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SEL1L (sel-1 suppressor of lin-12-like (C. elegans))

Written2005-10Ida Biunno, Monica Cattaneo
Istituto Tecnologie Biomediche,V. Fratelli Cervi, 93, 20090 Segrate (MI), Italy

(Note : for Links provided by Atlas : click)

Identity

Alias_namessel-1 suppressor of lin-12-like (C. elegans)
Alias_symbol (synonym)IBD2
SEL1L1
Other aliasIBD2;
SEL1-like
HGNC (Hugo) SEL1L
LocusID (NCBI) 6400
Atlas_Id 42246
Location 14q31.1  [Link to chromosome band 14q31]
Location_base_pair Starts at 81965154 and ends at 82000205 bp from pter ( according to hg19-Feb_2009)  [Mapping SEL1L.png]
Local_order SEL1L is located within a "Gene Desert area" or "Genome Deserts"; centromeric to FLRT2 (fibronectin leucine rich transmembrane protein 2) and telomeric to GTF2A1 (general transcription factor IIA) and TSHR (thyroid stimulating hormone receptor)
Fusion genes
(updated 2016)
RAP1A (1p13.2) / SEL1L (14q31.1)SEL1L (14q31.1) / SEL1L (14q31.1)SEL1L (14q31.1) / SERTAD2 (2p14)
Note SEL1L is the human ortholog of the C.Elegans sel-1 (suppressor enhancer of lin-12) gene. It shows a high degree of cross-species conservation in its nucleotide and protein sequence.

DNA/RNA

 
  A graphical representation of SEL1L isorforms. The black numbered rectangles correspond to the exons, while the white rectangles correspond to the intronic sequence which is retained in the alternative isoforms. The SEL1L domains are indicated on the top of the isoforms. (FN2=fibronectin type II domain;I, II and III clusters of SEL-1 like repeats; Hrd3; TM=transmembrane; P= proline rich domain)
Description SEL1L genomic size is of 62,24 Kb localized from 81069886 to 81007646. 3' the first exon lies the basal core of the promter, a TATA-less promoter containing four SP1 binding sites and a CAAT box. A CpG island is located between -550bp and the start codon. SEL1L promoter is highly active in pancreatic beta and embryonic kidney cells. The C-terminal tail consists of over 5,0Kb untranslated sequences likely containing key regulatory elements.
Transcription The sequence is composed of 21 exons and produces at least five different alternative transcripts(A-E) which originate from alternative splicing and putative promoter usage. Exons 1-6 are common to forms A-B-C-E.
Pseudogene No known pseudogens

Protein

Note SEL1L is a multimodular protein consisting of several domains and signal sequences that confer the multifaceted specificities to the molecule
 
  SEL1L protein structure: SEL1L is a multimodular protein containing several structural and functional domains as well as signal sequences. The signal peptide (from 1 to 22 amino acid residues) and the Pest sequence (from 80 to 102 amino acid residues) are represented by red and pink rectangles. The fibronectin type II domain (from 120 to 168 residues) is symbolized by the hexagon (FNII), the SEL-1-like repeats are represented by rhombi and are distributed in tandem along the central portion of the protein in three large clusters (I cluster: 183-326; II cluster: 373-554 and III cluster: 664-675 residues). The Hrd3 like motif is located within the last SEL-1-like repeat (664-675 residues) and is represented by an circle. The transmembrane region (TM) (739-761 residues) and the proline-rich tail (770-793 residues) are symbolized by a blue rectangle. The N-linked glycosilation is also underlined.
Description SEL1L is not a member of a vast family of proteins but the several described isoforms (over 4) give the appearance of belonging to a multifamily of molecules having perhaps redundant functions.
Expression Ubiquitously expressed only in fetal and neoplastic tissues. In normal adult tissues is highly expressed in the acini and in the alpha cells of the pancreas; in general is highly represented in secretory cells such as plasma cells.
Localisation SEL1L protein can have a nuclear, cytoplasmic and nuclear-cytoplasmic location
Function
  • May have a role in the ER-associated protein degradation (ERAD) system (similarity with Hrd3).
  • Negative regulator of the NOTCH pathway in C. Elegans.
  • May play a role in TGF beta signalling.
  • In breast and pancreatic tumor decrease tumor growth and aggressiveness, possibly involving cell-matrix interaction
  • Homology Comparative sequence analysis across different regna, including metazoa, fungi, viridiplantae and bacteria, revealed the remarkable conservation of its primary sequence, although the gene structural complexity increased in evolution. Among mammals, SEL1L shares strict amino acid identity with chimpanzee (99%), dog (97%), hamster (92%), mouse (93%) and rat (92%). It also shows a good similarity with the model organisms such as xenopus (82%), chicken (83%), zebrafish (73%), Drosophila melanogaster (51%) and C. elegans (46%) (Table 1). Arabidopsis thaliana and Saccharomyces cerevisiae display lower similarity (34% and 28%, respectively).

    Mutations

    Note Neither causative nor functional mutations were found except for the presence of two base substitutions in the minimal promoter region in two well differentiated lung adenocarcinoma that led to a significant increase in the transcription. A polymorphic base substitution was reported in the fibronectin type II domain of the gene in children affected by persistent hyperinsulinemic hypoglycemia (insulinoma) of infancy which induces a major change in the amino acid composition.

    Implicated in

    Note
      
    Entity Considering the overall results published on SEL1L by various investigators working in different organisms, it can, perhaps, safely be deduced that this gene plays a fundamental role in eukaryotic intracellular protein degradation processes. Protein degradation is becoming a central theme in cancer biology and recently therapeutic approaches that use inhibitors of proteins belonging to ubiquitin-proteosoma pathway have been developed in solid tumors and haematological diseases. A survey of the expression of SEL1L mRNA as well as its encoded protein on a series of cancerous and pre-neoplastic lesion, revealed the role of SEL1L in cancer progression. Furthermore, its expression in breast cancer correlated with patient's survival. In vitro studies indicated that SEL1L protein affects those pathways which regulate signalling (cell-cell and or cell-matrix) interactions. Available data derived from several organisms indicate that it may function in the protein degradation processes through ubiquitin-proteosome system and perhaps in regulating important pathways such as Notch and TGF-beta. The fundamental question raised by the observation that SEL1L gets up-modulated during the early steps of tumor transformation is of paramount importance for early diagnosis. Currently it is only possible to hypothesize that the increased SEL1L levels are required in order to meet the advent of genetic and/or genomic structural alterations acquired during cancer initiation or to influence intra-cellular signalling. Its presence may be important in protecting cellular homeostasis from genetic mutations.
      

    Bibliography

    Promoter selection for the cytosine deaminase suicide gene constructs in gastric cancer.
    Aberle S, Schug N, Mathlouthi R, Seitz G, Küpper JH, Schröder K, Blin N
    European journal of gastroenterology & hepatology. 2004 ; 16 (1) : 63-67.
    PMID 15095854
     
    SEL1L microsatellite polymorphism in Japanese patients with autoimmune thyroid diseases.
    Ban Y, Taniyama M, Tozaki T, Yanagawa T, Tomita M, Ban Y
    Thyroid : official journal of the American Thyroid Association. 2001 ; 11 (4) : 335-338.
    PMID 11349831
     
    Protein profile changes in the human breast cancer cell line MCF-7 in response to SEL1L gene induction.
    Bianchi L, Canton C, Bini L, Orlandi R, Ménard S, Armini A, Cattaneo M, Pallini V, Bernardi LR, Biunno I
    Proteomics. 2005 ; 5 (9) : 2433-2442.
    PMID 15880780
     
    Isolation of a pancreas-specific gene located on human chromosome 14q31: expression analysis in human pancreatic ductal carcinomas.
    Biunno I, Appierto V, Cattaneo M, Leone BE, Balzano G, Socci C, Saccone S, Letizia A, Della Valle G, Sgaramella V
    Genomics. 1997 ; 46 (2) : 284-286.
    PMID 9417916
     
    SEL1L, the human homolog of C. elegans sel-1: refined physical mapping, gene structure and identification of polymorphic markers.
    Biunno I, Bernard L, Dear P, Cattaneo M, Volorio S, Zannini L, Bankier A, Zollo M
    Human genetics. 2000 ; 106 (2) : 227-235.
    PMID 10746565
     
    Cross-species conservation of SEL1L, a human pancreas-specific expressing gene.
    Biunno I, Castiglioni B, Rogozin IB, DeBellis G, Malferrari G, Cattaneo M
    Omics : a journal of integrative biology. 2002 ; 6 (2) : 187-198.
    PMID 12143964
     
    Identification of a region within SEL1L protein required for tumour growth inhibition.
    Cattaneo M, Canton C, Albertini A, Biunno I
    Gene. 2004 ; 326 : 149-156.
    PMID 14729273
     
    Allele frequency of two intragenic microsatellite loci of SEL1L gene in Northern Italian population.
    Chiaramonte R, Sabbadini M, Balordi F, Comi P, Sherbet GV
    Molecular and cellular biochemistry. 2002 ; 232 (1-2) : 159-161.
    PMID 12030374
     
    RNA-mediated interference indicates that SEL1L plays a role in pancreatic beta-cell growth.
    Diaferia G, Cattaneo M, Saltini G, Proverbio MC, Monferini E, Malferrari G, Albertini A, Biunno I
    DNA and cell biology. 2004 ; 23 (8) : 510-518.
    PMID 15307954
     
    SEL-1L maps to human chromosome 14, near the insulin-dependent diabetes mellitus locus 11.
    Donoviel DB, Bernstein A
    Genomics. 1999 ; 56 (2) : 232-233.
    PMID 10051412
     
    SEL1L and squamous cell carcinoma of the esophagus.
    Granelli P, Cattaneo M, Ferrero S, Bottiglieri L, Bosari S, Fichera G, Biunno I
    Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 ; 10 (17) : 5857-5861.
    PMID 15355917
     
    Complete cDNA sequence and genomic organization of a human pancreas-specific gene homologous to Caenorhabditis elegans sel-1.
    Harada Y, Ozaki K, Suzuki M, Fujiwara T, Takahashi E, Nakamura Y, Tanigami A
    Journal of human genetics. 1999 ; 44 (5) : 330-336.
    PMID 10496078
     
    ER signaling in unfolded protein response.
    Kaneko M, Nomura Y
    Life sciences. 2003 ; 74 (2-3) : 199-205.
    PMID 14607247
     
    Genetic modifiers of the age at diagnosis of diabetes (MODY3) in carriers of hepatocyte nuclear factor-1alpha mutations map to chromosomes 5p15, 9q22, and 14q24.
    Kim SH, Ma X, Klupa T, Powers C, Pezzolesi M, Warram JH, Rich SS, Krolewski AS, Doria A
    Diabetes. 2003 ; 52 (8) : 2182-2186.
    PMID 12882939
     
    Complete mutation scanning of the human SEL 1L gene: a candidate gene for type 1 diabetes.
    Larsen ZM, Angelo AD, Cattaneo M, Nerup J, Biunno I, Zollo M, Pociot F
    Acta diabetologica. 2001 ; 38 (4) : 191-192.
    PMID 11855798
     
    Assessing optimal promoter activity for constructs in gastrointestinal gene therapy.
    Mathlouthi R, Aberle S, Schug N, Küpper JH, Schröder K, Seitz G, Blin N
    Anticancer research. 2003 ; 23 (5A) : 4011-4015.
    PMID 14666711
     
    SEL1L expression decreases breast tumor cell aggressiveness in vivo and in vitro.
    Orlandi R, Cattaneo M, Troglio F, Casalini P, Ronchini C, Ménard S, Biunno I
    Cancer research. 2002 ; 62 (2) : 567-574.
    PMID 11809711
     
    Identification of a novel polymorphism in the fibronectin type II domain of the SEL1L gene and possible relation to the persistent hyperinsulinemic hypoglycemia of infancy.
    Saltini G, Proverbio MC, Malferrari G, Biagiotti L, Boettcher P, Dominici R, Monferini E, Lorenzini E, Cattaneo M, Antonello D, Moore PS, Zamproni I, Viscardi M, Chiumello G, Biunno I
    Mutation research. 2004 ; 554 (1-2) : 159-163.
    PMID 15450414
     

    Citation

    This paper should be referenced as such :
    Biunno, I ; Cattaneo, M. SEL1L (sel-1 suppressor of lin-12-like (C
    elegans))
    Atlas Genet Cytogenet Oncol Haematol. 2006;10(2):93-96.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/SEL1LID42246ch14q24.html


    External links

    Nomenclature
    HGNC (Hugo)SEL1L   10717
    Cards
    AtlasSEL1LID42246ch14q24
    Entrez_Gene (NCBI)SEL1L  6400  SEL1L ERAD E3 ligase adaptor subunit
    AliasesPRO1063; SEL1-LIKE; SEL1L1
    GeneCards (Weizmann)SEL1L
    Ensembl hg19 (Hinxton)ENSG00000071537 [Gene_View]  chr14:81965154-82000205 [Contig_View]  SEL1L [Vega]
    Ensembl hg38 (Hinxton)ENSG00000071537 [Gene_View]  chr14:81965154-82000205 [Contig_View]  SEL1L [Vega]
    ICGC DataPortalENSG00000071537
    TCGA cBioPortalSEL1L
    AceView (NCBI)SEL1L
    Genatlas (Paris)SEL1L
    WikiGenes6400
    SOURCE (Princeton)SEL1L
    Genetics Home Reference (NIH)SEL1L
    Genomic and cartography
    GoldenPath hg19 (UCSC)SEL1L  -     chr14:81965154-82000205 -  14q31   [Description]    (hg19-Feb_2009)
    GoldenPath hg38 (UCSC)SEL1L  -     14q31   [Description]    (hg38-Dec_2013)
    EnsemblSEL1L - 14q31 [CytoView hg19]  SEL1L - 14q31 [CytoView hg38]
    Mapping of homologs : NCBISEL1L [Mapview hg19]  SEL1L [Mapview hg38]
    OMIM602329   
    Gene and transcription
    Genbank (Entrez)AB020335 AF052059 AK075511 AY358651 BC040498
    RefSeq transcript (Entrez)NM_001244984 NM_005065
    RefSeq genomic (Entrez)NC_000014 NC_018925 NG_030335 NT_026437 NW_004929393
    Consensus coding sequences : CCDS (NCBI)SEL1L
    Cluster EST : UnigeneHs.181300 [ NCBI ]
    CGAP (NCI)Hs.181300
    Alternative Splicing GalleryENSG00000071537
    Gene ExpressionSEL1L [ NCBI-GEO ]   SEL1L [ EBI - ARRAY_EXPRESS ]   SEL1L [ SEEK ]   SEL1L [ MEM ]
    Gene Expression Viewer (FireBrowse)SEL1L [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)6400
    GTEX Portal (Tissue expression)SEL1L
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ9UBV2   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtQ9UBV2  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProQ9UBV2
    Splice isoforms : SwissVarQ9UBV2
    PhosPhoSitePlusQ9UBV2
    Domaine pattern : Prosite (Expaxy)FN2_1 (PS00023)    FN2_2 (PS51092)   
    Domains : Interpro (EBI)FN_type2_col-bd    Kringle-like    Sel1-like    TPR-like_helical_dom   
    Domain families : Pfam (Sanger)fn2 (PF00040)    Sel1 (PF08238)   
    Domain families : Pfam (NCBI)pfam00040    pfam08238   
    Domain families : Smart (EMBL)FN2 (SM00059)  SEL1 (SM00671)  
    Conserved Domain (NCBI)SEL1L
    DMDM Disease mutations6400
    Blocks (Seattle)SEL1L
    SuperfamilyQ9UBV2
    Human Protein AtlasENSG00000071537
    Peptide AtlasQ9UBV2
    HPRD07532
    IPIIPI00002790   IPI00555723   IPI00382747   IPI01026453   
    Protein Interaction databases
    DIP (DOE-UCLA)Q9UBV2
    IntAct (EBI)Q9UBV2
    FunCoupENSG00000071537
    BioGRIDSEL1L
    STRING (EMBL)SEL1L
    ZODIACSEL1L
    Ontologies - Pathways
    QuickGOQ9UBV2
    Ontology : AmiGOHrd1p ubiquitin ligase complex  protein binding  endoplasmic reticulum membrane  Notch signaling pathway  integral component of membrane  ER-associated ubiquitin-dependent protein catabolic process  retrograde protein transport, ER to cytosol  ERAD pathway  Derlin-1 retrotranslocation complex  endoplasmic reticulum quality control compartment  protein stabilization  endoplasmic reticulum mannose trimming  
    Ontology : EGO-EBIHrd1p ubiquitin ligase complex  protein binding  endoplasmic reticulum membrane  Notch signaling pathway  integral component of membrane  ER-associated ubiquitin-dependent protein catabolic process  retrograde protein transport, ER to cytosol  ERAD pathway  Derlin-1 retrotranslocation complex  endoplasmic reticulum quality control compartment  protein stabilization  endoplasmic reticulum mannose trimming  
    Pathways : KEGGProtein processing in endoplasmic reticulum   
    REACTOMEQ9UBV2 [protein]
    REACTOME Pathways1912420 [pathway]   382556 [pathway]   5358346 [pathway]   5362768 [pathway]   5678895 [pathway]   901032 [pathway]   
    NDEx NetworkSEL1L
    Atlas of Cancer Signalling NetworkSEL1L
    Wikipedia pathwaysSEL1L
    Orthology - Evolution
    OrthoDB6400
    GeneTree (enSembl)ENSG00000071537
    Phylogenetic Trees/Animal Genes : TreeFamSEL1L
    HOVERGENQ9UBV2
    HOGENOMQ9UBV2
    Homologs : HomoloGeneSEL1L
    Homology/Alignments : Family Browser (UCSC)SEL1L
    Gene fusions - Rearrangements
    Fusion : MitelmanSEL1L/SERTAD2 [14q31.1/2p14]  
    Fusion: TCGASEL1L 14q31.1 SERTAD2 2p14 LUAD
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerSEL1L [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)SEL1L
    dbVarSEL1L
    ClinVarSEL1L
    1000_GenomesSEL1L 
    Exome Variant ServerSEL1L
    ExAC (Exome Aggregation Consortium)SEL1L (select the gene name)
    Genetic variants : HAPMAP6400
    Genomic Variants (DGV)SEL1L [DGVbeta]
    DECIPHER (Syndromes)14:81965154-82000205  ENSG00000071537
    CONAN: Copy Number AnalysisSEL1L 
    Mutations
    ICGC Data PortalSEL1L 
    TCGA Data PortalSEL1L 
    Broad Tumor PortalSEL1L
    OASIS PortalSEL1L [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICSEL1L  [overview]  [genome browser]  [tissue]  [distribution]  
    Mutations and Diseases : HGMDSEL1L
    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 SEL1L
    DgiDB (Drug Gene Interaction Database)SEL1L
    DoCM (Curated mutations)SEL1L (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)SEL1L (select a term)
    intoGenSEL1L
    NCG5 (London)SEL1L
    Cancer3DSEL1L(select the gene name)
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Diseases
    OMIM602329   
    Orphanet
    MedgenSEL1L
    Genetic Testing Registry SEL1L
    NextProtQ9UBV2 [Medical]
    TSGene6400
    GENETestsSEL1L
    Huge Navigator SEL1L [HugePedia]
    snp3D : Map Gene to Disease6400
    BioCentury BCIQSEL1L
    ClinGenSEL1L
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD6400
    Chemical/Pharm GKB GenePA35639
    Clinical trialSEL1L
    Miscellaneous
    canSAR (ICR)SEL1L (select the gene name)
    Other databasetable S7d
    Probes
    Litterature
    PubMed73 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineSEL1L
    EVEXSEL1L
    GoPubMedSEL1L
    iHOPSEL1L
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    indexed on : Wed Apr 12 11:39:19 CEST 2017

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