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RARA (Retinoic acid receptor, alpha)

Identity

HGNC (Hugo) RARA
LocusID (NCBI) 5914
Location 17q21.2
Location_base_pair Starts at 38465423 and ends at 38513895 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
  c-RARA (17q21) in normal cells: PAC 833D9 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

DNA/RNA

Description 9 exons; total gene sequence: 7450 bp
Transcription 2.8 and 3.6 kb transcripts

Protein

 
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

    Implicated in

    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)
      
    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.
      
    Entity t(5;17)(q35;q12) / acute promyelocytic leukemia --> NPM-RARA
    Disease exceptional; probable response to ATRA
      
    Entity t(11;17)(q13;q12) / acute promyelocytic leukemia --> NuMA-RARA
    Disease exceptional: probable response to ATRA
      
    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
      

    Breakpoints

     

    Other Leukemias implicated (Data extracted from papers in the Atlas)

    Leukemias t0817q24q22ID1494 t1119q23p13ID1540 t614p25q32IRF4IGHID1175 t1213p13q14ID1323 t1117q23q12AF17ID1027
    t1117p15p13ID2134 t1114ID1070 dic920ID1143 dic0709p11p12ID1554 i17qID1038
    t0109p34q34ID2143 t0109q24q34ID2109 t0112ID1147 t0411q35q23ID1423 t0422q12q11ID1153

    External links

    Nomenclature
    HGNC (Hugo)RARA   9864
    Cards
    AtlasRARAID46
    Entrez_Gene (NCBI)RARA  5914  retinoic acid receptor, alpha
    GeneCards (Weizmann)RARA
    Ensembl (Hinxton) [Gene_View]  chr17:38465423-38513895 [Contig_View]  RARA [Vega]
    cBioPortalRARA
    AceView (NCBI)RARA
    Genatlas (Paris)RARA
    WikiGenes5914
    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)
    EnsemblRARA - 17q21 [CytoView]
    Mapping of homologs : NCBIRARA [Mapview]
    OMIM180240   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 : UnigeneHs.654583 [ NCBI ]
    CGAP (NCI)Hs.654583
    Alternative Splicing : Fast-db (Paris)GSHG0012478
    Gene ExpressionRARA [ NCBI-GEO ]     RARA [ SEEK ]   RARA [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP10276 (Uniprot)
    NextProtP10276  [Medical]
    With graphics : InterProP10276
    Splice isoforms : SwissVarP10276 (Swissvar)
    Domaine pattern : Prosite (Expaxy)NUCLEAR_REC_DBD_1 (PS00031)    NUCLEAR_REC_DBD_2 (PS51030)   
    Domains : Interpro (EBI)Nucl_hormone_rcpt_ligand-bd [organisation]   Nucl_hrmn_rcpt_lig-bd_core [organisation]   Retinoic_acid_rcpt [organisation]   Str_hrmn_rcpt [organisation]   Znf_hrmn_rcpt [organisation]   Znf_NHR/GATA [organisation]  
    Related proteins : CluSTrP10276
    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 mutations5914
    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 AtlasP10276
    HPRD06769
    IPIIPI00020071   IPI00218375   IPI00908598   IPI00470378   IPI00922641   IPI00014923   IPI00791851   
    Protein Interaction databases
    DIP (DOE-UCLA)P10276
    IntAct (EBI)P10276
    BioGRIDRARA
    InParanoidP10276
    Interologous Interaction database P10276
    IntegromeDBRARA
    STRING (EMBL)RARA
    Ontologies - Pathways
    Ontology : AmiGOnegative 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-EBInegative 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 : BIOCARTAMap 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 : KEGGPathways in cancer    Transcriptional misregulation in cancer    Acute myeloid leukemia   
    Protein Interaction DatabaseRARA
    Wikipedia pathwaysRARA
    Gene fusion - rearrangments
    Rearrangement : TICdbBCOR [Xp11.4]  -  RARA [5q32]
    Rearrangement : TICdbFIP1L1 [4q12]  -  RARA [8q22.2]
    Rearrangement : TICdbNABP1 [2q32.3]  -  RARA [7p15.2]
    Rearrangement : TICdbNPM1 [5q35.1]  -  RARA [3q12.2]
    Rearrangement : TICdbNUMA1 [11q13.4]  -  RARA [1q24.2]
    Rearrangement : TICdbPML [15q24.1]  -  RARA [8q21.3]
    Rearrangement : TICdbPRKAR1A [17q24.2]  -  RARA [1p35.3]
    Rearrangement : TICdbSTAT5B [17q21.2]  -  RARA [-]
    Rearrangement : TICdbZBTB16 [11q23.2]  -  RARA []
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)RARA
    snp3D : Map Gene to Disease5914
    SNP (GeneSNP Utah)RARA
    SNP : HGBaseRARA
    Genetic variants : HAPMAPRARA
    Exome VariantRARA
    1000_GenomesRARA 
    Cancer Gene: CensusRARA 
    Somatic Mutations in Cancer : COSMICRARA 
    CONAN: Copy Number AnalysisRARA 
    Mutations and Diseases : HGMDRARA
    Genomic VariantsRARA  RARA [DGVbeta]
    dbVarRARA
    ClinVarRARA
    Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
    Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
    Diseases
    OMIM180240    612376   
    MedgenRARA
    GENETestsRARA
    Disease Genetic AssociationRARA
    Huge Navigator RARA [HugePedia]  RARA [HugeCancerGEM]
    General knowledge
    Homologs : HomoloGeneRARA
    Homology/Alignments : Family Browser (UCSC)RARA
    Phylogenetic Trees/Animal Genes : TreeFamRARA
    Chemical/Protein Interactions : CTD5914
    Chemical/Pharm GKB GenePA34225
    Clinical trialRARA
    Other databases
    Probes
    ProbeRARA (17q21) in normal cells (Bari)
    Litterature
    PubMed319 Pubmed reference(s) in Entrez
    CoreMineRARA
    iHOPRARA

    Bibliography

    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
     
    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
     
    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
     
    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
     
    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
     
    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
     
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    Contributor(s)

    Written10-2000Franck Viguié

    Citation

    This paper should be referenced as such :
    Viguié, F
    RARA (retinoic acid receptor, alpha)
    Atlas Genet Cytogenet Oncol Haematol. 2000;4(4):195-196.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Genes/RARAID46.html

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    indexed on : Fri Jul 11 17:13:34 CEST 2014
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