Affinage

RARA

Retinoic acid receptor alpha · UniProt P10276

Length
462 aa
Mass
50.8 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 43 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

RARα is a ligand-activated nuclear receptor that heterodimerizes with RXRα on retinoic acid response elements to control gene programs of myeloid differentiation, cell-cycle arrest, and tissue homeostasis, acting bidirectionally to stimulate differentiation when bound to retinoic acid and to limit it in the unliganded state (PMID:11222375). Mechanistically, RARα drives granulocytic cell-cycle arrest through a RARα→C/EBPε→Mad1→p27(Kip1) axis (PMID:14576045), and in the unliganded state maintains epigenetic memory by setting CpG methylation and histone-modification states at target promoters (PMID:21911359). Tissue-specific signaling further governs intestinal epithelial lineage specification via KLF4 suppression (PMID:29139475), Langerhans cell development through Runx3 induction and C/EBPβ repression (PMID:30254197), and macrophage cholesterol efflux gene expression (PMID:36291054). Beyond transcription, RARα associates with FMRP- and Purα-containing dendritic RNA transport granules, binds target mRNAs, and represses translation initiation independent of cap or poly(A) tail to drive retinoic-acid-stimulated dendritic growth (PMID:18495661). RARα activity is tuned by phosphorylation: CAK phosphorylation at Ser77 shifts the balance toward repression, while its loss couples G1 arrest to differentiation through coactivator exchange (N-CoR off, NCoA-3 on) (PMID:19917671). In acute promyelocytic leukemia, fusion of RARα to PML enforces homodimerization, which enhances corepressor (SMRT) binding and dramatically expands the DNA-binding site repertoire required for hematopoietic progenitor immortalization (PMID:16757557); the fusion recruits HDAC3-MBD1 complexes to establish spreading chromatin silencing of differentiation genes (PMID:16432238) and additionally exerts P300-dependent activating functions through super-enhancer formation (PMID:32854112), reorganizing genome-wide chromatin topology toward a repressive configuration (PMID:32393309). Therapeutic response depends on destruction of the fusion protein, not merely transcriptional reactivation (PMID:23509325): retinoic acid targets the RARα moiety while arsenic triggers SUMO-dependent RNF4-mediated polyubiquitination of the PML moiety (PMID:18408733), with subsequent p97/VCP-UFD1-NPLOC4 extraction for proteasomal degradation (PMID:36880596).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 High

    Established that the defining oncogenic lesion of APL acts by aberrant transcriptional repression, reframing the disease as an epigenetic differentiation block reversible by combining HDAC inhibition with retinoic acid.

    Evidence Transgenic mouse models with co-repressor interaction assays and HDAC inhibitor rescue for PML-RARα and PLZF-RARα

    PMID:9462740

    Open questions at the time
    • Did not identify the specific HDAC-containing complexes or genomic targets
    • Mechanism of RA resistance only attributed to PLZF moiety, not molecularly resolved
  2. 2001 High

    Defined endogenous RARα as a modulatory rather than obligatory regulator of granulopoiesis, distinguishing its normal physiological role from the dominant block imposed by fusion proteins.

    Evidence RARα knockout mice, vitamin A-deficiency model, and RAR antagonist treatment with granulocyte differentiation assays

    PMID:11222375

    Open questions at the time
    • Did not identify direct transcriptional targets driving the modulatory effect
    • Redundancy with other RAR isotypes not resolved
  3. 2003 High

    Mapped the cell-cycle arrest arm of RARα differentiation signaling to a defined transcription factor cascade, placing RARα upstream of an indirect C/EBPε→Mad1→p27 pathway.

    Evidence Primary cells from p27 and Mad1 knockout mice, isoform-specific agonists, and ChIP of C/EBPε at the Mad1 promoter

    PMID:14576045

    Open questions at the time
    • Direct RARα target genes between RARα and C/EBPε not fully enumerated
    • Did not address contribution of this axis in fusion-driven leukemia
  4. 2006 High

    Resolved how PML-RARα homodimerization confers gain-of-function, showing it both enhances corepressor binding and relaxes DNA-site specificity to enable hematopoietic immortalization, and identified the HDAC3-MBD1 complex as the silencing effector.

    Evidence Dimerization/DNA-binding domain mutagenesis with primary progenitor immortalization, plus ChIP, RNAi and dominant-negative MBD1 rescue

    PMID:16432238 PMID:16757557

    Open questions at the time
    • Full genomic catalog of expanded binding sites not defined at this stage
    • How HDAC3-MBD1 spreading is initiated and bounded unresolved
  5. 2008 High

    Established that arsenic therapy works by catabolizing the fusion protein, defining SUMOylation of the PML moiety and RNF4-mediated ubiquitination as the degradation trigger required for differentiation.

    Evidence Co-IP, non-degradable SUMO mutant, dominant-negative RNF4, and proteasome inhibition in APL cells

    PMID:18408733

    Open questions at the time
    • Did not identify the segregase/extraction machinery downstream of ubiquitination
    • Relationship to the parallel RA-induced degradation pathway not addressed
  6. 2008 High

    Extended RARα function beyond transcription by identifying a translational repressor role in neuronal dendritic RNA granules, providing a mechanism for rapid retinoic-acid-stimulated dendritic growth.

    Evidence LC/MS immunoaffinity isolation, TAP, confocal microscopy, in vitro translation assays and RARα knockdown in hippocampal neurons

    PMID:18495661

    Open questions at the time
    • Structural basis of RARα mRNA binding not defined
    • Generality across other neuronal mRNAs and cell types untested
  7. 2013 High

    Separated transcriptional reactivation from protein clearance, proving that PML-RARα degradation, not differentiation induction per se, is required to eradicate leukemia-initiating cells.

    Evidence Uncoupling synthetic retinoids in a mouse APL transplantation model with secondary transplantation of sorted differentiated cells

    PMID:23509325

    Open questions at the time
    • Molecular basis distinguishing transcriptional from degradative activity of retinoids not detailed
    • Did not address whether arsenic-mediated clearance behaves identically
  8. 2014 High

    Demonstrated that APL differentiation is a default program released by clearing the fusion from chromatin, with RXRA required both for transformation and for the fusion's tight DNA binding.

    Evidence Genetic RXRA ablation with ex vivo and in vivo differentiation assays and sumoylation mutant analysis

    PMID:25258343

    Open questions at the time
    • Mechanism by which RXRA loss loosens DNA binding not structurally defined
    • Role of RXRA sumoylation in transformation only partially mapped
  9. 2015 High

    Identified a fusion-protein-specific epigenetic dependency, showing PML-RARA uniquely requires DNMT3A methyltransferase activity for self-renewal and leukemogenesis.

    Evidence PML-RARA expression in DNMT3A-deficient bone marrow, competitive transplantation, and Ctsg-PML-RARA transgenic mice on DNMT3A-null background

    PMID:26595813

    Open questions at the time
    • Specific DNMT3A target loci enforcing self-renewal not identified
    • Mechanistic link between DNMT3A and HDAC3-MBD1 silencing unexplored
  10. 2020 High

    Revealed that PML-RARα reshapes 3D genome topology and possesses an activating, super-enhancer-forming function alongside repression, broadening the oncogenic mechanism beyond simple corepressor recruitment.

    Evidence ChIP-seq, Hi-C and super-enhancer mapping in inducible and patient-derived APL cells with in vivo functional validation of GFI1

    PMID:32393309 PMID:32854112

    Open questions at the time
    • How a single fusion both activates super-enhancers and represses differentiation loci mechanistically unresolved
    • Determinants of locus-specific activation versus repression not defined
  11. 2023 High

    Completed the arsenic-induced degradation pathway by identifying the p97/VCP segregase and its UFD1-NPLOC4 cofactors as the machinery that extracts ubiquitinated, SUMOylated PML-RARA from nuclear bodies for proteasomal destruction.

    Evidence PML-body proteomics, p97 pharmacological inhibition, siRNA depletion of p97/UFD1/NPLOC4, and imaging

    PMID:36880596

    Open questions at the time
    • Whether p97 also participates in RA-induced RARα-moiety degradation untested
    • Stoichiometry and timing of extraction relative to RNF4 action unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the multiple post-translational modification systems controlling RARα/fusion stability (SUMO, ubiquitin, ISG15, NEDD8, acetylation, phosphorylation) are integrated and prioritized to determine therapeutic protein clearance.
  • No unified model linking the competing modification pathways
  • Relative contribution of each pathway to durable leukemia eradication unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 4 GO:0003723 RNA binding 1 GO:0045182 translation regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
EP300FMRPHDAC3NCOR2PMLRXRAS100A3SMRT
Complex memberships
HDAC3-MBD1 corepressor complexPML-RARα fusion oncoproteinRARα-RXRα heterodimer

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 PML-RARα and PLZF-RARα both interact with nuclear receptor co-repressors (e.g., SMRT) and act as transcriptional repressors; PLZF-RARα additionally forms RA-insensitive co-repressor complexes via its PLZF moiety, explaining RA resistance. Histone deacetylase inhibitors (TSA) combined with RA can overcome repression by both fusion proteins, demonstrating that transcriptional silencing via HDAC recruitment is mechanistically central to APL pathogenesis. Transgenic mouse models, co-repressor interaction assays, transcriptional reporter assays, HDAC inhibitor rescue experiments Nature genetics High 9462740
2008 Arsenic-induced SUMOylation of the PML moiety of PML-RARα triggers Lys48-linked polyubiquitination and proteasome-dependent degradation via recruitment of RNF4 (the human SUMO-dependent E3 ubiquitin ligase). A non-degradable SUMOylation mutant of PML-RARα or dominant-negative RNF4 impairs arsenic-induced differentiation, directly implicating PML-RARα catabolism in therapeutic response. Co-immunoprecipitation, dominant-negative RNF4 transduction, SUMOylation mutant expression, proteasome inhibitor experiments, immunofluorescence of PML nuclear bodies Nature cell biology High 18408733
2001 Endogenous RARα bidirectionally modulates granulopoiesis: it stimulates differentiation in the presence of retinoic acid and limits differentiation in the absence of ligand. RARα-deficient mice have a normal granulocyte population, showing RARα is modulatory rather than obligatory for neutrophil generation. RARα knockout mouse analysis, granulocyte differentiation assays, vitamin A-deficient mouse model, RAR antagonist treatment Blood High 11222375
2008 RARα associates with RNA-binding proteins (including Pur α and FMRP) in dendritic RNA transport granules in hippocampal neurons, binds mRNA (e.g., GluR1, CaMKIIα), inhibits translation initiation independent of cap or poly(A) tail, and redistributes mRNA to silencing ribonucleoprotein particles, providing a mechanism for rapid all-trans-retinoic acid-stimulated dendritic growth. LC/MS immunoaffinity isolation, tandem affinity purification, confocal microscopy, in vitro translation assay, RARα knockdown The Journal of biological chemistry High 18495661
2006 During RA-dependent activation, p38MAPK phosphorylates the coactivator SRC-3/AIB1 within RARα complexes; initial phosphorylation facilitates RARα-target gene activation, while subsequent phosphorylation promotes SRC-3 degradation and transcriptional inhibition. The RAR isotype dictates accessibility of SRC-3 to p38MAPK, defining an isotype-specific phosphorylation code. Phosphorylation assays, co-immunoprecipitation, p38MAPK inhibitor experiments, gene expression analysis, mutagenesis The EMBO journal High 16456540
2006 PML-RARα recruits MBD1 to target promoters through an HDAC3-mediated mechanism; HDAC3-MBD1 complex binding spreads across the locus. Knockdown of HDAC3 alleviates PML-RARα-induced promoter silencing, and dominant-negative MBD1 restores differentiation in hematopoietic precursors, demonstrating that the HDAC3-MBD1 complex is required for PML-RARα-mediated chromatin silencing. ChIP, RNA interference knockdown, retroviral dominant-negative expression, hematopoietic differentiation assay Proceedings of the National Academy of Sciences of the United States of America High 16432238
2006 PML/RARα homodimerization (enforced by the PML moiety) enhances binding of the corepressor SMRT and dramatically extends the spectrum of DNA-binding sites compared to wild-type RARα. Both dimerization-induced SMRT binding and relaxed DNA-binding site specificity are required for efficient immortalization of primary hematopoietic progenitors. Mutagenesis of dimerization and DNA-binding domains, primary mouse hematopoietic progenitor immortalization assay, co-repressor binding assays Proceedings of the National Academy of Sciences of the United States of America High 16757557
2003 ATRA treatment of PML-RARα-expressing APL cells induces a rapid increase in C/EBPβ protein and binding activity; PML-RARα directly transactivates the C/EBPβ promoter in an ATRA-dependent manner (PML-RARα transactivation mutants fail to do so). C/EBPβ induction is required for ATRA-induced granulocytic differentiation of APL cells. Transactivation reporter assays, Western blot, electrophoretic mobility shift assay, RNA interference, differentiation assays in NB4 cells The EMBO journal High 14592978
2013 Uncoupled synthetic retinoids that activate PML/RARα-dependent transcription but fail to induce PML/RARα degradation elicit terminal differentiation but do not impair leukemia-initiating activity ex vivo or in vivo; differentiated cells sorted from uncoupled retinoid-treated mice retain PML/RARα and reinitiate APL upon transplant. This establishes that PML/RARα protein loss, not merely transcriptional activation, is required for APL eradication. Synthetic retinoid treatment, mouse APL transplantation model, ex vivo differentiation assays, secondary transplantation of sorted cells The Journal of experimental medicine High 23509325
2014 Ablation of retinoid X receptor (RXRA) loosens PML/RARα DNA binding and induces terminal differentiation of APL cells ex vivo and in vivo; RXRA sumoylation contributes to PML/RARα-dependent transformation. APL differentiation is a default program triggered by clearance of PML/RARα from promoters, rather than requiring obligatory active transcriptional activation. RXRA ablation in APL cells (genetic), ex vivo and in vivo differentiation assays, transformation assay, sumoylation mutant analysis Blood High 25258343
2001 PML interacts with co-repressors c-Ski, N-CoR, mSin3A and HDAC1, and this interaction is required for Mad-mediated transcriptional repression. PML-RARα has two co-repressor-binding sites and inhibits Mad-mediated repression by aberrantly binding co-repressor complexes, potentially dissociating them from their normal function. Co-immunoprecipitation, in vitro binding assays, luciferase reporter assays, dominant-negative approaches Molecular cell Medium 11430826
2002 Stat5-RARα fusion protein represses transcription through the coiled-coil domain of Stat5 (aa 133-333), which mediates stable binding of the co-repressor SMRT independent of ATRA stimulation. Oligomerization via this domain blocks dissociation of co-repressors in response to ATRA, causing a differentiation block in hematopoietic cells. Reporter gene assays, domain deletion mutagenesis, co-repressor binding assays, hematopoietic differentiation assays Blood Medium 11929749
2003 RARα-mediated cell cycle arrest during granulocytic differentiation specifically requires both Mad1 and p27(Kip1); RARα does not directly regulate Mad1 or p27(Kip1), but the RARα target gene C/EBPε directly activates Mad1 transcription. ChIP confirmed direct binding of C/EBPε to the Mad1 promoter, establishing a RARα→C/EBPε→Mad1→p27 pathway for cell cycle arrest. Primary cells from p27(Kip1) and Mad1 knockout mice, RAR isoform-specific agonist treatment, chromatin immunoprecipitation Blood High 14576045
2009 PRKAR1A-RARα (R1A-RARα) fusion protein transforms bone marrow progenitor/stem cells and binds retinoic acid response elements as homodimer and heterodimer with RXRα. Leukemic transformation critically depends on RXRα: mutations in the RARα portion eliminating RXRα interaction, RXRα shRNA knockdown, or RXRα agonist treatment all reduce transformation capability. The RIIa domain is not required for transformation. Murine bone marrow retroviral transduction/transformation assay, gel-shift assays, point mutagenesis, shRNA knockdown, pharmacological RXRα activation Blood High 19965660
2009 p38αMAPK physically interacts with RARα in a ligand-independent manner, stabilizing RARα and PML-RARα by blocking their constitutive proteasomal degradation, thereby inhibiting ligand-dependent transactivation. Ser-369 in the E-region of RARα is essential for p38α binding and its functional inhibitory effects. Co-immunoprecipitation, mutagenesis (Ser-369), p38α pharmacological inhibition and gene silencing, transcriptional reporter assays, proliferation/differentiation assays Leukemia Medium 22354283
2009 RA suppresses CAK (CDK-activating kinase) phosphorylation of RARα at Ser77; mutation RARαS77A (phosphorylation-defective) coordinates G1 arrest with cancer cell differentiation. Hypophosphorylated RARα reduces binding to RARE in target gene promoters while stimulating gene transcription, accompanied by dissociation from transcriptional repressor N-CoR and association with coactivator NCoA-3. RARαS77A mutagenesis, chromatin immunoprecipitation, co-immunoprecipitation, xenograft tumor assay, gene expression analysis in myeloid leukemia and teratocarcinoma stem cells FASEB journal Medium 19917671
2010 RARα binds to the MMP-9 promoter in mammary gland cells during weaning, together with the coactivator p300, driving increased MMP-9 mRNA and protein expression. Administration of retinol palmitate to lactating rats also induces MMP-9 expression, demonstrating RARα-dependent transcriptional regulation of MMP-9 during mammary gland remodeling. Chromatin immunoprecipitation (ChIP), Western blot, zymography, in vivo retinol palmitate administration American journal of physiology. Endocrinology and metabolism Medium 17164434
2010 RA treatment or RARαS77A (phosphorylation-defective mutant) expression inhibits proliferation and induces differentiation in U2OS osteosarcoma cells; FGF8f is identified as a downstream target induced by both RA and RARαS77A, and overexpression of FGF8f inhibits proliferation and induces osteoblastic differentiation markers, linking RA-suppressed RARα phosphorylation to a FGF8f-dependent differentiation pathway. RARαS77A mutagenesis, retroviral transduction, gene expression analysis, FGF8f overexpression, xenograft tumor assay Oncogene Medium 20190807
2002 PML inhibits STAT3 activity by forming a complex with STAT3 through its B-box and C-terminal regions, inhibiting STAT3 DNA binding. PML-RARα does not interact with STAT3 but dissociates PML from STAT3, restoring STAT3 activity suppressed by PML. This leads to enhanced gp130-mediated growth when PML-RARα is expressed. Luciferase reporter assays, co-immunoprecipitation in vitro and in vivo, electrophoretic mobility shift assay, cytokine-dependent growth assays in Ba/F3 cells Blood Medium 12506013
2007 PML-RARα fusion protein activates ID1 and ID2 promoters (which wild-type RARα/RXR does not), through indirect interaction with Sp1 and NF-Y transcription factors without direct DNA binding, demonstrating a gain-of-function mechanism for the oncogenic fusion protein at a novel class of target genes. Reporter gene assays, ChIP, mutagenesis of DNA-binding domain, co-immunoprecipitation with Sp1 and NF-Y Blood Medium 18025157
2010 PML/RARα transactivates the tissue factor (TF) promoter through indirect interaction with a GAGC-containing element at position -230 to -242 without direct DNA association (EMSA showed no direct binding). AP-1 sites are dispensable for this regulation. Luciferase reporter assays with TF promoter deletion/mutation constructs, ChIP, EMSA Proceedings of the National Academy of Sciences of the United States of America Medium 20133705
2008 UBE1L (ubiquitin-activating enzyme E1-like) induces ISG15ylation of the PML domain of PML-RARα (not the RARα domain), causing its proteasomal degradation; RA treatment preferentially degrades the RARα domain of PML-RARα via a distinct pathway. USP18/UBP43 (ISG15 deconjugase) opposes UBE1L- but not RA-dependent PML-RARα degradation, confirming two independent degradation pathways converging on PML-RARα. Domain-specific transient transfection, ISG15ylation assay, proteasome inhibitor, USP18 deconjugase competition, domain mutagenesis Molecular cancer therapeutics Medium 18413804
2015 PML-RARA requires the methyltransferase activity of DNMT3A (but not DNMT3B) for aberrant self-renewal ex vivo, competitive transplantation advantage, and development of APL in vivo. DNMT3A is dispensable for RUNX1-RUNX1T1- and MLL-AF9-driven self-renewal, demonstrating a fusion-protein-specific epigenetic dependency. Retroviral expression of PML-RARA in DNMT3A-deficient mouse bone marrow cells, ex vivo self-renewal assays, competitive transplantation, Ctsg-PML-RARA transgenic mice on DNMT3A-null background The Journal of clinical investigation High 26595813
2011 S100A3 calcium-binding protein directly interacts with RARα constitutively via the RARα ligand-binding domain (I396 residue is critical); this interaction controls the constitutive and ATRA-dependent degradation of RARα. In APL cells, S100A3 also interacts with PML-RARα; S100A3 knockdown decreases RARα levels and induces resistance to ATRA anti-proliferative effects in breast/lung cancer, while in APL/AML cells it increases basal and ATRA-induced differentiation. Co-immunoprecipitation, mutagenesis (I396), RARα interactome by LC-MS, knockdown and overexpression studies across multiple cell lines Oncogene Medium 30532072
2009 TNIP1 interacts with liganded RARα and RARγ via its NR boxes and requires the AF-2 domain of the receptor (characteristic of coactivators), but functionally represses RAR activity; repression is partially relieved by SRC1, suggesting TNIP1 interferes with coactivator recruitment. TNIP1 preferential interaction with RARα over RARγ maps to RARα LBD helices 5-9. Co-immunoprecipitation, domain mutagenesis, reporter gene assay, SRC1 competition assay Biochemical and biophysical research communications Low 19732752
2014 RARα forms a functional ternary complex with TDG (thymine DNA glycosylase) and CBP (histone acetylase). A TDG point mutation reducing ternary complex stability leads to deregulation of RA-target genes without affecting TDG's BER activity, demonstrating a direct coupling of TDG epigenomic function with RARα-dependent transcription. Co-immunoprecipitation, point mutagenesis of TDG, transcriptome profiling, reporter gene assay Genomics, proteomics & bioinformatics Low 24394593
2013 RARα-PLZF (reciprocal fusion from t(11;17)) inhibits myeloid differentiation by interacting with C/EBPα tethered to DNA, recruiting HDAC1, and causing histone H3 deacetylation at C/EBPα target loci, thereby decreasing C/EBPα target gene expression. HDAC inhibitors partially restore C/EBPα target gene expression. ChIP, DNA capture assays, HDAC inhibitor rescue, Co-immunoprecipitation with C/EBPα, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America Medium 23898169
2011 PML-RARα enhances constitutive autophagy by inhibiting the Akt/mTOR pathway; this autophagic upregulation is specific to PML-RARα and not observed with PLZF-RARα or NPM-RARα. Autophagy contributes to the anti-apoptotic function of PML-RARα, and autophagic flux assay revealed increased on-rate of autophagic sequestration. Transmission electron microscopy, autophagic flux assay, 3-methyladenine inhibitor, Western blot for Akt/mTOR pathway, inducible PML-RARα expression, leukemic mouse model Autophagy Medium 21673516
2011 Ligand-free RARα maintains epigenetic memory by regulating CpG methylation status at specific promoters (e.g., Mest, Tex13); RARα-KO cells show increased promoter CpG methylation and H3K9me3 at repressed genes, and decreased methylation with increased H3K9/K14ac at activated genes. Stable PML-RARα expression recapitulates the Mest downregulation seen in RARα-KO cells, and specific RARα/RXRα association with the Mest promoter was demonstrated. Microarray expression analysis, ChIP (H3K9me3, H3K9/K14ac, H3K4me3), bisulfite sequencing, RARα-KO cells, PML-RARα stable transfection, Co-IP of RARα/RXRα at Mest promoter Nucleic acids research Medium 21911359
2017 Intestinal epithelial cell-specific RARα signaling is required for proper epithelial lineage specification: RARα-deficient IECs show increased goblet cells and Paneth cells, increased KLF4+ goblet cell precursors, and an underdeveloped intestinal immune system (near-complete absence of lymphoid follicles and gut-resident mononuclear phagocytes). RA treatment inhibited klf4 expression and goblet cell differentiation in zebrafish, mechanistically linking RARα to KLF4 suppression. IEC-specific RARα conditional knockout mouse, zebrafish RA treatment/klf4 expression assay, histological analysis, infection clearance assay Mucosal immunology Medium 29139475
2018 Myeloid RARα protects against atherosclerosis by inducing cholesterol efflux transporter expression (Abca1, Abcg1) and inhibiting inflammation. Myeloid-specific RARα ablation reduces macrophage Abca1/Abcg1 expression and cholesterol efflux, increases inflammatory genes, and aggravates Western diet-induced atherosclerosis in Ldlr−/− mice. Myeloid-specific RARα conditional knockout (Rarα-flox × LysM-Cre), macrophage lipid accumulation assay, cholesterol efflux assay, atherosclerosis plaque quantitation, ATRA treatment Cells Medium 36291054
2018 RARα supports Langerhans cell (LC) development from embryonic and bone marrow-derived progenitors by promoting expression of the LC-promoting transcription factor Runx3 and suppressing LC-inhibiting C/EBPβ. RARα promotes LC and langerin+ conventional DC development only under hypo-RA conditions, with this function suppressed at systemic RA levels. RARα conditional knockout, bone marrow-derived LC differentiation assays, Runx3 and C/EBPβ expression analysis, RA dose-response experiments Nature communications Medium 30254197
2013 PML-RARα acts through both repressive and activating transcriptional functions; the activating function involves recruiting P300 and forming super-enhancers. PML-RARα oligomers transactivate GFI1 through chromatin conformation changes at super-enhancers, and GFI1 is required for APL cell maintenance. ChIP-seq, Hi-C chromatin conformation, in vitro and in vivo functional assays, super-enhancer mapping Blood High 32854112
2020 PML-RARα mediates extensive chromatin interactions genome-wide, redefining chromatin topology toward a more condensed configuration in APL cells. Locally, PML-RARα intrudes RNAPII-associated interaction domains, interrupts myeloid-specific transcription factor binding at enhancers and super-enhancers, and leads to transcriptional repression of myeloid differentiation genes. 3D genome/Hi-C analysis of inducible PML-RARα system and patient-derived APL cells, ChIP-seq, RNA-seq Genome biology High 32393309
2023 p97/VCP segregase is required for arsenic-induced degradation of PML-RARA and PML. After arsenic treatment, p97 localizes to PML nuclear bodies and extracts poly-ubiquitinated, poly-SUMOylated PML for proteasomal degradation; UFD1 and NPLOC4 cofactors of p97 are critical for this process. Proteomics of PML bodies, pharmacological p97 inhibition, siRNA depletion of p97/UFD1/NPLOC4, immunofluorescence, Western blot, PML body morphology analysis The Journal of cell biology High 36880596
2023 HDAC3 deacetylates PML-RARα at lysine 394, which reduces PIAS1-mediated PML-RARα SUMOylation and subsequent RNF4-induced ubiquitylation. HDAC3 inhibition promotes PML-RARα ubiquitylation and degradation in both wild-type and ATRA/ATO-resistant APL cells. Co-immunoprecipitation, deacetylation assay, SUMOylation assay, ubiquitylation assay, pharmacological HDAC3 inhibition, xenograft models, primary patient samples Cell death and differentiation High 36894687
2022 PML/RARα is neddylated in its RARα moiety; neddylation enhances PML/RARα DNA-binding ability and impedes phase separation of the PML moiety, disrupting PML nuclear body assembly. Deneddylation of PML/RARα restores its phase separation and reconstructs functional PML nuclear bodies; MLN4924 (neddylation inhibitor) eradicates APL cells in vitro and in vivo. Neddylation assay, DNA-binding assay, phase separation imaging, PML nuclear body reconstitution, MLN4924 pharmacological inhibition, in vitro and in vivo APL models Cell death and differentiation Medium 35194189
2020 TRIB3 (pseudokinase) interacts with PML-RARα to inhibit PPARγ activity by disrupting the PPARγ/RXR interaction and promoting PPARγ degradation; reduced PPARγ activity in APL cells causes dyslipidemia. Arsenic/ATRA therapy degrades PML-RARα but elevates TRIB3, which then suppresses PPARγ/RXR dimerization, contributing to therapy-induced dyslipidemia. Co-immunoprecipitation, dual luciferase reporter assay, gene set enrichment analysis, Western blot, APL transgenic and transplantation mouse models, primary patient samples Theranostics Medium 32929351
2013 PML-RARα phosphorylation by PKA blocks its ability to inhibit PML oligomerization and destabilize HIPK2 at nuclear bodies; PML oligomerization and HIPK2 stabilization at nuclear bodies are both required for APL cell differentiation. Nuclear body disruption assay, PML oligomerization assay, HIPK2 stability assay, PKA phosphorylation assay, APL cell differentiation assay Cancer research Medium 23722549
2021 YOD1 deubiquitinase stabilizes PML/RARα by removing ubiquitin chains; siRNA-mediated YOD1 suppression promotes PML/RARα degradation and inhibits APL cells. The YOD1 inhibitor G5 degrades PML/RARα and eradicates APL cells including drug-resistant cells and patient-derived blasts. DUB siRNA library screen, siRNA knockdown of YOD1, ubiquitination assay, PML/RARα protein stability assay, APL cell and mouse model, primary patient blasts Acta pharmaceutica Sinica. B Medium 35847510
2012 USP37 deubiquitinase interacts with PLZF/RARA through the PLZF moiety and the N-terminal domain of USP37, sustaining PLZF/RARA steady-state levels by controlling its poly-ubiquitination. USP37 knockdown alleviates PLZF/RARA-mediated target gene suppression and cell transformation potential. RNAi screen, Co-immunoprecipitation, domain mapping, protein half-life assay, poly-ubiquitination assay, hematopoietic progenitor transformation assay Oncogene Medium 23208507
2011 PML-RARα directly represses S100A10 expression; ATRA-induced PML-RARα degradation rapidly downregulates S100A10 on the APL cell surface, reducing plasminogen receptor activity and fibrinolytic generation of plasmin at the cell surface. This provides a molecular link between PML-RARα expression and the hemorrhagic phenotype of APL. Flow cytometry for cell-surface S100A10, RNA interference knockdown of S100A10, inducible PML-RARα expression, fibrinolytic activity assay Blood Medium 21310922
2002 RAR alpha:RXR alpha heterodimers activate the rat Mrp2 (Abcc2) promoter; in obstructive cholestasis, cytokine (IL-1β)-dependent reduction of nuclear RAR alpha:RXR alpha levels and their binding to the Mrp2 promoter is associated with organ-specific suppression of hepatic Mrp2 expression while renal expression is preserved. Electrophoretic mobility shift assay (EMSA), immunoblot, ribonuclease protection assay, primary hepatocyte cytokine treatment, bile duct ligation model Gastroenterology Medium 12145812

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nature cell biology 611 18408733
1998 Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL. Nature genetics 488 9462740
1997 Acute leukemia with promyelocytic features in PML/RARalpha transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 304 9144232
2002 PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proceedings of the National Academy of Sciences of the United States of America 257 12060771
2001 Translocations of the RARalpha gene in acute promyelocytic leukemia. Oncogene 162 11704847
1992 Expression pattern of the RAR alpha-PML fusion gene in acute promyelocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America 155 1317574
2003 C/EBPbeta: a major PML-RARA-responsive gene in retinoic acid-induced differentiation of APL cells. The EMBO journal 147 14592978
2001 Role of PML and PML-RARalpha in Mad-mediated transcriptional repression. Molecular cell 125 11430826
2001 Positive and negative regulation of granulopoiesis by endogenous RARalpha. Blood 113 11222375
2013 Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia. The Journal of experimental medicine 112 24344243
1991 RAR-alpha gene rearrangements as a genetic marker for diagnosis and monitoring in acute promyelocytic leukemia. Blood 112 1849030
2020 Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene. Cancers 111 32182684
1996 Transgenic expression of PML/RARalpha impairs myelopoiesis. Proceedings of the National Academy of Sciences of the United States of America 93 8755574
2006 The methyl-CpG binding protein MBD1 is required for PML-RARalpha function. Proceedings of the National Academy of Sciences of the United States of America 84 16432238
2014 RARA fusion genes in acute promyelocytic leukemia: a review. Expert review of hematology 82 24720386
2009 Therapy-induced PML/RARA proteolysis and acute promyelocytic leukemia cure. Clinical cancer research : an official journal of the American Association for Cancer Research 79 19808868
2008 The nuclear transcription factor RARalpha associates with neuronal RNA granules and suppresses translation. The Journal of biological chemistry 76 18495661
2001 Function of RARalpha during the maturation of neutrophils. Oncogene 74 11704846
2013 Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies. The Journal of experimental medicine 73 23509325
2006 P38MAPK-dependent phosphorylation and degradation of SRC-3/AIB1 and RARalpha-mediated transcription. The EMBO journal 68 16456540
2021 A PML/RARα direct target atlas redefines transcriptional deregulation in acute promyelocytic leukemia. Blood 67 32854112
2000 A mutated PML/RARA found in the retinoid maturation resistant NB4 subclone, NB4-R2, blocks RARA and wild-type PML/RARA transcriptional activities. Leukemia 66 10673742
2002 Organ-specific alterations in RAR alpha:RXR alpha abundance regulate rat Mrp2 (Abcc2) expression in obstructive cholestasis. Gastroenterology 64 12145812
2011 Regulation of S100A10 by the PML-RAR-α oncoprotein. Blood 60 21310922
2004 Acute promyelocytic leukemia: PML/RARalpha and the leukemic stem cell. Leukemia 60 15103387
1994 PML/RAR alpha+ U937 mutant and NB4 cell lines: retinoic acid restores the monocytic differentiation response to vitamin D3. Cancer research 60 7519122
2012 Chromatin accessibility, p300, and histone acetylation define PML-RARα and AML1-ETO binding sites in acute myeloid leukemia. Blood 58 22923494
2011 Genome-wide functions of PML-RARα in acute promyelocytic leukaemia. British journal of cancer 51 21245861
1991 Rearrangements of the RAR-alpha gene in acute promyelocytic leukaemia: correlations with morphology and immunophenotype. British journal of haematology 50 1911341
2006 Leukemia with distinct phenotypes in transgenic mice expressing PML/RAR alpha, PLZF/RAR alpha or NPM/RAR alpha. Oncogene 49 16331271
2017 Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system. Mucosal immunology 46 29139475
2006 Dimerization-induced corepressor binding and relaxed DNA-binding specificity are critical for PML/RARA-induced immortalization. Proceedings of the National Academy of Sciences of the United States of America 46 16757557
2018 Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation. Cancer research 44 29921692
2011 Epigenetic regulation by RARα maintains ligand-independent transcriptional activity. Nucleic acids research 44 21911359
1997 Characterisation of the PML/RAR alpha rearrangement associated with t(15;17) acute promyelocytic leukaemia. Current topics in microbiology and immunology 43 9103677
2008 UBE1L represses PML/RAR{alpha} by targeting the PML domain for ISG15ylation. Molecular cancer therapeutics 42 18413804
1995 The PML/RAR alpha fusion gene in the diagnosis and monitoring of acute promyelocytic leukemia. Haematologica 39 7628753
2012 The deubiquitinating enzyme USP37 regulates the oncogenic fusion protein PLZF/RARA stability. Oncogene 38 23208507
2002 The Stat5-RARalpha fusion protein represses transcription and differentiation through interaction with a corepressor complex. Blood 38 11929749
2015 PML-RARa modulates the vascular signature of extracellular vesicles released by acute promyelocytic leukemia cells. Angiogenesis 37 26374632
2003 Identification of the molecular requirements for an RAR alpha-mediated cell cycle arrest during granulocytic differentiation. Blood 37 14576045
2015 PML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemia. The Journal of clinical investigation 35 26595813
2011 PML-RARα enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway. Autophagy 35 21673516
2002 The retinoic acid receptors RARalpha and RARgamma are required for inner ear development. Mechanisms of development 35 12464434
2023 Targeting HDAC3 to overcome the resistance to ATRA or arsenic in acute promyelocytic leukemia through ubiquitination and degradation of PML-RARα. Cell death and differentiation 34 36894687
2014 Enhanced expression of retinoic acid receptor alpha (RARA) induces epithelial-to-mesenchymal transition and disruption of mammary acinar structures. Molecular oncology 34 25300573
2012 Reversal by RARα agonist Am580 of c-Myc-induced imbalance in RARα/RARγ expression during MMTV-Myc tumorigenesis. Breast cancer research : BCR 34 22920668
2007 PML-RARalpha inhibitors (ATRA, tamibaroten, arsenic troxide) for acute promyelocytic leukemia. International journal of clinical oncology 34 17929112
2014 Clearance of PML/RARA-bound promoters suffice to initiate APL differentiation. Blood 33 25258343
2010 Retinoid-suppressed phosphorylation of RARalpha mediates the differentiation pathway of osteosarcoma cells. Oncogene 33 20190807
2002 Opposing effects of PML and PML/RAR alpha on STAT3 activity. Blood 33 12506013
2023 Targeting RARA overexpression with tamibarotene, a potent and selective RARα agonist, is a novel approach in AML. Blood advances 32 36477975
2015 Varying responses of PML-RARA with different genetic mutations to arsenic trioxide. Blood 32 26537301
2021 Blockade of deubiquitinase YOD1 degrades oncogenic PML/RARα and eradicates acute promyelocytic leukemia cells. Acta pharmaceutica Sinica. B 31 35847510
2019 MED12, TERT and RARA in fibroepithelial tumours of the breast. Journal of clinical pathology 30 31662438
2004 The PML-RARalpha fusion protein and targeted therapy for acute promyelocytic leukemia. Leukemia & lymphoma 30 15160934
2013 RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells. Proceedings of the National Academy of Sciences of the United States of America 29 23898169
1992 RARA and PML genes in acute promyelocytic leukemia. Leukemia & lymphoma 29 1337847
2020 PML-RARα interaction with TRIB3 impedes PPARγ/RXR function and triggers dyslipidemia in acute promyelocytic leukemia. Theranostics 28 32929351
2006 Retinoids induce MMP-9 expression through RARalpha during mammary gland remodeling. American journal of physiology. Endocrinology and metabolism 28 17164434
2004 The serine-threonine kinase MNK1 is post-translationally stabilized by PML-RARalpha and regulates differentiation of hematopoietic cells. Oncogene 27 15516979
2007 Gene transactivation without direct DNA binding defines a novel gain-of-function for PML-RARalpha. Blood 24 18025157
2022 Deneddylation of PML/RARα reconstructs functional PML nuclear bodies via orchestrating phase separation to eradicate APL. Cell death and differentiation 23 35194189
2009 Liganded RARalpha and RARgamma interact with but are repressed by TNIP1. Biochemical and biophysical research communications 23 19732752
1993 PML/RAR alpha fusion gene is expressed in both granuloid/macrophage and erythroid colonies in acute promyelocytic leukaemia. British journal of haematology 23 8136268
2018 RARA and RARG gene downregulation associated with EZH2 mutation in acute promyelocytic-like morphology leukemia. Human pathology 22 29530751
2015 MicroRNA-27a Contributes to Rhabdomyosarcoma Cell Proliferation by Suppressing RARA and RXRA. PloS one 22 25915942
2014 A TDG/CBP/RARα ternary complex mediates the retinoic acid-dependent expression of DNA methylation-sensitive genes. Genomics, proteomics & bioinformatics 22 24394593
2012 p38αMAPK interacts with and inhibits RARα: suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells. Leukemia 22 22354283
2010 PML-RAR{alpha} and Dnmt3a1 cooperate in vivo to promote acute promyelocytic leukemia. Cancer research 22 20861188
2003 Combined RAR alpha- and RXR-specific ligands overcome N-myc-associated retinoid resistance in neuroblastoma cells. Biochemical and biophysical research communications 22 12615055
2018 S100A3 a partner protein regulating the stability/activity of RARα and PML-RARα in cellular models of breast/lung cancer and acute myeloid leukemia. Oncogene 21 30532072
2011 Characterisation of genome-wide PLZF/RARA target genes. PloS one 21 21949697
2010 PML/RARalpha fusion protein transactivates the tissue factor promoter through a GAGC-containing element without direct DNA association. Proceedings of the National Academy of Sciences of the United States of America 21 20133705
2010 Atypical mRNA fusions in PML-RARA positive, RARA-PML negative acute promyelocytic leukemia. Genes, chromosomes & cancer 21 20155840
2009 Loss of CAK phosphorylation of RAR{alpha} mediates transcriptional control of retinoid-induced cancer cell differentiation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 19917671
2009 Leukemic transformation by the APL fusion protein PRKAR1A-RAR{alpha} critically depends on recruitment of RXR{alpha}. Blood 21 19965660
2020 Chromatin topology reorganization and transcription repression by PML-RARα in acute promyeloid leukemia. Genome biology 20 32393309
2020 RecA-independent recombination: Dependence on the Escherichia coli RarA protein. Molecular microbiology 20 33247976
2016 LG-362B targets PML-RARα and blocks ATRA resistance of acute promyelocytic leukemia. Leukemia 20 27012866
2022 Retinoic Acid Receptor Alpha (RARα) in Macrophages Protects from Diet-Induced Atherosclerosis in Mice. Cells 19 36291054
2019 Acute promyelocytic leukemia and variant fusion proteins: PLZF-RARα fusion protein at a glance. Seminars in oncology 19 31126665
2018 RARα supports the development of Langerhans cells and langerin-expressing conventional dendritic cells. Nature communications 19 30254197
2018 PML/RARA inhibits expression of HSP90 and its target AKT. British journal of haematology 19 30536958
2001 Acute promyelocytic leukemia with a PLZF-RARalpha fusion protein. Seminars in hematology 19 11172538
2016 PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity. Oncotarget 18 27626703
2023 The p97/VCP segregase is essential for arsenic-induced degradation of PML and PML-RARA. The Journal of cell biology 17 36880596
2020 Recent advances in the design of RAR α and RAR β agonists as orally bioavailable drugs. A review. Bioorganic & medicinal chemistry 17 33069074
2023 Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia. Nature communications 16 36759620
2022 Typical, atypical and cryptic t(15;17)(q24;q21) (PML::RARA) observed in acute promyelocytic leukemia: A retrospective review of 831 patients with concurrent chromosome and PML::RARA dual-color dual-fusion FISH studies. Genes, chromosomes & cancer 16 35639830
2019 SP1 and RARα regulate AGAP2 expression in cancer. Scientific reports 16 30674964
2008 Changes in the expression and subcellular localization of RARalpha in the rat hippocampus during postnatal development. Brain research 16 18619947
2001 Expression of RARalpha and RARbeta in human oral potentially malignant and neoplastic lesions. International journal of cancer 16 11149416
2023 Kuijieling decoction regulates the Treg/Th17 cell balance in ulcerative colitis through the RA/RARα signaling pathway. Journal of ethnopharmacology 15 37451490
2021 Mutational profile of ZBTB16-RARA-positive acute myeloid leukemia. Cancer medicine 15 34042280
2021 The rarA gene as part of an expanded RecFOR recombination pathway: Negative epistasis and synthetic lethality with ruvB, recG, and recQ. PLoS genetics 15 34936656
2013 PML-RARα and its phosphorylation regulate pml oligomerization and HIPK2 stability. Cancer research 15 23722549
2003 C-fms expression correlates with monocytic differentiation in PML-RAR alpha+ acute promyelocytic leukemia. Leukemia 15 12529666
2018 Bacillus subtilis RarA modulates replication restart. Nucleic acids research 14 29947798
2017 DNA flap creation by the RarA/MgsA protein of Escherichia coli. Nucleic acids research 14 28053120

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