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| Description | 462 amino acids - 5 functional domains A/B (transcriptional regulation), C (DNA binding domain, contains 2 zinc fingers), D (cellular localization signal), E (ligand-binding domain) and F (function?) |
| Expression | in hematopoietic cells |
| Localisation | nuclear |
| Function | ligand-dependent transcription factor specifically involved in hematopoietic cells differentiation and maturation = receptor for all-trans retinoic acid (ATRA) and 9-cis RA which are intracellular metabolites of vitamine A, active in cellular differentiation and morphogenesis after linking with ATRA, RARA binds with a high affinity as a heterodimer with RXR (retinoid X receptor protein) to the RARE domain (retinoic acid response elements), a DNA sequence common to a number of genes and located in their promoter the gene response to RARA binding is modulated by a series of co-repressors and co-activators |
| Homology | with RARB and RARG (retinoic acid receptors ? and ?), 9-cis RA receptors (RXRs) and receptors for thyroid and steroid hormones and for vitamine D3 |
| Entity | t(15;17)(q24;q21) / acute promyelocytic leukemia (APL) -->PML - RARA |
| Disease | typical APL (or M3 ANLL, FAB classification), approximately 98% of APL cases; abnormal promyelocytes with Auer rods and bundles (faggots); disruption of the PODs with a microspeckeled pattern; maturation response to all-trans retinoic acid (ATRA) therapy |
| Prognosis | immediate prognosis impaired by intravascular disseminated coagulopathy; long term prognosis is favorable with treatment combining ATRA plus chemotherapy |
| Cytogenetics | variant or complex t(15;17) translocation in 5% of cases, no known prognosis implication; secondary chromosomal abnormalities in 30 to 35% of APL at diagnosis; association with +8 in 17 to 28% of cases; other associations are rare but recurrent: del(7q), del(9q), ider(17)t(15;17), +21 |
| Hybrid/Mutated Gene | the crucial fusion transcript is 5'PML-3'RARA, encoded by der(15) chromosome; the counterpart 5'RARA-3'PML encoded by der(17) is inconstant breakpoint in RARA gene is always located in intron between A and B domains three breakpoint clusters in PML gene: bcr1 (70% of patients), bcr2 (10%) and bcr3 (20%), giving rise respectively to the long (L), intermediate (V) and short (S) length hybrid PML-RARAtranscripts; V form would be linked to ATRA decreased sensitivity and S form to association with an excess of secondary chromosome changes. |
| Abnormal Protein | 106 Kda fusion protein; role in the leukemogenic process by probable interference with the signalling pathway leading to differentiation and maturation of myeloid precursors (mainly dysregulation of retinoid-inducible genes involved in myeloid differentiation) |
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| Entity | t(11;17)(q23;q12) / acute promyelocytic leukemia -->PLZF-RARA |
| Disease | variant acute promyelocytic leukemia (APL) form with atypical cytologic aspects (intermediate morphology between M2 and M3, no Auer rods) and no response to ATRA therapy; less than 1% of APL cases. |
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| Entity | t(5;17)(q35;q12) / acute promyelocytic leukemia --> NPM-RARA |
| Disease | exceptional; probable response to ATRA |
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| Entity | t(11;17)(q13;q12) / acute promyelocytic leukemia --> NuMA-RARA |
| Disease | exceptional: probable response to ATRA |
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| Entity | t(11;17)(q23;q12) / M5 acute non lymphocytic leukemia --> MLL-RARA |
| Disease | 1 case to date; not to be confused with the t(11;17)(q23;q12) mentioned above; not found in APL; belongs to the MLL/11q23 leukemias |
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| Nomenclature | | HGNC (Hugo) | RARA 9864 |
| Cards | | Atlas | RARAID46 |
| Entrez_Gene (NCBI) | RARA 5914 retinoic acid receptor, alpha |
| GeneCards (Weizmann) | RARA |
| Ensembl (Hinxton) | [Gene_View] chr17:38465423-38513895 [Contig_View] RARA [Vega] |
| AceView (NCBI) | RARA |
| Genatlas (Paris) | RARA |
| WikiGenes | 5914 |
| SOURCE (Princeton) | NM_000964 NM_001024809 NM_001033603 NM_001145301 NM_001145302 |
| Genomic and cartography | | GoldenPath (UCSC) | RARA - 17q21.2 chr17:38465423-38513895 + 17q21 [Description] (hg19-Feb_2009) |
| Ensembl | RARA - 17q21 [CytoView] |
| Mapping of homologs : NCBI | RARA [Mapview] |
| OMIM | 180240 612376 |
| Gene and transcription |
| Genbank (Entrez) | AK098172 AK130192 AK292205 AK303868 AK312564 |
| RefSeq transcript (Entrez) | NM_000964 NM_001024809 NM_001033603 NM_001145301 NM_001145302 |
| RefSeq genomic (Entrez) | AC_000149 NC_000017 NC_018928 NG_027701 NT_010783 NW_001838435 NW_004929407 |
| Consensus coding sequences : CCDS (NCBI) | RARA |
| Cluster EST : Unigene | Hs.654583 [ NCBI ] |
| CGAP (NCI) | Hs.654583 |
| Alternative Splicing : Fast-db (Paris) | GSHG0012478 |
| Gene Expression | RARA [ NCBI-GEO ] RARA [ SEEK ] RARA [ MEM ] |
| Protein : pattern, domain, 3D structure |
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| UniProt/SwissProt | P10276 (Uniprot) |
| NextProt | P10276 [Medical] |
| With graphics : InterPro | P10276 |
| Splice isoforms : SwissVar | P10276 (Swissvar) |
| Domaine pattern : Prosite (Expaxy) | NUCLEAR_REC_DBD_1 (PS00031) NUCLEAR_REC_DBD_2 (PS51030) |
| Domains : Interpro (EBI) | Nucl_hormone_rcpt_ligand-bd Nucl_hrmn_rcpt_lig-bd_core Retinoic_acid_rcpt Str_hrmn_rcpt Znf_hrmn_rcpt Znf_NHR/GATA |
| Related proteins : CluSTr | P10276 |
| Domain families : Pfam (Sanger) | Hormone_recep (PF00104) zf-C4 (PF00105) |
| Domain families : Pfam (NCBI) | pfam00104 pfam00105 |
| Domain families : Smart (EMBL) | HOLI (SM00430) ZnF_C4 (SM00399) |
| DMDM Disease mutations | 5914 |
| Blocks (Seattle) | P10276 |
| PDB (SRS) | 1DKF 1DSZ 3A9E 3KMR 3KMZ 4DQM |
| PDB (PDBSum) | 1DKF 1DSZ 3A9E 3KMR 3KMZ 4DQM |
| PDB (IMB) | 1DKF 1DSZ 3A9E 3KMR 3KMZ 4DQM |
| PDB (RSDB) | 1DKF 1DSZ 3A9E 3KMR 3KMZ 4DQM |
| Peptide Atlas | P10276 |
| HPRD | 06769 |
| IPI | IPI00020071 IPI00218375 IPI00908598 IPI00470378 IPI00922641 IPI00014923 IPI00791851 |
| Protein Interaction databases |
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| DIP (DOE-UCLA) | P10276 |
| IntAct (EBI) | P10276 |
| BioGRID | RARA |
| InParanoid | P10276 |
| Interologous Interaction database | P10276 |
| IntegromeDB | RARA |
| STRING (EMBL) | RARA |
| Ontologies - Pathways | | Ontology : AmiGO | negative regulation of transcription from RNA polymerase II promoter nuclear chromatin ureteric bud development retinoic acid binding growth plate cartilage development sequence-specific DNA binding transcription factor activity steroid hormone receptor activity retinoic acid receptor activity transcription coactivator activity transcription coactivator activity transcription corepressor activity receptor binding protein binding nucleus nucleoplasm cytoplasm transcription initiation from RNA polymerase II promoter protein phosphorylation signal transduction germ cell development spermatogenesis transcription factor binding zinc ion binding positive regulation of cell proliferation cell surface gene expression positive regulation of phosphatidylinositol 3-kinase cascade enzyme binding protein domain specific binding dendrite intracellular estrogen receptor signaling pathway negative regulation of granulocyte differentiation chromatin DNA binding response to estradiol response to retinoic acid negative regulation of interferon-gamma production negative regulation of tumor necrosis factor production positive regulation of interleukin-13 production positive regulation of interleukin-4 production positive regulation of interleukin-5 production phosphatidylinositol 3-kinase regulator activity multicellular organism growth neuronal cell body apoptotic cell clearance protein kinase B binding sequence-specific DNA binding retinoic acid-responsive element binding positive regulation of T-helper 2 cell differentiation positive regulation of cell cycle negative regulation of transcription, DNA-dependent positive regulation of transcription, DNA-dependent positive regulation of transcription, DNA-dependent positive regulation of transcription from RNA polymerase II promoter positive regulation of transcription from RNA polymerase II promoter negative regulation of translational initiation protein heterodimerization activity retinoic acid receptor signaling pathway protein kinase A binding positive regulation of binding positive regulation of protein kinase B signaling cascade ventricular cardiac muscle cell differentiation Sertoli cell fate commitment chondroblast differentiation negative regulation of cartilage development positive regulation of ERK1 and ERK2 cascade cellular response to lipopolysaccharide cellular response to retinoic acid cellular response to estrogen stimulus |
| Ontology : EGO-EBI | negative regulation of transcription from RNA polymerase II promoter nuclear chromatin ureteric bud development retinoic acid binding growth plate cartilage development sequence-specific DNA binding transcription factor activity steroid hormone receptor activity retinoic acid receptor activity transcription coactivator activity transcription coactivator activity transcription corepressor activity receptor binding protein binding nucleus nucleoplasm cytoplasm transcription initiation from RNA polymerase II promoter protein phosphorylation signal transduction germ cell development spermatogenesis transcription factor binding zinc ion binding positive regulation of cell proliferation cell surface gene expression positive regulation of phosphatidylinositol 3-kinase cascade enzyme binding protein domain specific binding dendrite intracellular estrogen receptor signaling pathway negative regulation of granulocyte differentiation chromatin DNA binding response to estradiol response to retinoic acid negative regulation of interferon-gamma production negative regulation of tumor necrosis factor production positive regulation of interleukin-13 production positive regulation of interleukin-4 production positive regulation of interleukin-5 production phosphatidylinositol 3-kinase regulator activity multicellular organism growth neuronal cell body apoptotic cell clearance protein kinase B binding sequence-specific DNA binding retinoic acid-responsive element binding positive regulation of T-helper 2 cell differentiation positive regulation of cell cycle negative regulation of transcription, DNA-dependent positive regulation of transcription, DNA-dependent positive regulation of transcription, DNA-dependent positive regulation of transcription from RNA polymerase II promoter positive regulation of transcription from RNA polymerase II promoter negative regulation of translational initiation protein heterodimerization activity retinoic acid receptor signaling pathway protein kinase A binding positive regulation of binding positive regulation of protein kinase B signaling cascade ventricular cardiac muscle cell differentiation Sertoli cell fate commitment chondroblast differentiation negative regulation of cartilage development positive regulation of ERK1 and ERK2 cascade cellular response to lipopolysaccharide cellular response to retinoic acid cellular response to estrogen stimulus |
| Pathways : BIOCARTA | Map Kinase Inactivation of SMRT Corepressor [Genes] Nuclear Receptors in Lipid Metabolism and Toxicity [Genes] Transcription Regulation by Methyltransferase of CARM1 [Genes] Degradation of the RAR and RXR by the proteasome [Genes] Regulation of transcriptional activity by PML [Genes] Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription in carcinoma cells [Genes] |
| Pathways : KEGG | Pathways in cancer Transcriptional misregulation in cancer Acute myeloid leukemia |
| REACTOME | RARA |
| Protein Interaction Database | RARA |
| Wikipedia pathways | RARA |
| Gene fusion - rearrangments | | Rearrangement : TICdb | BCOR [Xp11.4] - RARA [17q21.2] |
| Rearrangement : TICdb | FIP1L1 [4q12] - RARA [17q21.2] |
| Rearrangement : TICdb | NABP1 [2q32.3] - RARA [17q21.2] |
| Rearrangement : TICdb | NPM1 [5q35.1] - RARA [17q21.2] |
| Rearrangement : TICdb | NUMA1 [11q13.4] - RARA [17q21.2] |
| Rearrangement : TICdb | PML [15q24.1] - RARA [17q21.2] |
| Rearrangement : TICdb | PRKAR1A [17q24.2] - RARA [17q21.2] |
| Rearrangement : TICdb | RARA [17q21.2] - BCOR [Xp11.4] |
| Rearrangement : TICdb | RARA [17q21.2] - FIP1L1 [4q12] |
| Rearrangement : TICdb | RARA [17q21.2] - NABP1 [2q32.3] |
| Rearrangement : TICdb | RARA [17q21.2] - NPM1 [5q35.1] |
| Rearrangement : TICdb | RARA [17q21.2] - NUMA1 [11q13.4] |
| Rearrangement : TICdb | RARA [17q21.2] - PML [15q24.1] |
| Rearrangement : TICdb | RARA [17q21.2] - PRKAR1A [17q24.2] |
| Rearrangement : TICdb | RARA [17q21.2] - STAT5B [17q21.2] |
| Rearrangement : TICdb | RARA [17q21.2] - ZBTB16 [11q23.2] |
| Rearrangement : TICdb | STAT5B [17q21.2] - RARA [17q21.2] |
| Rearrangement : TICdb | ZBTB16 [11q23.2] - RARA [17q21.2] |
| Polymorphisms : SNP, mutations, diseases |
| SNP Single Nucleotide Polymorphism (NCBI) | RARA |
| SNP (GeneSNP Utah) | RARA |
| SNP : HGBase | RARA |
| Genetic variants : HAPMAP | RARA |
| 1000_Genomes | RARA |
| Cancer Gene: Census | RARA |
| Somatic Mutations in Cancer : COSMIC | RARA |
| CONAN: Copy Number Analysis | RARA |
| Mutations and Diseases : HGMD | RARA |
| OMIM | 180240 612376 |
| GENETests | RARA |
| Disease Genetic Association | RARA |
| Huge Navigator |
RARA [HugePedia] RARA [HugeCancerGEM] |
| Genomic Variants | RARA RARA [DGVbeta] |
| Exome Variant | RARA |
| dbVar | RARA |
| ClinVar | RARA |
| snp3D : Map Gene to Disease | 5914 |
| General knowledge |
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| Homologs : HomoloGene | RARA |
| Homology/Alignments : Family Browser (UCSC) | RARA |
| Phylogenetic Trees/Animal Genes : TreeFam | RARA |
| Chemical/Protein Interactions : CTD | 5914 |
| Chemical/Pharm GKB Gene | PA34225 |
| Clinical trial | RARA |
| Other databases | | Probes |
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| Probe | RARA (17q21) in normal cells (Bari) |
| Litterature |
| PubMed | 319 Pubmed reference(s) in Entrez |
| CoreMine | RARA |
| iHOP | RARA |
| The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. |
| de Thˆ© H, Chomienne C, Lanotte M, Degos L, Dejean A |
| Nature. 1990 ; 347 (6293) : 558-561. |
| PMID 2170850 |
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| Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. |
| Kakizuka A, Miller WH Jr, Umesono K, Warrell RP Jr, Frankel SR, Murty VV, Dmitrovsky E, Evans RM |
| Cell. 1991 ; 66 (4) : 663-674. |
| PMID 1652368 |
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| Characterization of the PML-RAR alpha chimeric product of the acute promyelocytic leukemia-specific t(15;17) translocation. |
| Nervi C, Poindexter EC, Grignani F, Pandolfi PP, Lo Coco F, Avvisati G, Pelicci PG, Jetten AM |
| Cancer research. 1992 ; 52 (13) : 3687-3692. |
| PMID 1319828 |
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| Genetics of APL and the molecular basis of retinoic acid treatment. |
| Casini T, Grignani F, Pelicci PG |
| International journal of cancer. Journal international du cancer. 1997 ; 70 (4) : 473-474. |
| PMID 9033658 |
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| The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease. |
| Grimwade D |
| British journal of haematology. 1999 ; 106 (3) : 591-613. |
| PMID 10468848 |
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| Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. |
| Melnick A, Licht JD |
| Blood. 1999 ; 93 (10) : 3167-3215. |
| PMID 10233871 |
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