Affinage

RXRA

Retinoic acid receptor RXR-alpha · UniProt P19793

Length
462 aa
Mass
50.8 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 41 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

RXRα is a nuclear receptor that operates as the obligatory heterodimerization partner for a broad array of nuclear receptors—RAR, T3R, VDR, PXR, CAR, PPARγ, PPARβ, PPARα, LXRβ, FXR, and Nurr1—enabling their stable binding to direct-repeat DNA response elements and ligand-dependent transcriptional control (PMID:1314167, PMID:11803135, PMID:23602807, PMID:24561505, PMID:29021580, PMID:30275017). Its proximate endogenous ligand is 9-cis retinoic acid (PMID:1309942), and it is additionally activated by docosahexaenoic acid and a chemically diverse set of small molecules that bind either the classical L-shaped ligand pocket or non-canonical surface sites including Cys432 and an alternate region centered on Gln275/Arg316/Arg371 (PMID:12844485, PMID:22140563, PMID:24704507, PMID:25795708, PMID:28846104). Within heterodimers RXRα acts as an allosteric platform: its oligomerization state and ligand occupancy tune coactivator (SRC-1, CBP) recruitment to the partner receptor, and partner LBDs form domain–domain contacts that transmit allosteric signals across the complex (PMID:23602807, PMID:29021580, PMID:30275017, PMID:34081964); ligand-driven dissociation of the Nurr1–RXRα heterodimer represents a distinct PPI-inhibition mode of transcriptional activation (PMID:37102494). Genetically, RXRα is essential in vivo for cardiac morphogenesis, where it acts non-cell-autonomously in a non-myocyte lineage to drive cardiomyocyte proliferation in a gene-dosage-dependent manner (PMID:7926783, PMID:8823298, PMID:9550727), for keratinocyte and hair-follicle homeostasis via RXRα/VDR complexes (PMID:11171393), for CAR/PXR-dependent hepatic xenobiotic metabolism (PMID:11803135), for neutrophil-versus-monocyte lineage decisions (PMID:17018855), and for PPARβ-RXRα-driven myelin lipid maintenance coactivated by Qki (PMID:32202512). Beyond transcription, RXRα is subject to regulatory phosphorylation: Cdk1 phosphorylates its N-terminal A/B domain at mitotic onset, driving centrosomal translocation and PLK1 activation to promote mitotic progression (PMID:33321102), and JNK2α phosphorylates Ser260 to suppress hepatic FGF21 expression (PMID:36282921). In tumors, an N-terminally truncated cytoplasmic form (tRXRα) interacts with the PI3K p85α subunit to activate AKT and with TRAF6 to drive NF-κB/IL-6/STAT3 signaling, linking RXRα to survival and inflammatory tumorigenesis; sulindac analogs and nitrostyrene derivatives that bind RXRα disrupt these interactions and restore apoptosis (PMID:20541701, PMID:24704507, PMID:25795708, PMID:30931933). Recurrent RXRA S427F/Y mutations allosterically activate the PPARγ/RXRα heterodimer to drive growth-factor-independent urothelial proliferation (PMID:29143738).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1992 High

    Establishing RXRα's endogenous ligand and its core biochemical role answered what activates the receptor and how it engages DNA, defining it as a ligand-controlled heterodimeric transcription factor.

    Evidence Ligand trapping/direct binding for 9-cis-RA, plus biochemical co-purification and EMSA with RAR/T3R/VDR

    PMID:1309942 PMID:1314167 PMID:1329088

    Open questions at the time
    • Full repertoire of physiological heterodimer partners not yet defined
    • Structural basis of DNA-element selectivity not addressed
  2. 1998 High

    Knockout and chimera studies answered whether RXRα is genetically required for development and where it acts, revealing an essential non-cell-autonomous role in cardiac morphogenesis with gene-dosage sensitivity.

    Evidence Conventional and heterozygous RXRα knockout mice plus RXRα-/- ES cell chimera analysis

    PMID:7926783 PMID:8823298 PMID:9550727

    Open questions at the time
    • Identity of the non-myocyte signal induced by RXRα not defined
    • Downstream transcriptional targets in the responsible lineage unresolved
  3. 2002 High

    Tissue-specific knockouts answered which physiological partner-receptor programs depend on RXRα in vivo, establishing it as the required dimer partner for VDR (hair cycling), CAR/PXR (xenobiotic metabolism), and PPARγ pathways.

    Evidence Keratinocyte- and hepatocyte-specific RXRα knockouts; cytotrophoblast reporter and invasion assays

    PMID:11171393 PMID:11564716 PMID:11600579 PMID:11803135 PMID:12145812

    Open questions at the time
    • Whether RXRα ligand occupancy is required versus a permissive scaffold role not separated for each partner
    • Mechanism of cytokine-driven RXRα downregulation in cholestasis incomplete
  4. 2006 High

    Gain- and loss-of-function in myeloid cells answered whether RXRα levels instruct lineage choice, showing its down-regulation is required for neutrophil differentiation and its persistence redirects cells toward the monocyte lineage.

    Evidence Ectopic and dominant-negative RXRα in human myeloid cultures and reconstituted mouse models

    PMID:17018855

    Open questions at the time
    • Target genes mediating the lineage switch not defined
    • Heterodimer partner responsible for the granulopoietic block unidentified
  5. 2003 Medium

    Ligand-activation assays answered whether RXRα senses dietary fatty acids, identifying DHA as a specific RXRα-activating ligand distinct from PPARγ activation.

    Evidence Mammalian one-hybrid and reporter assays with RXRα versus PPARγ antagonists in colonocytes

    PMID:12844485

    Open questions at the time
    • Direct binding affinity of DHA for RXRα not measured
    • Physiological relevance of DHA-RXRα signaling in vivo not established
  6. 2010 High

    Discovery of cytoplasmic truncated tRXRα answered how RXRα contributes to tumor survival outside transcription, linking it to PI3K/p85α-driven AKT signaling that is druggable by sulindac analogs.

    Evidence Reciprocal Co-IP, COX-inactive analog K-80003, AKT and apoptosis assays, tumor model

    PMID:20541701

    Open questions at the time
    • Protease generating tRXRα not identified
    • Determinants of cytoplasmic versus nuclear partitioning unresolved
  7. 2017 High

    A series of crystal structures answered how heterodimer architecture and ligand binding are coordinated, revealing partner-specific DNA-element geometries, allosteric domain coupling, and cooperative coregulator recruitment.

    Evidence X-ray structures of RXRα with PXR, LXRβ, FXR, RARβ, and PPARγ LBDs plus HDX-MS, coregulator binding, and DNA-binding assays

    PMID:22140563 PMID:23602807 PMID:24561505 PMID:29021580 PMID:30275017

    Open questions at the time
    • Full-length heterodimer-on-DNA conformational dynamics in solution not fully resolved
    • How distinct response-element geometries map to in vivo target selection incomplete
  8. 2017 High

    Mapping non-canonical small-molecule binding sites answered how diverse compounds modulate RXRα beyond the classical pocket, defining Cys432 and an alternate Gln275/Arg316/Arg371 region as functional sites controlling tRXRα interactions and β-catenin degradation.

    Evidence Crystallography, site-directed mutagenesis, Co-IP, ubiquitination, NF-κB and xenograft assays for sulindac analogs, nitrostyrenes, and berberine

    PMID:24704507 PMID:25795708 PMID:28846104

    Open questions at the time
    • Endogenous ligands for these surface sites unknown
    • Selectivity of these compounds across nuclear receptors not fully characterized
  9. 2017 High

    Characterizing recurrent RXRA S427F/Y mutations answered how RXRα itself can be an oncogenic driver, showing the substitution allosterically activates the PPARγ/RXRα heterodimer to drive ligand-independent urothelial proliferation.

    Evidence Structure-function mutagenesis, reporter assays, bladder organoid growth, and PPAR inhibitor rescue

    PMID:29143738

    Open questions at the time
    • Frequency and tissue range of the activating mechanism beyond bladder not defined
    • Whether the mutant alters other heterodimers not tested
  10. 2022 High

    Phosphorylation studies answered how kinase signaling repurposes RXRα, identifying Cdk1-driven centrosomal PLK1 activation in mitosis and JNK2α-Ser260 suppression of hepatic FGF21.

    Evidence Phosphoproteomics, Cdk1/JNK2α phosphorylation assays, PLK1 Co-IP, and Ser260 knock-in mice

    PMID:30518934 PMID:33321102 PMID:36282921

    Open questions at the time
    • Interplay between these phosphorylation events and transcriptional output not integrated
    • Whether centrosomal RXRα requires its DNA-binding function unresolved
  11. 2020 High

    Coactivator and metabolic studies answered how RXRα heterodimers control lipid programs, showing Qki coactivates PPARβ-RXRα to maintain myelin lipids and that allosteric heterodimer formation gains coactivator affinity even without ligand.

    Evidence Oligodendrocyte-specific Qki knockout with lipidomics and agonist rescue; FRET coactivator-recruitment and RXRα oligomerization assays

    PMID:32202512 PMID:33422545 PMID:33684567 PMID:34081964

    Open questions at the time
    • How RXRα oligomerization state is set in vivo not defined
    • Generality of the ligand-independent coactivator gain across partners untested
  12. 2023 Medium

    Newer mechanistic and disease-context studies answered how RXRα ligands act through dimer dissociation and how lipid carriers and lncRNAs route RXRα into cancer programs, expanding the activation paradigm beyond classical agonism.

    Evidence NMR and PPI assays for Nurr1-RXRα dissociation; FABP7 PUFA delivery, RNA-IP/ChIP for LINC00511 and DANCR, and senescence calcium-signaling assays

    PMID:30216632 PMID:32067228 PMID:37102494 PMID:37499046

    Open questions at the time
    • Several cancer-context mechanisms rest on single-lab data
    • How dimer-dissociation activation generalizes to other RXRα partners unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how RXRα's nuclear transcriptional, cytoplasmic tRXRα, and centrosomal/phosphorylation-dependent functions are coordinately controlled within a single cell, and what governs the switch between heterodimer scaffold, allosteric coactivator platform, and non-genomic signaling roles.
  • No unified model linking RXRα localization, proteolysis, and phosphorylation states
  • Protease and trafficking determinants of tRXRα generation unidentified
  • In vivo balance of ligand-dependent versus permissive heterodimer functions unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 5 GO:0008289 lipid binding 4 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 3 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-1266738 Developmental Biology 5 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 1
Partners
FXRLXRBPLK1PPARGPXRRARATRAF6VDR
Complex memberships
PXR/RXRα LBD heterotetramerRXRα/PPARγ heterodimerRXRα/RAR heterodimerRXRα/VDR heterodimer

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 9-cis retinoic acid directly binds and activates RXRα, identifying it as the proximate endogenous ligand for this receptor via a nuclear receptor-dependent ligand trapping assay. Nuclear receptor-dependent ligand trapping assay, direct binding measurement Nature High 1309942
1992 RXRα functions as an obligatory heterodimerization partner for RAR, T3R, and VDR, co-purifying with these receptors and enabling their stable binding to DNA response elements organized as direct repeats. Extensive biochemical purification, co-purification, electrophoretic mobility shift assay (EMSA), functional transactivation assays The EMBO journal High 1314167
1994 Targeted loss-of-function mutation of RXRα in mice causes embryonic lethality with hypoplastic ventricular chamber development, establishing RXRα as a genetic component of the vitamin A signaling pathway in cardiac morphogenesis. Gene targeting (knockout mouse), histological and morphological analysis Genes & development High 7926783
1992 RXRα binds to a retinoic acid response element within the hepatitis B virus enhancer in vitro, and transactivates an HBV enhancer-reporter construct in vivo upon retinoic acid treatment when co-transfected with RXRα; a single-base mutation in the response element abolishes both binding and enhancer activity. In vitro binding assay, in vivo reporter gene assay, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 1329088
1996 RXRα-null mice exhibit complex cardiac defects including ventricular septal, atrioventricular cushion, and conotruncal ridge defects; RXRα heterozygous embryos show an intermediate phenotype, demonstrating a gene dosage effect for RXRα in cardiac morphogenesis. Microdissection, scanning electron microscopy, genetic analysis of RXRα-/- and +/- embryos The Journal of clinical investigation High 8823298
1998 RXRα functions non-cell-autonomously in cardiac morphogenesis: chimera analysis shows that RXRα-deficient cardiomyocytes develop normally when surrounded by wild-type cells, indicating RXRα acts in a non-myocyte lineage to induce cardiomyocyte proliferation; RXRα and N-myc regulate convergent but non-epistatic pathways. Chimera analysis with RXRα-/- ES cells, genetic epistasis analysis Development (Cambridge, England) High 9550727
2001 Cre-mediated ablation of RXRα in epidermal keratinocytes causes progressive alopecia and epidermal hyperplasia, demonstrating that RXRα plays a key role in anagen initiation during hair follicle cycling; RXRα/VDR heterodimers are implicated as a major regulatory complex in hair cycling. Conditional knockout (Cre-loxP in keratinocytes), histological analysis Development (Cambridge, England) High 11171393
2001 PPARγ/RXRα heterodimers are functional transcriptional units in human cytotrophoblast differentiation; specific ligands for both receptors additively stimulate human CG secretion, and RXRα and PPARγ proteins from cytotrophoblast nuclear extracts bind to the human CG β5 gene regulatory region. Transient transfection/reporter assay, nuclear extract DNA binding, hormone secretion assays, in vitro cytotrophoblast differentiation Endocrinology High 11564716
2001 PPARγ/RXRα heterodimers inhibit human extravillous cytotrophoblast invasion in vitro; PPARγ agonists synergize with RXR agonists, and a pan-RXR antagonist reverses PPARγ agonist-induced inhibition, placing RXRα as a required partner in this pathway. Primary extravillous cytotrophoblast invasion assay, pharmacological agonist/antagonist treatment The Journal of clinical endocrinology and metabolism Medium 11600579
2002 Hepatocyte RXRα deficiency prevents TCPOBOP-induced hepatomegaly and abolishes induction of CYP2A5, CYP2B10, and CYP3A1 (but not CYP2E1 or CYP2D6), establishing RXRα as an essential in vivo partner for CAR- and PXR-mediated xenobiotic metabolism. Hepatocyte-specific RXRα knockout mice challenged with CAR/PXR ligands, Northern blotting, morphological analysis European journal of pharmaceutical sciences High 11803135
2002 Obstructive cholestasis reduces hepatic RAR α:RXRα nuclear protein levels and their binding to the Mrp2 promoter, with IL-1β treatment of primary hepatocytes reducing both Mrp2 and RXRα expression; renal RAR α:RXRα and Mrp2 are preserved, establishing organ-specific cytokine-dependent regulation of RXRα abundance as a mechanism for Mrp2 downregulation. Bile duct ligation model, EMSA, immunoblotting, ribonuclease protection assay, primary hepatocyte treatment Gastroenterology High 12145812
2003 Docosahexaenoic acid (DHA, an n-3 PUFA) dose-dependently activates RXRα in colonocytes using a mammalian one-hybrid assay; this activation is abolished by an RXRα antagonist but not a PPARγ antagonist, identifying DHA as a specific RXRα ligand in colonocytes. Mammalian one-hybrid assay, reporter gene assay with RXRα antagonist Carcinogenesis Medium 12844485
2010 Sulindac and its analog K-80003 bind to RXRα and inhibit an N-terminally truncated form (tRXRα) that interacts with p85α subunit of PI3K; TNFα promotes tRXRα/p85α interaction to activate PI3K/AKT signaling, and sulindac inhibits this interaction leading to activation of death receptor-mediated apoptosis. Co-immunoprecipitation, drug binding assay, AKT activation assay, cell apoptosis assay, animal tumor model Cancer cell High 20541701
2011 Magnolol acts as a dual agonist for both RXRα and PPARγ; co-crystal structures of magnolol bound to RXRα and PPARγ LBDs reveal magnolol occupies the L-shaped ligand-binding pocket of RXRα with two hydroxyphenyl moieties in acidic and hydrophobic cavities; magnolol shows biased agonism on PPRE-mediated (RXRα:PPARγ heterodimer) transcription over RXRE-mediated (RXRα homodimer) transcription. Co-crystal structure (X-ray crystallography), transactivation assays PloS one High 22140563
2013 Crystal structure of the PXR/RXRα ligand-binding domain heterotetramer at 2.8 Å resolution reveals an unprecedented heterotetramer arrangement; both PXR and RXRα bind SRC-1 coregulator with higher affinity as part of this complex than as monomers; full-length receptors show defined binding preferences for direct and everted repeat DNA elements. X-ray crystallography, coregulator binding assay, recombinant full-length receptor DNA binding assay Journal of molecular biology High 23602807
2014 Crystal structure of the RXRα-LXRβ heterodimer on its cognate AGGTCA DR4 element reveals an extended X-shaped arrangement with crossed DNA- and ligand-binding domains, contrasting with the parallel domain arrangement of NRs on DR1 elements; LXRβ uses auxiliary DNA contacts and RXRα adapts flexibly to the heterodimeric complex. X-ray crystallography Nature structural & molecular biology High 24561505
2014 Sulindac analogs K-8008 and K-8012 bind to a novel site on the RXRα LBD (distinct from the classical ligand-binding pocket) in tetrameric RXRα, inhibit tRXRα/p85α interaction, suppress AKT activation and induce apoptosis; crystal structures define this non-canonical binding mechanism. X-ray crystallography, Co-IP, AKT activation assay, apoptosis assay Chemistry & biology High 24704507
2015 Nitrostyrene derivatives bind to RXRα through the nitro group interacting with Cys432, activating Gal4-DBD-RXRα-LBD transactivation; they inhibit tRXRα interaction with TRAF2, reduce TNFα-induced ubiquitination of RIP1, and potently inhibit TNFα/NF-κB signaling in a tRXRα-dependent manner. Ligand binding assay, site-directed mutagenesis (Cys432 substitution), transactivation assay, Co-IP, ubiquitination assay, NF-κB reporter assay Cancer research High 25795708
2017 Crystal structure of multi-domain RARβ-RXRα heterodimer bound to DNA, ligands, and coactivator peptides reveals that RARβ LBD and DBD are physically connected to foster allosteric signal transmission; RXRα maintains flexible loosely organized domains, while heterodimerization partners use their LBD surface to form domain-domain interactions with DBDs. X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, mutagenesis, functional assays Nature communications High 29021580
2017 Recurrent RXRA S427F/Y mutations in bladder cancer allosterically activate the PPARγ/RXRα heterodimer; structure-function studies show the substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine in PPARs; mutant RXRA drives growth-factor-independent urothelial proliferation reversible by PPAR inhibition. Structure-function mutagenesis, enhancer/promoter reporter assays, bladder organoid growth assay, PPAR inhibitor treatment eLife High 29143738
2017 Berberine directly binds RXRα at a unique region (residues Gln275, Arg316, Arg371) distinct from the classical 9-cis-RA binding pocket, promoting RXRα interaction with nuclear β-catenin and leading to c-Cbl-mediated degradation of β-catenin; berberine suppresses colon xenograft growth in an RXRα-dependent manner. Direct binding assay, site-directed mutagenesis, Co-IP, protein degradation assay, xenograft model Oncogene High 28846104
2018 FXR/RXRα LBD heterodimer crystal structures show that both FXR and RXRα bind SRC-1 coregulator with higher affinity in the heterodimer than as monomers; heterodimerization and ligand binding induce conformational changes in FXR helix 11 C-terminus affecting coactivator binding surface stability. X-ray crystallography, coregulator binding affinity assay The Journal of biological chemistry High 30275017
2018 RXRα is phosphorylated at its N-terminal A/B domain by Cdk1 at the onset of mitosis, triggering its translocation to the centrosome where phosphorylated RXRα (p-RXRα) interacts with PLK1 through its N-terminal A/B domain to promote PLK1 activation, centrosome maturation, and mitotic progression. Live cell imaging, subcellular fractionation, Co-IP, phosphorylation assays, Cdk1 activity assay, kinase inhibitor studies Developmental cell High 33321102
2018 lncRNA DANCR binds RXRA and increases its serine 49/78 phosphorylation via GSK3β, resulting in activation of PIK3CA transcription and enhanced PI3K/AKT signaling in triple-negative breast cancer. RNA-protein binding assay, phosphorylation assay, reporter assay, knockdown/overexpression in vitro and in vivo Cell death & disease Medium 30518934
2018 RXRA knockdown in senescent cells induces ITPR2-MCU calcium signaling, leading to ROS production, DNA damage, and p53-dependent cellular senescence; RXRA overexpression decreases DNA damage and delays replicative senescence. siRNA screen, knockdown/overexpression, calcium signaling measurement, ROS assay, DNA damage markers Aging cell Medium 30216632
2019 Truncated RXRα (tRXRα) expressed in myeloid cells interacts extensively with TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and NF-κB activation, which induces IL-6 secretion and STAT3 activation to promote colitis-associated colorectal tumorigenesis. Transgenic mouse model, Co-IP, ubiquitination assay, cytokine measurement, NF-κB reporter assay Nature communications High 30931933
2020 Qki serves as a coactivator of the PPARβ-RXRα complex in oligodendrocytes, controlling transcription of lipid metabolism genes (especially fatty acid desaturation and elongation) required for mature myelin lipid maintenance; Qki depletion causes rapid demyelination rescuable by PPARβ/RXR agonists. Oligodendrocyte-specific Qki knockout, Co-IP, transcriptome analysis, pharmacological rescue with PPARβ/RXR agonists, high-fat diet rescue The Journal of clinical investigation High 32202512
2021 RXRα agonist SR11237 destabilizes the RXRα homodimer but promotes PPARγ:RXRα heterodimer formation; incorporation of PPARγ into the heterodimer results in substantial gain in coactivator CBP-1 affinity even without ligands, and SR11237 indirectly promotes coactivator binding to PPARγ by shifting RXRα oligomerization preference. FRET-based coactivator recruitment assay, RXRα LBD mutagenesis (coactivator-binding-deficient mutant), heterodimer formation assay The Journal of biological chemistry High 34081964
2022 JNK2α phosphorylates RXRα at Ser260 in vivo; hepatocyte-specific expression of phosphorylation-site mutant RXRα demonstrates that Ser260 phosphorylation is required for JNK2α-mediated suppression of FGF21 gene expression and metabolic dysregulation. Quantitative phosphoproteomics, hepatocyte-specific knock-in of wild-type vs. mutant RXRα (Ser260 site), Fgf21 expression measurement Proceedings of the National Academy of Sciences of the United States of America High 36282921
2023 RXRα ligands activate Nurr1-RXRα transcription through a mechanism involving weakening of the Nurr1-RXRα LBD heterodimer affinity and heterodimer dissociation (PPI inhibition), releasing a transcriptionally active Nurr1 monomer from a repressive complex; this is distinct from classical agonist mechanisms and correlates with RXRα homodimer antagonism rather than agonism. NMR spectroscopy, protein-protein interaction assay, cellular transcription assays eLife High 37102494
1999 Dexamethasone increases RXRα mRNA and protein expression in primary rat hepatocytes, and adenoviral overexpression of RXRα enhances T3-dependent type I 5'-deiodinase mRNA induction, demonstrating that glucocorticoid-induced RXRα upregulation augments thyroid hormone receptor signaling by increasing the availability of this obligatory heterodimerization partner. Northern blot, Western blot, EMSA, adenoviral overexpression, primary hepatocyte culture Journal of molecular endocrinology High 9924183
2006 RXRα down-regulation is required for neutrophil differentiation from granulocyte/monocyte progenitors; ectopic RXRα expression inhibits granulopoiesis and redirects G-CSF-dependent granulocyte differentiation to the monocyte lineage; dominant-negative RXRα promotes late-stage granulocyte generation in vitro and in vivo. Ectopic RXRα overexpression, dominant-negative RXRα, human in vitro myeloid cultures, in vivo reconstituted mouse model Blood High 17018855
2009 PRKAR1A-RARα leukemic transformation critically depends on RXRα interaction: point mutations eliminating RXRα interaction with the RARα portion of the fusion protein, shRNA knockdown of RXRα, or RXRα agonist treatment all reduce transformation capability in murine bone marrow retroviral transduction assay. Bone marrow retroviral transduction/transformation assay, gel-shift assay, point mutagenesis, shRNA knockdown Blood High 19965660
2008 Retinol treatment increases RXRα-β-catenin protein interaction and triggers relocation of both proteins to the cytosol; RXRα lacking the AF-1 and DNA-binding domains abolishes β-catenin co-purification and proteasomal degradation of β-catenin, establishing that RXRα/β-catenin binding is required for proteasomal degradation of β-catenin. Co-immunoprecipitation, domain deletion mutant transfection, proteasome inhibitor treatment, subcellular fractionation Nutrition and cancer Medium 18444141
2021 PPARα/RXRα complex promotes proteasomal degradation of HNF4α in the presence of RXRα, downregulating amino acid catabolism genes in the liver; chromatin immunoprecipitation shows HNF4α binds the SDS promoter, and RXRα presence is essential for PPARα-mediated repression of this activity. PPARα knockout mouse model, chromatin immunoprecipitation, protein degradation assay, gene expression analysis Metabolism: clinical and experimental Medium 33422545
2023 SILENCING RXRA in A431 squamous carcinoma cells only partially reduces 1,25(OH)2D3-induced differentially expressed genes at 24 h (unlike VDR knockout which abolishes the response), and classic 1,25(OH)2D3 targets CYP24A1 and CAMP are regulated in an RXRA-independent manner, demonstrating that a subset of VDR genomic actions do not require RXRA. RXRA gene silencing/knockout, transcriptome analysis, immunofluorescence co-localization Molecular and cellular endocrinology Medium 38123121
2021 RXRA directly activates the PLD1 promoter in cervical cancer cells; LINC00511 binds RXRA (demonstrated by RNA immunoprecipitation) and recruits it to the PLD1 promoter (shown by chromatin immunoprecipitation), upregulating PLD1 expression to promote cervical cancer cell proliferation. RNA immunoprecipitation, chromatin immunoprecipitation, dual-luciferase reporter assay, siRNA knockdown Journal of cellular physiology Medium 32067228
2021 TET1-mediated DNA demethylation at the Rxra locus promotes RXRα expression during adipogenesis; Tet1 knockout decreases 5hmC at Rxra, reduces RXRα expression, and impairs adipocyte differentiation; RXRα agonist partially rescues the Tet1 KO adipogenesis defect. TET1 knockout, 5mC/5hmC DNA immunoprecipitation, RNA-seq, RXRα agonist rescue Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 33684567
2020 Qki acts as coactivator of PPARβ-RXRα: Qki depletion in oligodendrocytes specifically reduces myelin lipid (monounsaturated and very-long-chain fatty acids) without affecting myelin proteins, and neurological deficits are alleviated by high-fat diet or PPARβ/RXR agonist treatment. Oligodendrocyte-specific Qki KO, lipidomics, PPARβ/RXR agonist treatment, high-fat diet rescue The Journal of clinical investigation High 32202512
2013 RXRα down-regulation in senescent macrophages mediates elevated COX2 expression and PGE2 production via increased NF-κB activity; systemic treatment of young mice with RXRα antagonist HX531 increases COX2, TNF-α, and IL-6 expression in splenocytes, establishing RXRα as a suppressor of NF-κB-driven inflammation in macrophages. Macrophage senescence model, COX2/PGE2 measurement, RXRα knockdown/antagonist treatment in vivo and in vitro Biochemical and biophysical research communications Medium 24051096
2023 FABP7 promotes glioblastoma stem cell migration through nuclear delivery of polyunsaturated fatty acids (PUFAs) to RXRα; FABP7-mediated activation of RXRα upregulates SOX2 and ZEB1 (demonstrated by gel shift and luciferase reporter assays), driving a stationary-to-migratory transition in GSCs. Gel shift assay, luciferase reporter assay, xenograft migration model, single-cell RNA sequencing Neuro-oncology Medium 37499046

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature 1210 1309942
1994 RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes & development 531 7926783
1992 RXR alpha, a promiscuous partner of retinoic acid and thyroid hormone receptors. The EMBO journal 433 1314167
2015 Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway. Cancer research 315 25592151
1996 RXR gamma null mice are apparently normal and compound RXR alpha +/-/RXR beta -/-/RXR gamma -/- mutant mice are viable. Proceedings of the National Academy of Sciences of the United States of America 185 8799145
2001 RXR-alpha ablation in skin keratinocytes results in alopecia and epidermal alterations. Development (Cambridge, England) 165 11171393
2001 PPAR gamma/RXR alpha heterodimers are involved in human CG beta synthesis and human trophoblast differentiation. Endocrinology 148 11564716
1996 RXR alpha deficiency confers genetic susceptibility for aortic sac, conotruncal, atrioventricular cushion, and ventricular muscle defects in mice. The Journal of clinical investigation 145 8823298
2001 PPARgamma/RXRalpha heterodimers control human trophoblast invasion. The Journal of clinical endocrinology and metabolism 126 11600579
2017 Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer. Nature communications 122 28740126
2017 Berberine binds RXRα to suppress β-catenin signaling in colon cancer cells. Oncogene 117 28846104
2010 NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling. Cancer cell 114 20541701
2002 Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB. Biochemical and biophysical research communications 100 11779144
2014 Structure of the retinoid X receptor α-liver X receptor β (RXRα-LXRβ) heterodimer on DNA. Nature structural & molecular biology 90 24561505
2013 Pro-apoptotic miRNA-128-2 modulates ABCA1, ABCG1 and RXRα expression and cholesterol homeostasis. Cell death & disease 89 23990020
2023 Forsythiaside A alleviates acute lung injury by inhibiting inflammation and epithelial barrier damages in lung and colon through PPAR-γ/RXR-α complex. Journal of advanced research 81 37579917
2018 LncRNA DANCR upregulates PI3K/AKT signaling through activating serine phosphorylation of RXRA. Cell death & disease 79 30518934
2003 Chemopreventive n-3 fatty acids activate RXRalpha in colonocytes. Carcinogenesis 76 12844485
2017 The quaternary architecture of RARβ-RXRα heterodimer facilitates domain-domain signal transmission. Nature communications 73 29021580
2017 Nurr1:RXRα heterodimer activation as monotherapy for Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 72 28348207
2011 Molecular determinants of magnolol targeting both RXRα and PPARγ. PloS one 67 22140563
2002 The role of hepatocyte RXR alpha in xenobiotic-sensing nuclear receptor-mediated pathways. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 67 11803135
1992 Retinoid X receptor RXR alpha binds to and trans-activates the hepatitis B virus enhancer. Proceedings of the National Academy of Sciences of the United States of America 67 1329088
2017 Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation. eLife 64 29143738
2002 Organ-specific alterations in RAR alpha:RXR alpha abundance regulate rat Mrp2 (Abcc2) expression in obstructive cholestasis. Gastroenterology 64 12145812
2014 Childhood bone mineral content is associated with methylation status of the RXRA promoter at birth. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 63 23907847
2020 Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα-mediated lipid metabolism. The Journal of clinical investigation 62 32202512
2017 OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. PLoS pathogens 62 28241052
2018 The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling. Aging cell 56 30216632
2018 Ligand binding and heterodimerization with retinoid X receptor α (RXRα) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding. The Journal of biological chemistry 55 30275017
1998 The RXRalpha gene functions in a non-cell-autonomous manner during mouse cardiac morphogenesis. Development (Cambridge, England) 55 9550727
2019 Oncogenic potential of truncated RXRα during colitis-associated colorectal tumorigenesis by promoting IL-6-STAT3 signaling. Nature communications 53 30931933
2000 RXRalpha overexpression in cardiomyocytes causes dilated cardiomyopathy but fails to rescue myocardial hypoplasia in RXRalpha-null fetuses. The Journal of clinical investigation 52 10675365
2013 Structural and functional analysis of the human nuclear xenobiotic receptor PXR in complex with RXRα. Journal of molecular biology 50 23602807
2010 Genetic polymorphisms in vitamin D receptor VDR/RXRA influence the likelihood of colon adenoma recurrence. Cancer research 47 20145122
2006 Characterization of retinoid-X receptor genes rxra, rxrba, rxrbb and rxrg during zebrafish development. Gene expression patterns : GEP 47 16448862
2003 Aberration in the expression of the retinoid receptor, RXRalpha, in prostate cancer. Cancer biology & therapy 46 12750559
2006 Down-regulation of RXRalpha expression is essential for neutrophil development from granulocyte/monocyte progenitors. Blood 45 17018855
2007 Disruption of Rxra gene in thymocytes and T lymphocytes modestly alters lymphocyte frequencies, proliferation, survival and T helper type 1/type 2 balance. Immunology 43 17433077
2016 Allosteric Pathways in the PPARγ-RXRα nuclear receptor complex. Scientific reports 42 26823026
2014 Sulindac-derived RXRα modulators inhibit cancer cell growth by binding to a novel site. Chemistry & biology 41 24704507
2015 RXRα, PXR and CAR xenobiotic receptors mediate the apoptotic and neurotoxic actions of nonylphenol in mouse hippocampal cells. The Journal of steroid biochemistry and molecular biology 40 26643981
2010 RXRα ablation in epidermal keratinocytes enhances UVR-induced DNA damage, apoptosis, and proliferation of keratinocytes and melanocytes. The Journal of investigative dermatology 39 20944655
2019 Gestational Vitamin D Supplementation Leads to Reduced Perinatal RXRA DNA Methylation: Results From the MAVIDOS Trial. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 38 30321476
2019 miR-191 promotes radiation resistance of prostate cancer through interaction with RXRA. Cancer letters 37 31874245
2016 Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling. PLoS computational biology 36 26727233
2020 Promotion of cell autophagy and apoptosis in cervical cancer by inhibition of long noncoding RNA LINC00511 via transcription factor RXRA-regulated PLD1. Journal of cellular physiology 35 32067228
1998 Retinoid receptors expression in human term placenta: involvement of RXR alpha in retinoid induced-hCG secretion. The Journal of clinical endocrinology and metabolism 35 9543171
2022 Alpha lipoamide inhibits diabetic kidney fibrosis via improving mitochondrial function and regulating RXRα expression and activation. Acta pharmacologica Sinica 34 36347997
2015 Nitrostyrene Derivatives Act as RXRα Ligands to Inhibit TNFα Activation of NF-κB. Cancer research 34 25795708
2019 Tributyltin chloride (TBT) induces RXRA down-regulation and lipid accumulation in human liver cells. PloS one 33 31710612
1992 Mapping of the mouse Rxr loci encoding nuclear retinoid X receptors RXR alpha, RXR beta, and RXR gamma. Genomics 33 1358808
2010 Association between polymorphic variation in VDR and RXRA and circulating levels of vitamin D metabolites. The Journal of steroid biochemistry and molecular biology 32 20307661
2009 RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism. Journal of cellular and molecular medicine 32 19374686
2021 α-Mangostin Induces Apoptosis and Inhibits Metastasis of Breast Cancer Cells via Regulating RXRα-AKT Signaling Pathway. Frontiers in pharmacology 31 34539418
1999 Glucocorticoids increase retinoid-X receptor alpha (RXRalpha) expression and enhance thyroid hormone action in primary cultured rat hepatocytes. Journal of molecular endocrinology 31 9924183
2021 Danthron ameliorates obesity and MAFLD through activating the interplay between PPARα/RXRα heterodimer and adiponectin receptor 2. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 29 33581653
2006 CAR2 displays unique ligand binding and RXRalpha heterodimerization characteristics. Drug metabolism and disposition: the biological fate of chemicals 29 17194715
2021 Heterodimer formation with retinoic acid receptor RXRα modulates coactivator recruitment by peroxisome proliferator-activated receptor PPARγ. The Journal of biological chemistry 28 34081964
2017 SNP rs11185644 of RXRA gene is identified for dose-response variability to vitamin D3 supplementation: a randomized clinical trial. Scientific reports 26 28079136
2013 Elevated COX2 expression and PGE2 production by downregulation of RXRα in senescent macrophages. Biochemical and biophysical research communications 26 24051096
2022 Forsythiae Fructuse extracts alleviates LPS-induced acute lung injury in mice by regulating PPAR-γ/RXR-α in lungs and colons. Journal of ethnopharmacology 25 35483561
2019 YAP1 regulates PPARG and RXR alpha expression to affect the proliferation and differentiation of ovine preadipocyte. Journal of cellular biochemistry 25 31297878
2019 PPARA/RXRA signalling regulates the fate of hepatic non-esterified fatty acids in a sheep model of maternal undernutrition. Biochimica et biophysica acta. Molecular and cell biology of lipids 25 31676441
2015 Targeting truncated RXRα for cancer therapy. Acta biochimica et biophysica Sinica 25 26494413
2023 Celastrol-regulated gut microbiota and bile acid metabolism alleviate hepatocellular carcinoma proliferation by regulating the interaction between FXR and RXRα in vivo and in vitro. Frontiers in pharmacology 24 36874033
2021 EGR1 and RXRA transcription factors link TGF-β pathway and CCL2 expression in triple negative breast cancer cells. Scientific reports 24 34239022
2014 Elevated methylation of the RXRA promoter region may be responsible for its downregulated expression in the myocardium of patients with TOF. Pediatric research 23 24513686
2022 Interleukin-17 promotes proliferation, migration, and invasion of trophoblasts via regulating PPAR-γ/RXR-α/Wnt signaling. Bioengineered 22 35258399
2015 MicroRNA-27a Contributes to Rhabdomyosarcoma Cell Proliferation by Suppressing RARA and RXRA. PloS one 22 25915942
2009 Leukemic transformation by the APL fusion protein PRKAR1A-RAR{alpha} critically depends on recruitment of RXR{alpha}. Blood 21 19965660
2022 Panaxytriol upregulates CYP3A4 expression based on the interaction of PXR, CAR, HSP90α, and RXRα. Phytomedicine : international journal of phytotherapy and phytopharmacology 20 35417848
2021 Pharmacological Activation of RXR-α Promotes Hematoma Absorption via a PPAR-γ-dependent Pathway After Intracerebral Hemorrhage. Neuroscience bulletin 20 34142331
2018 RXRα-enriched cancer stem cell-like properties triggered by CDDP in head and neck squamous cell carcinoma (HNSCC). Carcinogenesis 20 29228308
2016 Genetic variants in the vitamin D pathway genes VDBP and RXRA modulate cutaneous melanoma disease-specific survival. Pigment cell & melanoma research 20 26575331
2011 RXRα and LXR activate two promoters in placenta- and tumor-specific expression of PLAC1. Placenta 20 21937108
2021 TET1 promotes RXRα expression and adipogenesis through DNA demethylation. Biochimica et biophysica acta. Molecular and cell biology of lipids 19 33684567
2018 Nuclear RXRα and RXRβ receptors exert distinct and opposite effects on RA-mediated neuroblastoma differentiation. Biochimica et biophysica acta. Molecular cell research 19 30529222
2012 Solution Structures of PPARγ2/RXRα Complexes. PPAR research 19 23319938
2003 RXRalpha-regulated liver SAMe and GSH levels influence susceptibility to alcohol-induced hepatotoxicity. Experimental and molecular pathology 18 14611810
2023 Molecular basis of ligand-dependent Nurr1-RXRα activation. eLife 17 37102494
2023 lncRNA RMST suppresses the progression of colorectal cancer by competitively binding to miR-27a-3p/RXRα axis and inactivating Wnt signaling pathway. Acta biochimica et biophysica Sinica 17 37246895
2023 Binding of Per- and Polyfluoroalkyl Substances (PFAS) to the PPARγ/RXRα-DNA Complex. Journal of chemical information and modeling 17 37990410
2018 Design, synthesis and biological evaluation of tetrazole-containing RXRα ligands as anticancer agents. European journal of medicinal chemistry 17 30634084
2012 PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms and lipid and lipoprotein levels in a Southern Brazilian population. Molecular biology reports 17 23079705
2008 Retinol Increases beta-catenin-RXRalpha binding leading to the increased proteasomal degradation of beta-catenin and RXRalpha. Nutrition and cancer 17 18444141
1997 DNA binding preferences of PPAR alpha/RXR alpha heterodimers. Biochemical and biophysical research communications 17 9144402
2023 Stationary-to-migratory transition in glioblastoma stem-like cells driven by a fatty acid-binding protein 7-RXRα neurogenic pathway. Neuro-oncology 16 37499046
2022 Phosphorylation of RXRα mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome. Proceedings of the National Academy of Sciences of the United States of America 16 36282921
2016 IL-1β induced RXRα overexpression through activation of NF-κB signaling in gastric carcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 16 26898458
2024 Inhibition of the RXRA-PPARα-FABP4 signaling pathway alleviates vascular cellular aging by an SGLT2 inhibitor in an atherosclerotic mice model. Science China. Life sciences 15 39225895
2021 PPARα/RXRα downregulates amino acid catabolism in the liver via interaction with HNF4α promoting its proteasomal degradation. Metabolism: clinical and experimental 15 33422545
2020 Centrosomal Localization of RXRα Promotes PLK1 Activation and Mitotic Progression and Constitutes a Tumor Vulnerability. Developmental cell 15 33321102
2016 Phytochemicals Mediate the Expression and Activity of OCTN2 as Activators of the PPARγ/RXRα Pathway. Frontiers in pharmacology 15 27445823
2019 Cytotoxic Components from Hypericum elodeoides Targeting RXRα and Inducing HeLa Cell Apoptosis through Caspase-8 Activation and PARP Cleavage. Journal of natural products 14 31038949
2016 Genetic characterisation of PPARG, CEBPA and RXRA, and their influence on meat quality traits in cattle. Journal of animal science and technology 14 27042330
2014 Flightless-1, a novel transcriptional modulator of PPARγ through competing with RXRα. Cellular signalling 14 25479590
2012 The PP2A-Aβ gene is regulated by multiple transcriptional factors including Ets-1, SP1/SP3, and RXRα/β. Current molecular medicine 14 22827437
2023 Dissection of an impact of VDR and RXRA on the genomic activity of 1,25(OH)2D3 in A431 squamous cell carcinoma. Molecular and cellular endocrinology 13 38123121
2022 Effects of PPAR-γ and RXR-α on mouse meibomian gland epithelial cells during inflammation induced by latanoprost. Experimental eye research 13 36150542

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