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ARNT (aryl hydrocarbon receptor nuclear translocator)

Written2004-10Oliver Hankinson
UCLA Medical Center, Center for the Health Sciences, Box 951732,Los Angeles, CA 90095-1732, USA

(Note : for Links provided by Atlas : click)

Identity

Other namesHIF-1b
HGNC (Hugo) ARNT
LocusID (NCBI) 405
Atlas_Id 223
Location 1q21.3  [Link to chromosome band 1q21]
Location_base_pair Starts at 150782181 and ends at 150849244 bp from pter ( according to hg19-Feb_2009)  [Mapping ARNT.png]
 
  Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
Fusion genes
(updated 2016)
ARNT (1q21.3) / ARNT (1q21.3)ARNT (1q21.3) / CRISPLD2 (16q24.1)ARNT (1q21.3) / CTSK (1q21.3)
ARNT (1q21.3) / ETV6 (12p13.2)ARNT (1q21.3) / F5 (1q24.2)ARNT (1q21.3) / RIIAD1 (1q21.3)
ARNT (1q21.3) / RP11-126K1.2 ()COL1A1 (17q21.33) / ARNT (1q21.3)ETV6 (12p13.2) / ARNT (1q21.3)
RRNAD1 (1q23.1) / ARNT (1q21.3)

DNA/RNA

Note The gene is about 65 kb in size and has 22 exons.
Transcription Five alternative transcriptional start sites have been identified, located from 27 to 147 nucleotides 5' to the ATG translational initiation codon. There are two alternative polyadenylation sites, giving rise to transcripts of about 2,600 and 4,200 nucleotides. The 45 nucleotide exon 5 is an alternative exon and is spliced out in approximately half of the transcripts. This proportion does not seem to vary much between different tissues.No observable effects on the resulting protein due to omission of exon 5 have been noted. A transcript of about 1,300 nucleotides is observed in some breast cancers and may be due to an alternative splicing event leading to elimination of the 3' end of the transcript.
Pseudogene No pseudogenes for ARNT are known.

Protein

 
  bHLH, basic helix-loop-helix domain; PAS, Per/ARNT/Sim homology domain; A and B, the two approximately 50 amino-acid degenerative direct repeats within the PAS domain; Q-rich, glutamine-rich transactivation domain.
Description The 87 kDa protein is comprised of 789 amino acids (if exon 5 is included) or 774 amino acids (if exon 5 is excluded).
Expression ARNT is expressed ubiquitously.
Localisation ARNT is a nuclear protein in most cell types, although it may also be located in the cytosol, particularly during embryogenesis.
Function ARNT serves as the dimerization partner for a number of other bHLH-PAS proteins, whose activity is modulated either by exogenous chemicals (the aryl hydrocarbon receptor ( AHR)), or by hypoxia (hypoxia inducible factors 1,2 and 3 alpha [HIF-1a, HIF-2a and HIF-3a), or which show restricted expression (e.g. SIM-1). The AHR/ARNT dimer activates transcription of several genes involved in metabolism of foreign chemicals, including CYP1A1, CYP1B1, and NADP(H): oxidoreductase ( NQO1). Transcriptional activation of these genes depends upon prior binding of AHR to xenobiotic ligands, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and benzo(a)pyrene. The AHR/ARNT dimer and ARNT itself can also impact signaling by the eostrogen receptor. The HIF-1a (and 2a and 3a) proteins are stabilized and activated by hypoxia (and hypoglycemia) and activate transcription of several genes involved in adapting to these adverse conditions, including the genes for erythropoietin ( EPO), vascular endothelial growth factor ( VEGF), and a number of enzymes of glycolysis. Unlike the AHR/ARNT and HIF/ARNT dimers, the SIM-1/ARNT dimer is probably not conditionally regulated. The above dimers bind specific DNA sequences in the regulatory regions of the responsive genes. The half-site for ARNT is on the 3' side of the recognition sequence and is 5'-GTG-3'. The sequence of the other half of the binding site depends upon the identity of the dimerization partner. DNA binding of ARNT is mediated by its basic region. There is evidence that the PAS region may also be involved. Dimerization between ARNT and other bHLH-PAS proteins is mediated by their HLH and PAS regions. The transcriptional activation domain of ARNT is located towards its carboxy terminus. ARNT appears capable of binding the E-box sequence 5'-CACGTG-3', although the affinity of ARNT for itself appears relatively low and no genes responsive to the homodimer have been identified.

Homology Two ARNT-related genes, ARNT-2 and ARNT-3 (also called BMAL-1 or MOP3) have been identified. ARNT-2 is more restricted in expression than ARNT, but appears to dimerize with the same partner proteins as ARNT. ARNT-3 has a somewhat different dimerization potential than ARNT.

Mutations

Germinal Several polymorphisms have been identified. None has shown an association with any disease.

Implicated in

Note
Note Involved in a t(1;12)(q21;p13) translocation with EVT6 fusion in acute myeloblastic leukemia.
Disease Leukemia, Myelocytic, Acute AML-M2
Prognosis Unknown.
Hybrid/Mutated Gene Amino-terminal half of TEL fused to the complete coding sequence of ARNT except for its 8 amino-terminal amino acids. The reciprocal translocation probably contributes little if at all to the cancer phenotype.
  

Bibliography

Orientation of the heterodimeric aryl hydrocarbon (dioxin) receptor complex on its asymmetric DNA recognition sequence.
Bacsi SG, Reisz-Porszasz S, Hankinson O
Molecular pharmacology. 1995 ; 47 (3) : 432-438.
PMID 7700240
 
Recruitment of thyroid hormone receptor/retinoblastoma-interacting protein 230 by the aryl hydrocarbon receptor nuclear translocator is required for the transcriptional response to both dioxin and hypoxia.
Beischlag TV, Taylor RT, Rose DW, Yoon D, Chen Y, Lee WH, Rosenfeld MG, Hankinson O
The Journal of biological chemistry. 2004 ; 279 (52) : 54620-54628.
PMID 15485806
 
The basic helix-loop-helix-PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription.
Brunnberg S, Pettersson K, Rydin E, Matthews J, Hanberg A, Pongratz I
Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (11) : 6517-6522.
PMID 12754377
 
Cloning of a factor required for activity of the Ah (dioxin) receptor.
Hoffman EC, Reyes H, Chu FF, Sander F, Conley LH, Brooks BA, Hankinson O
Science (New York, N.Y.). 1991 ; 252 (5008) : 954-958.
PMID 1852076
 
The Ah receptor nuclear translocator gene (ARNT) is located on q21 of human chromosome 1 and on mouse chromosome 3 near Cf-3.
Johnson B, Brooks BA, Heinzmann C, Diep A, Mohandas T, Sparkes RS, Reyes H, Hoffman E, Lange E, Gatti RA
Genomics. 1993 ; 17 (3) : 592-598.
PMID 8244375
 
Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt.
Keith B, Adelman DM, Simon MC
Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (12) : 6692-6697.
PMID 11381139
 
ARNT-deficient mice and placental differentiation.
Kozak KR, Abbott B, Hankinson O
Developmental biology. 1997 ; 191 (2) : 297-305.
PMID 9398442
 
Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT.
Maltepe E, Schmidt JV, Baunoch D, Bradfield CA, Simon MC
Nature. 1997 ; 386 (6623) : 403-407.
PMID 9121557
 
Modulation of oestrogen receptor signalling by association with the activated dioxin receptor.
Ohtake F, Takeyama K, Matsumoto T, Kitagawa H, Yamamoto Y, Nohara K, Tohyama C, Krust A, Mimura J, Chambon P, Yanagisawa J, Fujii-Kuriyama Y, Kato S
Nature. 2003 ; 423 (6939) : 545-550.
PMID 12774124
 
Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT).
Reisz-Porszasz S, Probst MR, Fukunaga BN, Hankinson O
Molecular and cellular biology. 1994 ; 14 (9) : 6075-6086.
PMID 8065341
 
Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor.
Reyes H, Reisz-Porszasz S, Hankinson O
Science (New York, N.Y.). 1992 ; 256 (5060) : 1193-1195.
PMID 1317062
 
The t(1;12)(q21;p13) translocation of human acute myeloblastic leukemia results in a TEL-ARNT fusion.
Salomon-Nguyen F, Della-Valle V, Mauchauffe M, Busson-Le Coniat M, Ghysdael J, Berger R, Bernard OA
Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (12) : 6757-6762.
PMID 10829078
 
Variability of the human aryl hydrocarbon receptor nuclear translocator (ARNT) gene.
Scheel J, Hussong R, Schrenk D, Schmitz HJ
Journal of human genetics. 2002 ; 47 (5) : 217-224.
PMID 12032587
 
Genomic structure of the human Ah receptor nuclear translocator gene (hARNT).
Scheel J, Schrenk D
Human genetics. 2000 ; 107 (4) : 397-399.
PMID 11129342
 
A mutation in the aryl hydrocarbon receptor (AHR) in a cultured mammalian cell line identifies a novel region of AHR that affects DNA binding.
Sun W, Zhang J, Hankinson O
The Journal of biological chemistry. 1997 ; 272 (50) : 31845-31854.
PMID 9395531
 
DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins.
Swanson HI, Chan WK, Bradfield CA
The Journal of biological chemistry. 1995 ; 270 (44) : 26292-26302.
PMID 7592839
 
Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function.
Takagi S, Tojo H, Tomita S, Sano S, Itami S, Hara M, Inoue S, Horie K, Kondoh G, Hosokawa K, Gonzalez FJ, Takeda J
The Journal of clinical investigation. 2003 ; 112 (9) : 1372-1382.
PMID 14597763
 
The aryl hydrocarbon receptor nuclear transporter is modulated by the SUMO-1 conjugation system.
Tojo M, Matsuzaki K, Minami T, Honda Y, Yasuda H, Chiba T, Saya H, Fujii-Kuriyama Y, Nakao M
The Journal of biological chemistry. 2002 ; 277 (48) : 46576-46585.
PMID 12354770
 
Patent ductus venosus and dioxin resistance in mice harboring a hypomorphic Arnt allele.
Walisser JA, Bunger MK, Glover E, Harstad EB, Bradfield CA
The Journal of biological chemistry. 2004 ; 279 (16) : 16326-16331.
PMID 14764592
 
Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.
Wang GL, Jiang BH, Rue EA, Semenza GL
Proceedings of the National Academy of Sciences of the United States of America. 1995 ; 92 (12) : 5510-5514.
PMID 7539918
 
Aryl hydrocarbon (Ah) nonresponsiveness in estrogen receptor-negative MDA-MB-231 cells is associated with expression of a variant arnt protein.
Wilson CL, Thomsen J, Hoivik DJ, Wormke MT, Stanker L, Holtzapple C, Safe SH
Archives of biochemistry and biophysics. 1997 ; 346 (1) : 65-73.
PMID 9328285
 
The role of the aryl hydrocarbon receptor nuclear translocator (ARNT) in hypoxic induction of gene expression. Studies in ARNT-deficient cells.
Wood SM, Gleadle JM, Pugh CW, Hankinson O, Ratcliffe PJ
The Journal of biological chemistry. 1996 ; 271 (25) : 15117-15123.
PMID 8662957
 

Citation

This paper should be referenced as such :
Hankinson, O
ARNT (aryl hydrocarbon receptor nuclear translocator)
Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):305-307.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/ARNTID223ch1q21.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 2 ]
  t(1;12)(q21;p13) ETV6/ARNT
der(12)t(1;12)(q11-21;p11-13)

External links

Nomenclature
HGNC (Hugo)ARNT   700
Cards
AtlasARNTID223ch1q21
Entrez_Gene (NCBI)ARNT  405  aryl hydrocarbon receptor nuclear translocator
AliasesHIF-1-beta; HIF-1beta; HIF1-beta; HIF1B; 
HIF1BETA; TANGO; bHLHe2
GeneCards (Weizmann)ARNT
Ensembl hg19 (Hinxton)ENSG00000143437 [Gene_View]  chr1:150782181-150849244 [Contig_View]  ARNT [Vega]
Ensembl hg38 (Hinxton)ENSG00000143437 [Gene_View]  chr1:150782181-150849244 [Contig_View]  ARNT [Vega]
ICGC DataPortalENSG00000143437
TCGA cBioPortalARNT
AceView (NCBI)ARNT
Genatlas (Paris)ARNT
WikiGenes405
SOURCE (Princeton)ARNT
Genomic and cartography
GoldenPath hg19 (UCSC)ARNT  -     chr1:150782181-150849244 -  1q21   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)ARNT  -     1q21   [Description]    (hg38-Dec_2013)
EnsemblARNT - 1q21 [CytoView hg19]  ARNT - 1q21 [CytoView hg38]
Mapping of homologs : NCBIARNT [Mapview hg19]  ARNT [Mapview hg38]
OMIM126110   
Gene and transcription
Genbank (Entrez)AB209877 AF001307 AK223459 AK290177 AK291705
RefSeq transcript (Entrez)NM_001197325 NM_001286035 NM_001286036 NM_001668 NM_178426 NM_178427
RefSeq genomic (Entrez)NC_000001 NC_018912 NG_028248 NT_004487 NW_004929293
Consensus coding sequences : CCDS (NCBI)ARNT
Cluster EST : UnigeneHs.632446 [ NCBI ]
CGAP (NCI)Hs.632446
Alternative Splicing GalleryENSG00000143437
Gene ExpressionARNT [ NCBI-GEO ]   ARNT [ EBI - ARRAY_EXPRESS ]   ARNT [ SEEK ]   ARNT [ MEM ]
Gene Expression Viewer (FireBrowse)ARNT [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)405
GTEX Portal (Tissue expression)ARNT
Protein : pattern, domain, 3D structure
UniProt/SwissProtP27540 (Uniprot)
NextProtP27540  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP27540
Splice isoforms : SwissVarP27540 (Swissvar)
PhosPhoSitePlusP27540
Domaine pattern : Prosite (Expaxy)BHLH (PS50888)    PAS (PS50112)   
Domains : Interpro (EBI)bHLH_dom    Nuc_translocat    PAC    PAS    PAS_fold   
Domain families : Pfam (Sanger)HLH (PF00010)    PAS (PF00989)   
Domain families : Pfam (NCBI)pfam00010    pfam00989   
Domain families : Smart (EMBL)HLH (SM00353)  PAC (SM00086)  PAS (SM00091)  
DMDM Disease mutations405
Blocks (Seattle)ARNT
PDB (SRS)1D7G    1X0O    2A24    2ARN    2B02    2HV1    2K7S    3F1N    3F1O    3F1P    3H7W    3H82    4EQ1    4GHI    4GS9    4H6J    4LPZ    4PKY    4XT2   
PDB (PDBSum)1D7G    1X0O    2A24    2ARN    2B02    2HV1    2K7S    3F1N    3F1O    3F1P    3H7W    3H82    4EQ1    4GHI    4GS9    4H6J    4LPZ    4PKY    4XT2   
PDB (IMB)1D7G    1X0O    2A24    2ARN    2B02    2HV1    2K7S    3F1N    3F1O    3F1P    3H7W    3H82    4EQ1    4GHI    4GS9    4H6J    4LPZ    4PKY    4XT2   
PDB (RSDB)1D7G    1X0O    2A24    2ARN    2B02    2HV1    2K7S    3F1N    3F1O    3F1P    3H7W    3H82    4EQ1    4GHI    4GS9    4H6J    4LPZ    4PKY    4XT2   
Structural Biology KnowledgeBase1D7G    1X0O    2A24    2ARN    2B02    2HV1    2K7S    3F1N    3F1O    3F1P    3H7W    3H82    4EQ1    4GHI    4GS9    4H6J    4LPZ    4PKY    4XT2   
SCOP (Structural Classification of Proteins)1D7G    1X0O    2A24    2ARN    2B02    2HV1    2K7S    3F1N    3F1O    3F1P    3H7W    3H82    4EQ1    4GHI    4GS9    4H6J    4LPZ    4PKY    4XT2   
CATH (Classification of proteins structures)1D7G    1X0O    2A24    2ARN    2B02    2HV1    2K7S    3F1N    3F1O    3F1P    3H7W    3H82    4EQ1    4GHI    4GS9    4H6J    4LPZ    4PKY    4XT2   
SuperfamilyP27540
Human Protein AtlasENSG00000143437
Peptide AtlasP27540
HPRD00524
IPIIPI00514749   IPI00218287   IPI00922490   IPI00910290   IPI00964540   IPI00965109   IPI00968237   
Protein Interaction databases
DIP (DOE-UCLA)P27540
IntAct (EBI)P27540
FunCoupENSG00000143437
BioGRIDARNT
STRING (EMBL)ARNT
ZODIACARNT
Ontologies - Pathways
QuickGOP27540
Ontology : AmiGOresponse to hypoxia  embryonic placenta development  positive regulation of endothelial cell proliferation  transcription factor activity, sequence-specific DNA binding  transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding  transcription coactivator activity  aryl hydrocarbon receptor activity  protein binding  nucleus  nucleoplasm  cytoplasm  transcription, DNA-templated  transcription factor binding  positive regulation of vascular endothelial growth factor production  aryl hydrocarbon receptor binding  cell differentiation  intracellular receptor signaling pathway  positive regulation of vascular endothelial growth factor receptor signaling pathway  positive regulation of protein sumoylation  enhancer binding  mRNA transcription from RNA polymerase II promoter  sequence-specific DNA binding  regulation of transcription from RNA polymerase II promoter in response to oxidative stress  positive regulation of erythrocyte differentiation  positive regulation of glycolytic process  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of hormone biosynthetic process  protein heterodimerization activity  regulation of transcription from RNA polymerase II promoter in response to hypoxia  RNA polymerase II transcription factor complex  
Ontology : EGO-EBIresponse to hypoxia  embryonic placenta development  positive regulation of endothelial cell proliferation  transcription factor activity, sequence-specific DNA binding  transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding  transcription coactivator activity  aryl hydrocarbon receptor activity  protein binding  nucleus  nucleoplasm  cytoplasm  transcription, DNA-templated  transcription factor binding  positive regulation of vascular endothelial growth factor production  aryl hydrocarbon receptor binding  cell differentiation  intracellular receptor signaling pathway  positive regulation of vascular endothelial growth factor receptor signaling pathway  positive regulation of protein sumoylation  enhancer binding  mRNA transcription from RNA polymerase II promoter  sequence-specific DNA binding  regulation of transcription from RNA polymerase II promoter in response to oxidative stress  positive regulation of erythrocyte differentiation  positive regulation of glycolytic process  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of hormone biosynthetic process  protein heterodimerization activity  regulation of transcription from RNA polymerase II promoter in response to hypoxia  RNA polymerase II transcription factor complex  
Pathways : BIOCARTAHypoxia-Inducible Factor in the Cardiovascular System [Genes]    Erythropoietin mediated neuroprotection through NF-kB [Genes]    VEGF, Hypoxia, and Angiogenesis [Genes]    Ahr Signal Transduction Pathway [Genes]   
Pathways : KEGGHIF-1 signaling pathway    Pathways in cancer    Chemical carcinogenesis    Renal cell carcinoma   
REACTOMEP27540 [protein]
REACTOME PathwaysR-HSA-1234158 Regulation of gene expression by Hypoxia-inducible Factor [pathway]
NDEx NetworkARNT
Atlas of Cancer Signalling NetworkARNT
Wikipedia pathwaysARNT
Orthology - Evolution
OrthoDB405
GeneTree (enSembl)ENSG00000143437
Phylogenetic Trees/Animal Genes : TreeFamARNT
Homologs : HomoloGeneARNT
Homology/Alignments : Family Browser (UCSC)ARNT
Gene fusions - Rearrangements
Fusion : MitelmanARNT/F5 [1q21.3/1q24.2]  
Fusion : MitelmanARNT/RIIAD1 [1q21.3/1q21.3]  [t(1;1)(q21;q21)]  
Fusion : MitelmanETV6/ARNT [12p13.2/1q21.3]  [t(1;12)(q21;p13)]  
Fusion : MitelmanRRNAD1/ARNT [1q23.1/1q21.3]  [t(1;1)(q21;q23)]  
Fusion: TCGAARNT 1q21.3 F5 1q24.2 LUAD
Fusion: TCGAARNT 1q21.3 RIIAD1 1q21.3 LUAD
Fusion: TCGAARNT 1q21.3 RP11-126K1.2 PRAD
Fusion: TCGARRNAD1 1q23.1 ARNT 1q21.3 BRCA
Fusion : TICdbETV6 [12p13.2]  -  ARNT [1q21.3]
Polymorphisms : SNP, variants
NCBI Variation ViewerARNT [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ARNT
dbVarARNT
ClinVarARNT
1000_GenomesARNT 
Exome Variant ServerARNT
ExAC (Exome Aggregation Consortium)ARNT (select the gene name)
Genetic variants : HAPMAP405
Genomic Variants (DGV)ARNT [DGVbeta]
Mutations
ICGC Data PortalARNT 
TCGA Data PortalARNT 
Broad Tumor PortalARNT
OASIS PortalARNT [ Somatic mutations - Copy number]
Cancer Gene: CensusARNT 
Somatic Mutations in Cancer : COSMICARNT 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch ARNT
DgiDB (Drug Gene Interaction Database)ARNT
DoCM (Curated mutations)ARNT (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ARNT (select a term)
intoGenARNT
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)1:150782181-150849244  ENSG00000143437
CONAN: Copy Number AnalysisARNT 
Mutations and Diseases : HGMDARNT
OMIM126110   
MedgenARNT
Genetic Testing Registry ARNT
NextProtP27540 [Medical]
TSGene405
GENETestsARNT
Huge Navigator ARNT [HugePedia]
snp3D : Map Gene to Disease405
BioCentury BCIQARNT
ClinGenARNT
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD405
Chemical/Pharm GKB GenePA24994
Clinical trialARNT
Miscellaneous
canSAR (ICR)ARNT (select the gene name)
Probes
Litterature
PubMed162 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineARNT
EVEXARNT
GoPubMedARNT
iHOPARNT
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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