriptional repression (PMID:19648967). As an RNA-binding protein it loads MDR1 mRNA onto polysomes and regulates FANCD2/FANCI mRNA to confer chemoresistance, and it stabilizes PARP1 via USP10 to promote DNA repair and radioresistance (PMID:23889990, PMID:31477281, PMID:37838281). MTDH expression is itself controlled epigenetically by DOT1L and post-transcriptionally by the translational regulators CPEB1 and CPEB3 (PMID:36017623, PMID:23360795, PMID:32968053).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2004 Medium

    Established the basic identity and localization of MTDH, defining it as a membrane protein associated with the secretory/nuclear envelope system rather than a soluble cytoplasmic factor.

    Evidence Gene-trap screen, subcellular fractionation, immunostaining, and tight-junction colocalization in epithelial cells

    PMID:14980505 PMID:15383321

    Open questions at the time
    • Topology and functional consequence of membrane residence unresolved
    • Relationship between TJ recruitment and downstream signaling undefined
  2. 2005 Medium

    Linked MTDH to oncogenic transcriptional and transformation phenotypes, showing it could repress EAAT2 and cooperate with Ha-ras.

    Evidence Recombinant protein production, promoter-reporter assay, and soft-agar transformation in melanocytes

    PMID:15927426

    Open questions at the time
    • Mechanism of EAAT2 repression not defined at this stage
    • Direct molecular partners unknown
  3. 2009 High

    Demonstrated MTDH is a bona fide transforming oncogene operating through PI3K/Akt and driving angiogenesis, and identified its first nuclear transcriptional partners (PLZF, BCCIPα).

    Evidence Stable transfection/tumor formation in CREF cells with Tie2 siRNA rescue; yeast two-hybrid plus co-IP for PLZF and BCCIPα; NLS-mapping constructs

    PMID:18440304 PMID:19383828 PMID:19648967 PMID:19940250

    Open questions at the time
    • How a membrane protein accesses nuclear partners not mechanistically resolved
    • Direct vs scaffold role in PI3K/Akt activation unclear
  4. 2011 High

    Defined the YY1/CBP mechanism of EAAT2 repression and uncovered an unexpected role in retroviral biology through HIV-1 Gag interaction.

    Evidence Transcriptional reporter and glutamate-uptake assays in astrocytes; affinity purification, domain mapping, and virion incorporation/infectivity assays

    PMID:21852380 PMID:21957284

    Open questions at the time
    • Physiological relevance of Gag interaction outside infection models unclear
    • Connection between membrane localization and transcriptional coactivator effects unresolved
  5. 2013 Medium

    Identified MTDH's RNA-related functions — SND1/RISC interaction, polysomal loading of MDR1 mRNA, and CPEB1-controlled local translation — establishing it as both an effector and target of post-transcriptional regulation.

    Evidence Polysome fractionation, co-IP of MTDH-SND1, CPEB1 mutant translational-arrest experiments with in vivo glioblastoma validation; NF-κB-coactivation ChIP for miR-130b

    PMID:23360795 PMID:23889990 PMID:28107197

    Open questions at the time
    • Direct RNA-binding specificity not biochemically defined
    • Whether SND1 link to RISC is direct or indirect unresolved
  6. 2014 High

    Established RXR as a key nuclear receptor target sequestered and inactivated by MTDH, and provided in vivo genetic proof that MTDH is required for NF-κB-driven hepatocarcinogenesis.

    Evidence Co-IP, fractionation, coactivator-recruitment and reporter assays with AEG-1 transgenic hepatocytes; AEG-1 knockout mouse DEN-HCC model; PI3K/Akt anoikis assays

    PMID:24941119 PMID:25125681 PMID:25193383

    Open questions at the time
    • Whether RXR sequestration is membrane-anchored is unclear
    • Relative contribution of NF-κB vs PI3K/Akt to tumorigenesis not partitioned
  7. 2015 High

    Pinpointed IKKβ phosphorylation at Ser298 as a direct activating modification for NF-κB signaling and extended MTDH-RXR function into systemic lipid homeostasis and thyroid hormone metabolism.

    Evidence Phosphoproteomics plus in vitro IKKβ kinase assay and S298 mutagenesis; AEG-1 knockout body-composition/fat-absorption studies; DIO1 reporter and NF-κB assays

    PMID:25849741 PMID:25880337 PMID:25944909 PMID:26070567

    Open questions at the time
    • Kinetics and stoichiometry of Ser298 phosphorylation in vivo unknown
    • How a single scaffold integrates IKKβ and RXR inputs not mechanistically reconciled
  8. 2017 High

    Demonstrated bidirectional in vivo control of metabolic liver disease by MTDH, linking its NF-κB and PPARα/lipogenic activities to NASH pathogenesis.

    Evidence Hepatocyte-specific transgenic and conditional knockout mice with HFD challenge and nanoparticle siRNA therapy

    PMID:28437865

    Open questions at the time
    • Cell-autonomous vs inflammatory contributions not fully separated
    • Direct molecular target driving lipogenesis undefined
  9. 2020 High

    Identified CPEB3 as a 3'UTR-binding translational suppressor of MTDH acting as a tumor suppressor, and confirmed the MTDH-SND1/ERK-EMT axis in additional cancer contexts.

    Evidence Transcriptome-wide RIP and 3'UTR reporter with CPEB3 knockout DEN-HCC mice; co-IP and SND1-knockdown rescue in ccRCC

    PMID:31978894 PMID:32968053

    Open questions at the time
    • Upstream control of CPEB3 in tumors undefined
    • Direct vs indirect MTDH-SND1 effect on ERK unresolved
  10. 2021 High

    Validated the MTDH-SND1 protein-protein interaction as a druggable node sustaining breast cancer and showed it suppresses antitumor immunity by destabilizing Tap1/2 mRNAs; defined TRAF6-TAK1 recruitment as the basis for TLR-driven inflammation.

    Evidence Mtdh-ablation mice and small-molecule PPI inhibitors (C26-A2/A6) in TNBC; mRNA-stability and T-cell assays with anti-PD-1 combination; MTDH knockout colitis model with monocyte adoptive transfer and K63-ubiquitination assays

    PMID:33987665 PMID:35121987 PMID:35121988

    Open questions at the time
    • Structural basis of the MTDH-SND1 interface not described in timeline
    • How the same complex selects Tap1/2 vs other mRNAs unknown
  11. 2022 High

    Revealed palmitoylation at Cys75 as a tumor-suppressive switch regulating MTDH stability and SND1 binding, and added DDX17 stabilization, β-catenin/LEF-1-driven PD-L1 induction, GSK-3β binding, and DOT1L-mediated transcriptional control to the regulatory network.

    Evidence Acyl-RAC, C75A knock-in and Zdhhc6 knockout mice in DEN-HCC; co-IP/ubiquitination/ChIP for DDX17-YB1-EGFR and β-catenin/LEF-1-PD-L1; co-IP/co-localization for GSK-3β; H3K79me3 ChIP for DOT1L

    PMID:34462446 PMID:35609735 PMID:36017623 PMID:36276642 PMID:36385375

    Open questions at the time
    • Interplay between Ser298 phosphorylation and Cys75 palmitoylation not jointly assayed
    • Which interactions are membrane-localized vs cytosolic/nuclear unresolved
  12. 2023 High

    Connected MTDH to DNA repair and radioresistance by showing it recruits USP10 to deubiquitinate and stabilize PARP1.

    Evidence Co-IP of AEG-1-USP10-PARP1 ternary complex, K48-linkage ubiquitination assay, PARP1 rescue, and irradiation/γH2AX assays in esophageal carcinoma

    PMID:37838281

    Open questions at the time
    • Whether MTDH directly contacts USP10 or PARP1 not distinguished
    • Generality across tumor types beyond ESCC untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single ER-anchored protein is spatially partitioned to execute membrane, cytoplasmic, and nuclear functions — and how its modifications (Ser298 phosphorylation, Cys75 palmitoylation) coordinately switch among its many partners — remains the central unresolved question.
  • No structural model of MTDH or its complexes in the corpus
  • Mechanism routing MTDH between ER membrane and nucleus undefined
  • Direct RNA-binding determinants not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 3 GO:0003723 RNA binding 2 GO:0045182 translation regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2 GO:0005635 nuclear envelope 1 GO:0005730 nucleolus 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-1430728 Metabolism 2 R-HSA-73894 DNA Repair 1
Partners
CTNNB1DDX17GSK3BPLZFRXRSND1TRAF6USP10
Complex memberships
MTDH-SND1 complexMTDH-TRAF6-TAK1 complexMTDH-USP10-PARP1 complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 AEG-1 (MTDH) is a single-pass transmembrane protein of ~64 kDa that predominantly localizes to the endoplasmic reticulum and perinuclear region; ectopic expression inhibits EAAT2 promoter activity and synergizes with oncogenic Ha-ras to enhance soft agar colony formation in immortalized melanocytes. Baculovirus recombinant protein production, subcellular localization by immunostaining, promoter-reporter assay, soft agar colony formation assay Gene Medium 15927426
2004 LYRIC/MTDH colocalizes with tight junction proteins ZO-1 and occludin in polarized epithelial cells; it dissociates from ZO-1 when junctional complexes are disrupted and is recruited after ZO-1 during tight junction maturation, suggesting it is not a structural TJ component but is recruited during maturation. Immunostaining of rat/human tissue sections and cell lines, co-localization with ZO-1 and occludin, calcium-switch disruption/reformation assay Experimental cell research Medium 15383321
2004 3D3/LYRIC (MTDH) is located in the endoplasmic reticulum, nuclear envelope, and nucleolus, consistent with a type-1b membrane protein with a single transmembrane domain; multiple isoforms detected by Northern blot correspond to multiple mRNAs. Gene-trap screen, subcellular fractionation, immunostaining, Northern blot analysis Experimental cell research Medium 14980505
2009 AEG-1 functions as a bona fide transforming oncogene: stable expression in normal rat embryo fibroblasts (CREF) induces morphological transformation, invasion, anchorage-independent growth, and aggressive tumor formation in nude mice; oncogenic activity operates through the PI3K/Akt pathway and promotes angiogenesis via upregulation of angiopoietin-1, MMP-2, HIF-1α, and Tie2. Stable transfection in CREF cells, soft agar assay, Matrigel invasion assay, nude mouse tumor formation, immunohistochemistry for microvessel density, Tie2 siRNA rescue, in vitro tube formation assay Proceedings of the National Academy of Sciences of the United States of America High 19940250
2009 Nuclear LYRIC/MTDH interacts with the transcriptional repressor PLZF via yeast two-hybrid and co-localization in mammalian cells; interaction involves the N- and C-termini of LYRIC and the region C-terminal to the RD2 domain of PLZF; co-expression reduces PLZF binding to target promoters and relieves PLZF-mediated repression, providing a mechanism for evasion of apoptosis. Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, co-localization to nuclear bodies containing HDACs, promoter-binding assay Oncogene High 19648967
2009 LYRIC/MTDH subcellular distribution is regulated by three nuclear localization signals (NLS): extended NLS-3 (aa 546–582) is the predominant regulator of nuclear localization; extended NLS-1 (aa 78–130) regulates nucleolar localization; within the NLS-2 region (aa 415–486), LYRIC is modified by ubiquitin almost exclusively in the cytoplasm. GFP-NLS fusion protein constructs, deletion constructs, immunoprecipitation and Western blot for ubiquitin modification, prostate tissue microarray immunohistochemistry Clinical cancer research Medium 19383828
2008 LYRIC/MTDH interacts with BCCIPα (a CDKN1A/BRCA2-associated cell cycle regulator) identified by yeast two-hybrid; co-expression leads to decreased BCCIPα protein levels via proteasomal degradation; a LYRIC truncation lacking the interaction region fails to reduce BCCIPα, establishing LYRIC as a negative regulator of BCCIPα. Yeast two-hybrid, co-immunoprecipitation in mammalian cells, proteasome inhibitor rescue, truncation mutant analysis, Western blot Biochemical and biophysical research communications Medium 18440304
2011 AEG-1/MTDH represses EAAT2 expression at the transcriptional level in glioblastoma by inducing YY1 activity to inhibit CBP function as a coactivator on the EAAT2 promoter; AEG-1-mediated EAAT2 repression reduces glutamate uptake and causes neuronal cell death. Gain- and loss-of-function in primary human fetal astrocytes and T98G cells, Pearson correlation analysis in patient samples, transcriptional reporter assay, YY1/CBP mechanistic analysis, glutamate uptake assay, neuronal death assay Cancer research High 21852380
2011 LYRIC/MTDH is incorporated into HIV-1 virions and interacts with HIV-1 Gag via Gag's matrix (MA) and nucleocapsid (NC) domains; this interaction requires Gag multimerization and Lyric amino acids 101–289; expression of the Gag-binding domain of Lyric increases Gag expression and viral infectivity, whereas a Lyric mutant lacking the Gag-binding site decreases Gag expression and infectivity. Interaction is also observed with murine leukemia virus and equine infectious anemia virus. Affinity purification, co-immunoprecipitation, Western blot, virion incorporation assay, domain mapping with deletion mutants, infectivity assay Journal of virology High 21957284
2014 AEG-1 interacts with retinoid X receptor (RXR) and profoundly inhibits RXR/RAR-mediated transcriptional activation; in non-tumorigenic cells AEG-1 interferes with recruitment of transcriptional coactivators to RXR in the nucleus; in tumor cells overexpressed AEG-1 sequesters RXR in the cytoplasm preventing nuclear translocation; ERK activated by AEG-1 phosphorylates RXR leading to its functional inactivation. Co-immunoprecipitation, nuclear/cytoplasmic fractionation, co-localization, transcriptional reporter assay, coactivator recruitment assay, ERK inhibitor treatment, primary hepatocytes from AEG-1 transgenic mice, nude mouse xenograft rescue with ATRA + AEG-1 knockdown Cancer research High 25125681
2014 AEG-1 is essential for NF-κB activation and hepatocarcinogenesis in vivo; AEG-1-deficient mice show resistance to DEN-induced HCC and have a relative defect in NF-κB activation in hepatocytes and macrophages, as well as impaired IL-6 production and STAT3 activation. AEG-1 knockout mouse model, DEN-induced hepatocarcinogenesis, NF-κB reporter assay, STAT3 and IL-6 measurement, tumor incidence and metastasis assessment Cancer research High 25193383
2015 AEG-1/MTDH is directly phosphorylated by IKKβ on serine 298 in response to TNF-α stimulation; this phosphorylation is essential for IκBα degradation, NF-κB-dependent gene expression, and cell proliferation. Quantitative phosphoproteomics by mass spectrometry with random forest bioinformatics, in vitro IKKβ kinase assay, site-directed mutagenesis (S298), NF-κB reporter assay, cell proliferation assay Nature communications High 25849741
2015 AEG-1/MTDH regulates lipid homeostasis by interacting with RXR and inhibiting its function; AEG-1 knockout mice are leaner, have less body fat, live longer, and are resistant to high-fat diet-induced weight gain due to decreased intestinal fat absorption; in enterocytes of knockout mice, increased activity of RXR heterodimer partners LXR and PPARα (key inhibitors of intestinal fat absorption) is observed. AEG-1 knockout mouse model, body composition analysis, fat absorption measurement (not fat synthesis or consumption), high-fat diet challenge, co-immunoprecipitation of AEG-1-RXR, nuclear receptor activity assays The Journal of biological chemistry High 26070567
2017 AEG-1/MTDH plays a role in non-alcoholic steatohepatitis (NASH): hepatocyte-specific AEG-1 transgenic mice develop spontaneous NASH while conditional hepatocyte-specific AEG-1 knockout mice are protected from HFD-induced NASH; mechanisms include inhibition of PPARα activity (decreasing fatty acid β-oxidation), augmentation of fatty acid synthase translation (de novo lipogenesis), and NF-κB-mediated inflammation. Hepatocyte-specific AEG-1 transgenic (Alb/AEG-1) and conditional knockout (AEG-1ΔHEP) mouse models, HFD challenge, PPARα reporter assay, fatty acid synthase translation assay, NF-κB activity assay, nanoparticle-delivered AEG-1 siRNA therapeutic experiment Hepatology High 28437865
2013 MTDH upregulates miR-130b transcription by acting as a coactivator of NF-κB; miR-130b promotes EMT-like changes and glioma invasion by targeting PTEN, PPP2CA, and SMAD7; additionally PTEN acts as a ceRNA to affect PPP2CA and SMAD7 expression. MTDH gain/loss-of-function, miRNA expression profiling, ChIP/luciferase reporter for NF-κB-driven miR-130b transcription, target validation by luciferase assay, invasion assay, Western blot Oncotarget Medium 28107197
2013 CPEB1 binds the MTDH/AEG-1 mRNA and regulates its translation in glioblastoma cells; a phosphorylation-deficient CPEB1 mutant that holds mRNAs in translational arrest blocks MTDH/AEG-1 expression in vitro and inhibits glioblastoma tumor growth in vivo; MTDH mRNA containing CPEB1-binding sites is transported to the leading edge of migrating cells and translated there. CPEB1 mutant expression (phosphorylation-deficient), Western blot for MTDH protein, in vivo xenograft assay, reporter mRNA localization with point mutations in binding sites, glioblastoma migration assay Molecular cancer research Medium 23360795
2020 CPEB3, a sequence-specific RNA-binding protein, directly binds the 3'UTR of MTDH mRNA and suppresses its translation in HCC; this post-transcriptional regulation inhibits EMT and metastasis of HCC cells; CPEB3 knockout mice are more susceptible to carcinogen-induced hepatocarcinogenesis. RNA immunoprecipitation (transcriptome-wide CPEB3-bound mRNAs), luciferase 3'UTR reporter assay, CPEB3 knockout mice with DEN-induced HCC, in vivo and in vitro metastasis assays Cell death & disease High 32968053
2021 The MTDH-SND1 protein-protein interaction is required to sustain breast cancer progression; genetic ablation of Mtdh inhibits breast cancer development through disrupting the MTDH-SND1 interaction; small-molecule inhibitors (C26-A2 and C26-A6) that specifically disrupt the MTDH-SND1 PPI suppress tumor growth, metastasis, and enhance chemotherapy sensitivity in triple-negative breast cancer preclinical models. Genetically modified mice (Mtdh ablation), small-molecule compound screening, biochemical MTDH-SND1 binding disruption assays, tumor growth and metastasis assays in TNBC preclinical models Nature cancer High 35121987
2021 The MTDH-SND1 complex suppresses antitumor T cell responses by binding to and destabilizing Tap1/Tap2 mRNAs (encoding key antigen-presentation machinery components), thereby reducing tumor antigen presentation and inhibiting T cell infiltration and activation; pharmacological disruption of the MTDH-SND1 complex with compound C26-A6 enhanced immune surveillance and sensitivity to anti-PD-1 therapy. Genetic and pharmacological targeting of MTDH-SND1 interaction, RNA-binding/mRNA stability assay for Tap1/2 mRNAs, T cell infiltration and activation assays, anti-PD-1 combination therapy in preclinical metastatic breast cancer models Nature cancer High 35121988
2022 AEG-1/MTDH undergoes palmitoylation on conserved cysteine residue Cys-75; palmitoylation is dynamically regulated by the palmitoyl transferase zDHHC6 (writer) and PPT1/2 (erasers); palmitoylation adversely regulates AEG-1 protein stability and weakens AEG-1-SND1 interaction, thereby affecting RISC activity and tumor suppressor expression; blocking palmitoylation (AEG-1-C75A knock-in or Zdhhc6 knockout) exacerbates DEN-induced HCC progression in vivo. Acyl-RAC assay, Cys-75 point mutation (C75A knock-in mouse), Zdhhc6 knockout mouse, DEN-induced HCC model, co-immunoprecipitation for AEG-1-SND1 interaction, immunofluorescence, HCQ (PPT1 inhibitor) xenograft treatment Theranostics High 36276642
2022 MTDH interacts with and stabilizes DDX17 by inhibiting its ubiquitination; DDX17 acts as a transcriptional regulator that interacts with YB1 in the nucleus, driving YB1 binding to the EGFR gene promoter to increase EGFR transcription and activate MEK/pERK signaling in HCC. Co-immunoprecipitation for MTDH-DDX17 interaction, ubiquitination assay, ChIP for YB1 binding to EGFR promoter, in vitro and in vivo tumor assays Oncogene Medium 36385375
2023 AEG-1 confers radioresistance in esophageal squamous cell carcinoma by recruiting the deubiquitinase USP10 to remove K48-linked polyubiquitin chains at Lys425 of PARP1, thereby preventing PARP1 proteasomal degradation; elevated PARP1 facilitates homologous recombination-mediated DNA double-strand break repair and mitigates irradiation-induced DNA damage. Co-immunoprecipitation for AEG-1-USP10-PARP1 complex, ubiquitination assay (K48-linkage specificity), PARP1 overexpression rescue, in vitro and in vivo irradiation assays, DNA damage (γH2AX) assay Cancer letters High 37838281
2014 AEG-1 promotes anoikis resistance in HCC cells via the PI3K/Akt pathway, characterized by regulation of Bcl-2 and Bad; PI3K inhibitor LY294002 reverses AEG-1-dependent Akt phosphorylation, Bcl-2 expression, and anoikis resistance; AEG-1 also activates CXCR4 expression to promote orientation chemotaxis toward CXCL12 secreted by endothelial cells. AEG-1 gain/loss-of-function in HCC cells, suspension culture anoikis assay, caspase-3 activation, PI3K inhibitor treatment, CXCR4 antagonist AMD3100 treatment, Bcl-2/Bad Western blot PloS one Medium 24941119
2014 AEG-1 promotes invasion in osteosarcoma via the JNK/c-Jun/MMP-2 pathway; AEG-1 overexpression increases phospho-JNK and phospho-c-Jun levels and upregulates MMP-2 transcriptional activity; JNK inhibitor SP600125 (but not ERK inhibitor PD98059) decreases phospho-c-Jun, MMP-2 levels, and invasion in AEG-1-overexpressing U2OS cells. Wound-healing and Matrigel invasion assays, MAPK inhibitor treatment, Western blot for phospho-JNK/ERK/c-Jun, MMP-2 luciferase reporter assay, immunohistochemistry in patient tissues Biochemical and biophysical research communications Medium 25204501
2016 AEG-1 upregulates transcription of the membrane protein tetraspanin 8 (TSPAN8); TSPAN8 knockdown in AEG-1-overexpressing HCC cells inhibits invasion and migration without affecting proliferation and abrogates AEG-1-induced primary tumor and intrahepatic metastasis in vivo; TSPAN8 inhibition also impairs HUVEC tube formation, suggesting AEG-1-driven angiogenesis is partially mediated through TSPAN8. TSPAN8 knockdown by siRNA, invasion/migration assay, proliferation assay, orthotopic xenograft in nude mice, HUVEC tube formation co-culture assay FEBS letters Medium 27339400
2016 AEG-1 activates Wnt/PCP-Rho signaling in tongue squamous cell carcinoma; recombinant AEG-1 activates Wnt/PCP-Rho signaling, and its stimulatory effects on invasion and EMT are reversed by an anti-Wnt5a neutralizing antibody or by inhibition of Rac1 or ROCK. Recombinant AEG-1 treatment, Wnt5a neutralizing antibody, Rac1 and ROCK inhibitors, invasion/EMT assays, xenograft-mouse model Oncotarget Medium 26689985
2013 AEG-1/MTDH promotes drug resistance in part by increasing loading of MDR1 mRNA onto polysomes, facilitating MDR1 protein translation; additionally AEG-1 acts as an RNA-binding protein and interacts with SND1 (a component of the RNA-induced silencing complex) to regulate microRNA-directed gene silencing. Polysome fractionation for MDR1 mRNA loading, RNA-binding protein assays, co-immunoprecipitation of AEG-1-SND1 complex, functional drug resistance assays Advances in cancer research Medium 23889990
2021 MTDH promotes TLR-induced NF-κB and MAPK signaling in macrophages by recruiting TRAF6 to TAK1, leading to TRAF6-mediated K63 ubiquitination and phosphorylation of TAK1; MTDH-knockout mice are protected from DSS-induced colitis; adoptive transfer of wild-type monocytes into MTDH-knockout mice partially restored susceptibility. MTDH knockout mouse model, DSS-induced colitis, monocyte adoptive transfer, co-immunoprecipitation of MTDH-TRAF6-TAK1, ubiquitination assay (K63-linkage), NF-κB/MAPK reporter assays in macrophages Journal of Crohn's & colitis High 33987665
2019 MTDH, through its RNA-binding protein function, post-transcriptionally regulates expression of FANCD2 and FANCI (Fanconi anemia pathway components involved in interstrand crosslink repair), as demonstrated by RNA-binding protein immunoprecipitation; this contributes to platinum-based chemotherapy resistance. RNA-binding protein immunoprecipitation (RIP) for FANCD2/FANCI mRNAs, MTDH knockdown with siRNA, patient-derived xenograft model with pristimerin nanoparticles + cisplatin Gynecologic oncology Medium 31477281
2013 AEG-1 participates in TGF-β1-induced EMT in proximal tubular epithelial cells through activation of p38 MAPK; AEG-1 expression is increased by TGF-β1 treatment; AEG-1 knockdown inhibits p38 phosphorylation and reverses TGF-β1-induced EMT; AEG-1 overexpression elicits p38 phosphorylation and promotes EMT; p38 inhibitor blocks these AEG-1 effects. AEG-1 siRNA knockdown and overexpression in HK-2 cells, Western blot for phospho-p38, EMT markers, p38-specific inhibitor treatment Cell biology international Medium 23640911
2022 MTDH increases PD-L1 expression by upregulating PD-L1 transcriptional activity through β-catenin/LEF-1 signaling; MTDH co-immunoprecipitates with β-catenin/LEF-1; ChIP assay demonstrated interaction of MTDH-associated machinery with the PD-L1 promoter when LEF-1 expression was silenced. siRNA library screen with PD-L1 luciferase reporter, co-immunoprecipitation of MTDH-β-catenin/LEF-1, ChIP assay for PD-L1 promoter, in vivo syngeneic tumor model + anti-PD-1 combination Cancer letters Medium 35609735
2015 AEG-1/MTDH induces EMT in lung cancer through direct targeting of multiple positive regulators of the Wnt/β-catenin signaling cascade, including GSK-3β and CKIδ, resulting in down-regulation of E-cadherin and up-regulation of Vimentin. AEG-1 overexpression in NSCLC cell lines, orthotopic xenograft-mouse model, Western blot for GSK-3β/CKIδ/EMT markers, immunofluorescence, immunohistochemistry BMC cancer Medium 25880337
2015 AEG-1/MTDH contributes to non-thyroidal illness syndrome (NTIS) in HCC context by inhibiting DIO1 expression through two mechanisms: interference with co-activator recruitment to RXR and activation of NF-κB; AEG-1 overexpression represses DIO1 and AEG-1 knockout induces DIO1 expression; inverse correlation confirmed in human HCC patients. AEG-1 transgenic and knockout mouse hepatocytes, human HCC cell lines with AEG-1 overexpression/knockdown, DIO1 transcriptional reporter, co-activator recruitment assay, NF-κB assay, serum T3/T4 measurement, immunohistochemistry in human HCC The Journal of biological chemistry Medium 25944909
2021 AEG-1 activates Wnt/β-catenin signaling by directly interacting with GSK-3β in the cytoplasm of glioma cells, as shown by co-immunoprecipitation and co-localization by immunofluorescence staining. Co-immunoprecipitation, Western blot, immunofluorescence co-localization, Wnt/β-catenin pathway assays Scientific reports Medium 34462446
2017 AEG-1 promotes gastric cancer metastasis through upregulation of eIF4E, which in turn increases MMP-9 and Twist expression; manipulating eIF4E by overexpression/siRNA partially eliminates AEG-1-regulated EMT, migration, and invasion. AEG-1 gain/loss-of-function, eIF4E overexpression/siRNA rescue experiments, Western blot for eIF4E/MMP-9/Twist, xenograft model, orthotopic metastasis model Journal of cellular and molecular medicine Medium 28661037
2019 AEG-1 induces autophagy via the PERK-eIF2α-ATF4-CHOP signaling axis in suspended HCC cells; AEG-1 promotes anoikis resistance through this autophagy pathway; inhibiting autophagy by siRNA-BECN1 prevented AEG-1-promoted metastasis in vivo. Suspension culture model, siRNA-BECN1 and siRNA-AEG-1, Western blot for autophagy markers and PERK/eIF2α/ATF4/CHOP, in vivo metastasis assay in nude mice Journal of cellular physiology Medium 31691973
2030 AEG-1 interacts with MMP9 in thyroid cancer cells as shown by co-immunoprecipitation; AEG-1 is associated with activation of NF-κB signaling and upregulation of MMP2/9; knockdown of AEG-1 reduces migration and invasion through downregulation of MMP2/9. Co-immunoprecipitation of AEG-1-MMP9, Western blot, zymography, immunofluorescence, immunohistochemistry, AEG-1 siRNA knockdown International journal of oncology Low 28731152
2022 DOT1L (a H3K79 methyltransferase) promotes MTDH-Wt and MTDHΔ7 transcription by increasing H3K79me3 levels on the MTDH promoter, as shown by ChIP assay; DOT1L-induced MTDH causes NF-κB occupancy on the HIF-1α promoter to increase its transcription, elevating proangiogenic mediators in TNBC. ChIP for H3K79me3 on MTDH promoter and NF-κB on HIF-1α promoter, DOT1L inhibitor EPZ004777, siDOT1L, in vitro angiogenesis assays, TNBC xenograft The FEBS journal Medium 36017623
2020 MTDH interacts with SND1 at the protein level in ccRCC cells, confirmed by immunoprecipitation and immunofluorescence; MTDH activates ERK signaling and EMT through SND1; knockdown of SND1 abolishes MTDH-mediated ERK and EMT signaling activation. Co-immunoprecipitation of MTDH-SND1, immunofluorescence co-localization, SND1 knockdown rescue, in vitro migration/invasion assays, in vivo metastatic mouse model Aging Medium 31978894

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1. Gene 244 15927426
2009 The multifaceted role of MTDH/AEG-1 in cancer progression. Clinical cancer research : an official journal of the American Association for Cancer Research 232 19723648
2009 Astrocyte elevated gene-1 (AEG-1) functions as an oncogene and regulates angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 176 19940250
2011 Astrocyte elevated gene-1 (AEG-1): A multifunctional regulator of normal and abnormal physiology. Pharmacology & therapeutics 113 21256156
2011 Tumor suppressive microRNA-375 regulates oncogene AEG-1/MTDH in head and neck squamous cell carcinoma (HNSCC). Journal of human genetics 106 21753766
2011 Oncogene AEG-1 promotes glioma-induced neurodegeneration by increasing glutamate excitotoxicity. Cancer research 99 21852380
2004 Identification of a novel protein, LYRIC, localized to tight junctions of polarized epithelial cells. Experimental cell research 97 15383321
2015 MiR-497 suppresses angiogenesis and metastasis of hepatocellular carcinoma by inhibiting VEGFA and AEG-1. Oncotarget 92 26336827
2013 AEG-1/MTDH/LYRIC: signaling pathways, downstream genes, interacting proteins, and regulation of tumor angiogenesis. Advances in cancer research 87 23889988
2004 3D3/lyric: a novel transmembrane protein of the endoplasmic reticulum and nuclear envelope, which is also present in the nucleolus. Experimental cell research 86 14980505
2009 LYRIC/AEG-1 is targeted to different subcellular compartments by ubiquitinylation and intrinsic nuclear localization signals. Clinical cancer research : an official journal of the American Association for Cancer Research 76 19383828
2013 AEG-1/MTDH/LYRIC: clinical significance. Advances in cancer research 74 23889987
2015 The role of MTDH/AEG-1 in the progression of cancer. International journal of clinical and experimental medicine 71 26131054
2021 Long non-coding RNA NORAD/miR-224-3p/MTDH axis contributes to CDDP resistance of esophageal squamous cell carcinoma by promoting nuclear accumulation of β-catenin. Molecular cancer 70 34893064
2015 Astrocyte elevated gene-1(AEG-1) induces epithelial-mesenchymal transition in lung cancer through activating Wnt/β-catenin signaling. BMC cancer 65 25880337
2010 Significance of AEG-1 expression in correlation with VEGF, microvessel density and clinicopathological characteristics in triple-negative breast cancer. Journal of surgical oncology 65 21259255
2012 Expression of AEG-1 mRNA and protein in colorectal cancer patients and colon cancer cell lines. Journal of translational medicine 62 22643064
2021 Pharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer. Nature cancer 61 35121988
2013 Huaier polysaccharides suppresses hepatocarcinoma MHCC97-H cell metastasis via inactivation of EMT and AEG-1 pathway. International journal of biological macromolecules 61 24321491
2009 Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression. Oncogene 60 19648967
2021 Small-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis. Nature cancer 57 35121987
2008 LYRIC/AEG-1 overexpression modulates BCCIPalpha protein levels in prostate tumor cells. Biochemical and biophysical research communications 57 18440304
2015 Quantitative analysis of the TNF-α-induced phosphoproteome reveals AEG-1/MTDH/LYRIC as an IKKβ substrate. Nature communications 56 25849741
2014 Genetic deletion of AEG-1 prevents hepatocarcinogenesis. Cancer research 54 25193383
2013 Drug resistance mediated by AEG-1/MTDH/LYRIC. Advances in cancer research 54 23889990
2013 miR-137 suppresses cell growth in ovarian cancer by targeting AEG-1. Biochemical and biophysical research communications 53 24144591
2013 AEG-1/MTDH/LYRIC in liver cancer. Advances in cancer research 52 23889992
2013 AEG-1 participates in TGF-beta1-induced EMT through p38 MAPK activation. Cell biology international 46 23640911
2022 Breast cancer derived exosomes promoted angiogenesis of endothelial cells in microenvironment via circHIPK3/miR-124-3p/MTDH axis. Cellular signalling 45 35460835
2017 AEG-1 associates with metastasis in papillary thyroid cancer through upregulation of MMP2/9. International journal of oncology 45 28731152
2019 MiR-182-5p inhibited proliferation and metastasis of colorectal cancer by targeting MTDH. European review for medical and pharmacological sciences 44 30840271
2014 AEG-1 regulates retinoid X receptor and inhibits retinoid signaling. Cancer research 44 25125681
2016 AEG-1/MTDH-activated autophagy enhances human malignant glioma susceptibility to TGF-β1-triggered epithelial-mesenchymal transition. Oncotarget 40 26909607
2011 MTDH/AEG-1-based DNA vaccine suppresses lung metastasis and enhances chemosensitivity to doxorubicin in breast cancer. Cancer immunology, immunotherapy : CII 40 21400023
2022 The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma. Theranostics 39 36276642
2018 Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro. Breast cancer research : BCR 39 30227879
2011 Correlation of MTDH/AEG-1 and HOTAIR Expression with Metastasis and Response to Treatment in Sarcoma Patients. Journal of cancer science & therapy 39 23543869
2013 CPEB1 regulates the expression of MTDH/AEG-1 and glioblastoma cell migration. Molecular cancer research : MCR 38 23360795
2011 Astrocyte-elevated gene-1 (AEG-1) induction by hypoxia and glucose deprivation in glioblastoma. Cancer biology & therapy 37 21084864
2019 circMTDH.4/miR-630/AEG-1 axis participates in the regulation of proliferation, migration, invasion, chemoresistance, and radioresistance of NSCLC. Molecular carcinogenesis 36 31749230
2016 AEG-1/MTDH/LYRIC: A Promiscuous Protein Partner Critical in Cancer, Obesity, and CNS Diseases. Advances in cancer research 34 27451125
2013 Pleiotropic roles of AEG-1/MTDH/LYRIC in breast cancer. Advances in cancer research 34 23889989
2020 CPEB3-mediated MTDH mRNA translational suppression restrains hepatocellular carcinoma progression. Cell death & disease 33 32968053
2019 Activation of EMT in colorectal cancer by MTDH/NF-κB p65 pathway. Molecular and cellular biochemistry 33 30825051
2019 Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway. Laboratory investigation; a journal of technical methods and pathology 33 30976056
2014 AEG-1 promotes anoikis resistance and orientation chemotaxis in hepatocellular carcinoma cells. PloS one 33 24941119
2021 Multifunctional Role of Astrocyte Elevated Gene-1 (AEG-1) in Cancer: Focus on Drug Resistance. Cancers 32 33918653
2017 A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH). Hepatology (Baltimore, Md.) 32 28437865
2017 miR-195 inhibits cell proliferation via targeting AEG-1 in hepatocellular carcinoma. Oncology letters 31 28529562
2014 Astrocyte elevated gene-1 (AEG-1) promotes osteosarcoma cell invasion through the JNK/c-Jun/MMP-2 pathway. Biochemical and biophysical research communications 30 25204501
2011 Astrocyte elevated gene-1 (AEG-1) is a marker for aggressive salivary gland carcinoma. Journal of translational medicine 30 22133054
2023 The AEG-1-USP10-PARP1 axis confers radioresistance in esophageal squamous cell carcinoma via facilitating homologous recombination-dependent DNA damage repair. Cancer letters 29 37838281
2015 Apoptosis of human non-small-cell lung cancer A549 cells triggered by evodiamine through MTDH-dependent signaling pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 29 25652471
2013 The role of AEG-1/MTDH/LYRIC in the pathogenesis of central nervous system disease. Advances in cancer research 29 23889991
2010 Expression patterns of astrocyte elevated gene-1 (AEG-1) during development of the mouse embryo. Gene expression patterns : GEP 29 20736086
2017 MTDH promotes glioma invasion through regulating miR-130b-ceRNAs. Oncotarget 28 28107197
2019 Astrocyte elevated gene 1 (AEG-1) promotes anoikis resistance and metastasis by inducing autophagy in hepatocellular carcinoma. Journal of cellular physiology 27 31691973
2016 AEG-1 is associated with hypoxia-induced hepatocellular carcinoma chemoresistance via regulating PI3K/AKT/HIF-1alpha/MDR-1 pathway. EXCLI journal 27 28337106
2017 MicroRNA-584 inhibits cell proliferation and invasion in non-small cell lung cancer by directly targeting MTDH. Experimental and therapeutic medicine 26 29434826
2015 Overexpression of astrocyte elevated gene-1 (AEG-1) in cervical cancer and its correlation with angiogenesis. Asian Pacific journal of cancer prevention : APJCP 26 25824750
2014 AEG-1 Promotes Metastasis Through Downstream AKR1C2 and NF1 in Liver Cancer. Oncology research 26 26351209
2013 AEG-1 is a target of perifosine and is over-expressed in gastric dysplasia and cancers. Digestive diseases and sciences 26 23912246
2018 MiR-1297 suppresses pancreatic cancer cell proliferation and metastasis by targeting MTDH. Molecular and cellular probes 25 29908229
2017 AEG-1 induces gastric cancer metastasis by upregulation of eIF4E expression. Journal of cellular and molecular medicine 25 28661037
2016 AEG-1 activates Wnt/PCP signaling to promote metastasis in tongue squamous cell carcinoma. Oncotarget 25 26689985
2016 The Universal 3D3 Antibody of Human PODXL Is Pluripotent Cytotoxic, and Identifies a Residual Population After Extended Differentiation of Pluripotent Stem Cells. Stem cells and development 25 26886504
2016 Tetraspanin 8 mediates AEG-1-induced invasion and metastasis in hepatocellular carcinoma cells. FEBS letters 25 27339400
2015 Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC). The Journal of biological chemistry 25 25944909
2015 Astrocyte Elevated Gene-1 (AEG-1) Regulates Lipid Homeostasis. The Journal of biological chemistry 25 26070567
2014 MTDH/AEG-1 contributes to central features of the neoplastic phenotype in bladder cancer. Urologic oncology 25 24495449
2020 MTDH promotes metastasis of clear cell renal cell carcinoma by activating SND1-mediated ERK signaling and epithelial-mesenchymal transition. Aging 24 31978894
2017 Hypoxia promotes migration/invasion and glycolysis in head and neck squamous cell carcinoma via an HIF-1α-MTDH loop. Oncology reports 24 28901527
2021 MTDH Promotes Intestinal Inflammation by Positively Regulating TLR Signalling. Journal of Crohn's & colitis 23 33987665
2017 MicroRNA‑30a‑5p suppresses tumor cell proliferation of human renal cancer via the MTDH/PTEN/AKT pathway. International journal of molecular medicine 23 29207012
2011 The cellular protein lyric interacts with HIV-1 Gag. Journal of virology 23 21957284
2021 Emerging Role and Clinicopathological Significance of AEG-1 in Different Cancer Types: A Concise Review. Cells 22 34203598
2021 Metadherin (AEG-1/MTDH/LYRIC) expression: Significance in malignancy and crucial role in colorectal cancer. Advances in clinical chemistry 22 35152973
2017 Clinical significance and effect of AEG-1 on the proliferation, invasion, and migration of NSCLC: a study based on immunohistochemistry, TCGA, bioinformatics, in vitro and in vivo verification. Oncotarget 22 28152520
2017 Novel Thiosemicarbazones Inhibit Lysine-Rich Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1) Coisolated (LYRIC) and the LYRIC-Induced Epithelial-Mesenchymal Transition via Upregulation of N-Myc Downstream-Regulated Gene 1 (NDRG1). Molecular pharmacology 22 28275050
2016 Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND. Progress in neurobiology 22 27090750
2019 MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy. Gynecologic oncology 21 31477281
2015 Molecular Modification of Metadherin/MTDH Impacts the Sensitivity of Breast Cancer to Doxorubicin. PloS one 21 25993398
2022 MTDH antisense oligonucleotides reshape the immunosuppressive tumor microenvironment to sensitize Hepatocellular Carcinoma to immune checkpoint blockade therapy. Cancer letters 20 35609735
2021 AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide. Scientific reports 20 34462446
2016 Elevated AEG-1 expression in macrophages promotes hypopharyngeal cancer invasion through the STAT3-MMP-9 signaling pathway. Oncotarget 20 27793010
2021 The Scope of Astrocyte Elevated Gene-1/Metadherin (AEG-1/MTDH) in Cancer Clinicopathology: A Review. Genes 19 33671513
2021 Circular RNA circHIPK3 modulates prostate cancer progression via targeting miR-448/MTDH signaling. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 19 34142340
2021 circ-NOL10 regulated by MTDH/CASC3 inhibits breast cancer progression and metastasis via multiple miRNAs and PDCD4. Molecular therapy. Nucleic acids 19 34729247
2018 AEG-1 Contributes to Metastasis in Hypoxia-Related Ovarian Cancer by Modulating the HIF-1alpha/NF-kappaB/VEGF Pathway. BioMed research international 19 29770329
2022 DOT1L regulates MTDH-mediated angiogenesis in triple-negative breast cancer: intermediacy of NF-κB-HIF1α axis. The FEBS journal 18 36017623
2019 AEG-1/miR-221 Axis Cooperatively Regulates the Progression of Hepatocellular Carcinoma by Targeting PTEN/PI3K/AKT Signaling Pathway. International journal of molecular sciences 18 31698701
2017 HIF-1α binding to AEG-1 promoter induced upregulated AEG-1 expression associated with metastasis in ovarian cancer. Cancer medicine 18 28401704
2015 The role of AEG-1 in the development of liver cancer. Hepatic oncology 18 26798451
2023 Molecular Dynamics Simulation-Driven Focused Virtual Screening and Experimental Validation of Inhibitors for MTDH-SND1 Protein-Protein Interaction. Journal of chemical information and modeling 17 37226724
2022 MTDH-stabilized DDX17 promotes tumor initiation and progression through interacting with YB1 to induce EGFR transcription in Hepatocellular Carcinoma. Oncogene 17 36385375
2018 AEG-1 is involved in hypoxia-induced autophagy and decreases chemosensitivity in T-cell lymphoma. Molecular medicine (Cambridge, Mass.) 17 30134829
2015 MicroRNA-377 inhibits non-small-cell lung cancer through targeting AEG-1. International journal of clinical and experimental pathology 17 26823698
2017 HIV-1 Tat inhibits EAAT-2 through AEG-1 upregulation in models of HIV-associated neurocognitive disorder. Oncotarget 16 28404980
2017 MTDH and MAP3K1 are direct targets of apoptosis-regulating miRNAs in colorectal carcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 16 28802228
2022 Structure-Based Design, Optimization, and Evaluation of Potent Stabilized Peptide Inhibitors Disrupting MTDH and SND1 Interaction. Journal of medicinal chemistry 15 36044768

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