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COPS2 (COP9 constitutive photomorphogenic homolog subunit 2 (Arabidopsis))

Written2009-09Susanne Jennek, Florian Kraft, Aria Baniahmad
Institute of Human Genetics, Anthropology, Jena University Hospital, Kollegiengasse 10, 07743 Jena, Germany

(Note : for Links provided by Atlas : click)

Identity

Alias_namesCOP9 constitutive photomorphogenic homolog subunit 2 (Arabidopsis)
Alias_symbol (synonym)TRIP15
ALIEN
CSN2
Other aliasSGN2
HGNC (Hugo) COPS2
LocusID (NCBI) 9318
Atlas_Id 47362
Location 15q21.1  [Link to chromosome band 15q21]
Location_base_pair Starts at 49125274 and ends at 49155657 bp from pter ( according to hg19-Feb_2009)  [Mapping COPS2.png]
Fusion genes
(updated 2016)
COPS2 (15q21.1) / COPS2 (15q21.1)COPS2 (15q21.1) / CSMD2 (1p35.1)
Note The beta casein is also abbreviated as CSN2.

DNA/RNA

 
  The CSN2 gene is localized on chromosome 15q21.2 (top panel). A homologous sequence is located on chromosome 9q33.2 (not shown).The gene structure highlights intron/exon arrangement, whereas red boxes display coding sequence (CDS) and grey the untranslated regions. The lower panel exhibits the CSN2/Alien cDNA. The green boxes indicate the 13 exons and the black line below illustrates the coding sequences CDS. The grey box in isoform 2 highlights the additional inserted 21bp stretch which is specific for this splice variant. Differential functions of these isoforms are not yet known. The italic numbers illustrate the base pairs.
Transcription The promoter region of CSN2 contains 4 NF-kB binding sites. Binding to these sites activates the transcription of CSN2 gene. Deletion of the C terminus of NF-kB abrogates the ability to induce CSN2 gene expression (Wu et al., 2009).
Furthermore, CSN2/Alien gene expression in vivo is activated by thyroid hormone receptor (TR) and thyroid hormone suggesting a regulatory feedback mechanism between TR and CSN2/Alien expression (Tenbaum et al., 2003).

Protein

 
  Schematic structure of the CSN2 protein (modified according to Akiyama et al., 2003). The N-terminal region contains a region for interaction with DAX-1/NiF3l1 (aa 1-275). The central part of the protein includes the nuclear localization signal (NLS), a leucine zipper (LZ) domain and a corepressor region (CR) which contains an I/LXXI/VI motif. The C-terminal region contains a PCI domain, might be used for interaction between CSN subunits (reviewed in: Wei and Deng, 2003). The numbers represent the amino acids (aa).
Description Three isoforms are known:
  • CSN2 short/Alien a: 305 amino acids (aa); 36 kDa protein.
  • CSN2 long 1/Alien b1: 443 aa; 51.6 kDa protein.
  • CSN2 long 2/Alien b2: 450 aa; 52.4 kDa protein.

    CSN2 activity can be regulated through phosphorylation and dephosphorylation (Kapelari et al., 2000).

  • Expression Mouse Csn2 is widely expressed in embryonic, fetal and adult tissues (Schaefer et al., 1998). Several mRNA levels have been described in mice: 1,8 kb ; 2,2 kb ; 4 kb and 6 kb (Schaefer et al.,1998; Altincicek et al., 2000; Tenbaum et al., 2003).
    Localisation CSN2 is localized in both the cytoplasm and the nucleus, predominantly being localized in the nucleus (Schaefer et al., 1998; Dressel et al., 1999; Tenbaum et al., 2003).
    Function CSN2 short/Alien a acts as a corepressor for nuclear hormone receptors (NHR). Originally in mammalians, Alien was identified as an interacting protein of the thyroid hormone receptor (TR) in a ligand-sensitive manner (Lee et al., 1995). Moreover, Alien enhances TR-mediated gene silencing through its autonomous silencing function (Dressel et al., 1999). Additionally, the vitamin D receptor (VDR), the androgen receptor (AR) and the orphan receptor DAX-1 can also interact with Alien. Functionally Alien enhances gene silencing mediated by these nuclear receptors (Altincicek et al., 2000; Polly et al., 2000; Moehren et al., 2007). Notably, Alien seems to lack interaction with retinoid X receptor (RXR), retinoid acid receptor (RAR), estrogen receptor (ER), glucocorticoid receptor (GR) and germ cell nuclear factor (GCNF) (Dressel et al., 1999; Fuhrmann et al., 2000; reviewed in: Papaioannou et al., 2007).

    Also, corepression function was identified by CSN2 short/Alien a for transcription factors involved in cell cycle regulation and DNA repair such as several members of the E2F transcription factor family (Escher et al., 2007; reviewed in: Papaioannou et al., 2007). Alien is recruited to the E2F1 gene promoter repressing endogenous E2F1 gene expression in vivo. The data also suggest that Alien inhibits transactivation of E2F1, a positive regulator of cell cycle progression. In line with this, Alien represses cell cycle progression. Remarkably, the inhibition of E2F1-mediated transactivation is independent of retinoblastoma protein pRB (Tenbaum et al., 2007). pRB represses E2F1 transcriptional activation. It is not yet known whether Alien is able to substitute pRB function during cell cycle progression (Tenbaum et al., 2007). Furthermore, a direct interaction between Alien and pRB is detected. Interestingly, a pRB-mutant lacking silencing function also lacks interaction with CSN2 short/Alien (Escher et al., 2007).

    In addition, Alien interacts with the highly conserved chromatin associated tumor suppressor proteins Inhibitor of growth 1 (p33-ING1b) and 2 (p33-ING2) in vivo and both p33ING1b and p33ING2 are known to induce premature cellular senescence. It is shown that p33ING proteins enhance Alien-mediated gene silencing (Fegers et al., 2007).

    The recruitment of HDAC-activity is one mechanism by which Alien realizes its corepression functions (Dressel et al., 1999). However, it is suggested that Alien exhibits both HDAC-dependent and -independent options for gene repression (reviewed in: Papaioannou et al., 2007). Moreover, CSN2 short/Alien a interacts with nucleosome assembly protein 1 (NAP1) in vivo and in vitro regulating its activity through enhancing NAP1-mediated nucleosome assembly on DNA and thereby leading to gene repression (Eckey et al., 2007).

    The CSN2 long/Alien b isoform is an essential part of the COP9 signalosome (CSN) complex which is highly conserved in eukaryotes and consists of eight subunits (reviewed in: Wie et al., 2008). The CSN complex plays a central role in the regulation of degradation of multiple proteins through the ability to de-neddylate cullin, which enables the association of cullin with CAND1, a negative regulator of the cullin-based E3 ubiquitin ligases (reviewed in: von Arnim, 2003; reviewed in: Wolf et al., 2003; Chamovitz, 2009; Wu et al., 2009). A role for CSN2 long/Alien b is suggested by the interaction between CSN2 and subunits of the 26S proteasome was already shown (Huang et al., 2005). The promoter region of the Csn2 gene contains NF-kB binding sites like other CSN subunits. Accordingly, these members of the CSN complex are regulated by NF-kB. Snail, a transcription factor, which is a part of the TGF-b pathway and is involved in inflammatory-triggered migration, invasiveness and metastasis of tumor cells, is stabilized by the induction of the CSN complex via NF-kB (Wu et al., 2009). There are also COP9 subcomplexes with yet unknown functions (reviewed in: Wei et al, 2008).

    Interaction of COP9 via CSN2 with p53 in tumors can raise the stability of p53, the most important protein involving in a variety of essential tumor suppressive functions and induction of cellular senescence. But in contrast to Snail, the lower turnover does not lead to an increase in transcription activity and therefore neither to an increased p21 expression nor to cell cycle arrest (Leal et al., 2008).

    Moreover, CSN2 protein interacts physically with the anaphase-promoting complex (APC/C), a major regulator of the cell cycle and affects specifically its stability (Kob et al., 2008).

    Homology CSN2 is a highly conserved protein from humans to Drosophila (Dressel et al., 1999). CSN2 has homologies in any multicellular organism including plants. It is over 60% identical between animal and plant counterparts (Wei and Deng, 2003; Schwechheimer, 2004).

    Originally, the name Alien was given to a gene in the Drosophila genome with an unknown function (Goubeaud et al., 1996). It shares high homologies with Thyroid hormone receptor-interacting protein 15 (TRIP15), a mammalian protein (Lee et al.,1995; Dressel et al., 1999).

    Mutations

    Note So far natural occurring point mutations of CSN2 in association with cancer and other disease were not yet described.

    Implicated in

    Note
      
    Entity Human tumors
    Oncogenesis Aberrant expression of CNS2/Alien seems to be associated with human tumors. CSN2 expression is lost in several human tumors. In thyroid tumors the loss of CSN2 is at least 50% (Leal et al., 2008). Moreover, high percentages of reduction (15-30%) of CSN2 mRNA level were observed in tumors of pancreas, breast, ovary, kidney, uterus und rectum (Leal et al., 2008).
    It was shown by quantitative analysis that the CSN2 expression is reduced up to 50% in tumors of prostate, lung and colon (Leal et al., 2008).
      

    Bibliography

    The role of transcriptional corepressor Nif311 in early stage of neural differentiation via cooperation with Trip15/CSN2.
    Akiyama H, Fujisawa N, Tashiro Y, Natsuko T, Akinori S, Fumio T.
    J Biol Chem. 2003; 278: 10752-62.
    PMID 12522100
     
    Interaction of the corepressor Alien with DAX-1 is abrogated by mutations of DAX-1 involved in adrenal hypoplasia congenita.
    Altincicek B, Tenbaum SP, Dressel U, Thormeyer D, Renkawitz R, Baniahmad A.
    J Biol Chem. 2000; 275:7662-7.
    PMID 10713076
     
    Revisiting the COP9 signalosome as a transcriptional regulator.
    Chamovitz DA.
    EMBO Rep. 2009; 10(4):352-8. (REVEW)
    PMID 19305390
     
    Alien, a highly conserved protein with characteristics of a corepressor for members of the nuclear hormone receptor superfamily.
    Dressel U, Thormeyer D, Altincicek B, Paululat A, Eggert M, Schneider S, Tenbaum SP, Renkawitz R, Baniahmad A.
    Mol Cell Biol. 1999; 19:3383-94.
    PMID 10207062
     
    The nucleosome assembly activity of NAP1 is enhanced by Alien.
    Eckey M, Hong W, Papaioannou M, Baniahmad A.
    Mol Cell Biol. 2007; 27:3557-68.
    PMID 17339334
     
    Various members of the E2F transcription factor family interact in vivo with the corepressor alien.
    Escher N, Kob R, Tenbam SP, Eisold M, Baniahmad A, von Eggeling F, Melle C.
    J Proteome Res. 2007; 6: 1158-64.
    PMID 17330949
     
    The tumor suppressors p33ING1 and p33ING2 interact with alien in vivo and enhance alien-mediated gene silencing.
    Fegers I, Kob R, Eckey M, Schmidt O, Goeman F, Papaioannou M, Escher N, von Eggeling F, Melle C, Baniahmad A.
    J Proteome Res. 2007; 6:4182-8.
    PMID 17929852
     
    Mouse germline restriction of Oct4 expression by germ cell nuclear factor.
    Fuhrmann G, Chung AC, Jackson KJ, Hummelke G, Baniahmad A, Sutter J, Sylvester I, Scholer HR, Cooney AJ.
    Dev Cell. 2001; 1: 377-87.
    PMID 11702949
     
    The Drosophila gene alien is expressed in the muscle attachment sites during embryogenesis and encodes a protein highly conserved between plants, Drosophila and vertebrates.
    Goubeaud A, Knirr S, Renkawitz-Pohl R, Paululat A.
    Mech Dev. 1996; 57:59-68.
    PMID 8817453
     
    Consequences of COP9 signalosome and 26S proteasome interaction.
    Huang X, Hetfeld BK, Seifert U, Kahne T, Kloetzel PM, Naumann M, Bech-Otschir D, Dubiel W.
    FEBS J. 2005; 272: 3909-17.
    PMID 16045761
     
    Electron microscopy and subunit-subunit interaction studies reveal a first architecture of COP9 signalosome.
    Kapelari B, Bech-Otschir D, Hegerl R, Schade R, Dumdey R, Dubiel W.
    J Mol Biol. 2000; 300: 1169-78.
    PMID 10903862
     
    Regulation of the anaphase-promoting complex by the COP9 signalosome.
    Kob R, Kelm J, Posorski N, Baniahmad A, von Eggeling F, Melle C.
    Cell Cycle. 2009; 8: 2041-9.
    PMID 19535905
     
    Cellular senescence bypass screen identifies new putative tumor suppressor genes.
    Leal JF, Fominaya J, Cascon A, Guijarro MV, Blanco-Aparicio C, Lleonart M, Castro ME, Ramon Y Cajal S, Robledo M, Beach DH, Carnero A.
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    PMID 17968325
     
    Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor.
    Lee JW, Choi HS, Gyuris J, Brent R, Moore DD.
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    PMID 7776974
     
    The coregulator Alien.
    Papaioannou M, Melle C, Baniahmad A.
    Nucl Recept Signal. 2007; 5:e008. (REVEW)
    PMID 18174916
     
    VDR-Alien: a novel, DNA-selective vitamin D(3) receptor-corepressor partnership.
    Polly P, Herdick M, Moehren U, Baniahmad A, Heinzel T, Carlberg C.
    FASEB J. 2000; 14:1455-63.
    PMID 10877839
     
    The COP9 signalosome (CSN): an evolutionary conserved proteolysis regulator in eukaryotic development.
    Schwechheimer C.
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    PMID 15571808
     
    Alien/CSN2 gene expression is regulated by thyroid hormone in rat brain.
    Tenbaum SP, Papaioannou M, Reeb CA, Goeman F, Escher N, Kob R, von Eggeling F, Melle C, Baniahmad A.
    Biochim Biophys Acta. 2007; 1773: 1447-54.
    PMID 17570542
     
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    Annu Rev Cell Dev Biol. 2003; 19: 261-86. (REVEW)
    PMID 14570571
     
    The COP9 signalosome: more than a Protease.
    Wie N, Serino G, Deng XW.
    Trends Biochem Sci. 2008; 33(12):592-600. (REVEW)
    PMID 19411070
     
    The COP9 signalosome: an assembly and maintenance platform for cullin ubiquitin ligases?
    Wolf DA, Zhou C, Wee S.
    Nat Cell Biol. 2003; 5(12):1029-33. (REVEW)
    PMID 14647295
     
    Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion.
    Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP.
    Cancer Cell. 2009; 15:416-28.
    PMID 19411070
     
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    von Arnim AG.
    Curr Opin Plant Biol. 2003; 6: 520-9. (REVEW)
    PMID 14611949
     

    Citation

    This paper should be referenced as such :
    Jennek, S ; Kraft, F ; Baniahmad, A
    COPS2 (COP9 constitutive photomorphogenic homolog subunit 2 (Arabidopsis))
    Atlas Genet Cytogenet Oncol Haematol. 2010;14(7):688-691.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/COPS2ID47362ch15q21.html


    External links

    Nomenclature
    HGNC (Hugo)COPS2   30747
    Cards
    AtlasCOPS2ID47362ch15q21
    Entrez_Gene (NCBI)COPS2  9318  COP9 signalosome subunit 2
    AliasesALIEN; CSN2; SGN2; TRIP15
    GeneCards (Weizmann)COPS2
    Ensembl hg19 (Hinxton)ENSG00000166200 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000166200 [Gene_View]  chr15:49125274-49155657 [Contig_View]  COPS2 [Vega]
    ICGC DataPortalENSG00000166200
    TCGA cBioPortalCOPS2
    AceView (NCBI)COPS2
    Genatlas (Paris)COPS2
    WikiGenes9318
    SOURCE (Princeton)COPS2
    Genetics Home Reference (NIH)COPS2
    Genomic and cartography
    GoldenPath hg38 (UCSC)COPS2  -     chr15:49125274-49155657 -  15q21.1   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)COPS2  -     15q21.1   [Description]    (hg19-Feb_2009)
    EnsemblCOPS2 - 15q21.1 [CytoView hg19]  COPS2 - 15q21.1 [CytoView hg38]
    Mapping of homologs : NCBICOPS2 [Mapview hg19]  COPS2 [Mapview hg38]
    OMIM604508   
    Gene and transcription
    Genbank (Entrez)AB209799 AF084260 AF100762 AF120268 AF212227
    RefSeq transcript (Entrez)NM_001143887 NM_004236
    RefSeq genomic (Entrez)
    Consensus coding sequences : CCDS (NCBI)COPS2
    Cluster EST : UnigeneHs.369614 [ NCBI ]
    CGAP (NCI)Hs.369614
    Alternative Splicing GalleryENSG00000166200
    Gene ExpressionCOPS2 [ NCBI-GEO ]   COPS2 [ EBI - ARRAY_EXPRESS ]   COPS2 [ SEEK ]   COPS2 [ MEM ]
    Gene Expression Viewer (FireBrowse)COPS2 [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)9318
    GTEX Portal (Tissue expression)COPS2
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP61201   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtP61201  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProP61201
    Splice isoforms : SwissVarP61201
    PhosPhoSitePlusP61201
    Domains : Interpro (EBI)PCI_dom    TPR-like_helical_dom    WHTH_DNA-bd_dom   
    Domain families : Pfam (Sanger)PCI (PF01399)   
    Domain families : Pfam (NCBI)pfam01399   
    Domain families : Smart (EMBL)PINT (SM00088)  
    Conserved Domain (NCBI)COPS2
    DMDM Disease mutations9318
    Blocks (Seattle)COPS2
    PDB (SRS)4D10    4D18    4WSN   
    PDB (PDBSum)4D10    4D18    4WSN   
    PDB (IMB)4D10    4D18    4WSN   
    PDB (RSDB)4D10    4D18    4WSN   
    Structural Biology KnowledgeBase4D10    4D18    4WSN   
    SCOP (Structural Classification of Proteins)4D10    4D18    4WSN   
    CATH (Classification of proteins structures)4D10    4D18    4WSN   
    SuperfamilyP61201
    Human Protein AtlasENSG00000166200
    Peptide AtlasP61201
    HPRD05146
    IPIIPI00743825   IPI00018813   IPI01010035   
    Protein Interaction databases
    DIP (DOE-UCLA)P61201
    IntAct (EBI)P61201
    FunCoupENSG00000166200
    BioGRIDCOPS2
    STRING (EMBL)COPS2
    ZODIACCOPS2
    Ontologies - Pathways
    QuickGOP61201
    Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  protein deneddylation  nucleotide-excision repair, DNA damage recognition  transcription corepressor activity  signal transducer activity  protein binding  nucleoplasm  cytoplasm  cytosol  transcription-coupled nucleotide-excision repair  transcription from RNA polymerase II promoter  signal transduction  COP9 signalosome  cell proliferation  neurogenesis  neuron differentiation  skeletal muscle cell differentiation  negative regulation of transcription, DNA-templated  negative regulation of nucleic acid-templated transcription  
    Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  protein deneddylation  nucleotide-excision repair, DNA damage recognition  transcription corepressor activity  signal transducer activity  protein binding  nucleoplasm  cytoplasm  cytosol  transcription-coupled nucleotide-excision repair  transcription from RNA polymerase II promoter  signal transduction  COP9 signalosome  cell proliferation  neurogenesis  neuron differentiation  skeletal muscle cell differentiation  negative regulation of transcription, DNA-templated  negative regulation of nucleic acid-templated transcription  
    Pathways : BIOCARTAControl of Gene Expression by Vitamin D Receptor [Genes]   
    REACTOMEP61201 [protein]
    REACTOME PathwaysR-HSA-8856825 [pathway]   
    NDEx NetworkCOPS2
    Atlas of Cancer Signalling NetworkCOPS2
    Wikipedia pathwaysCOPS2
    Orthology - Evolution
    OrthoDB9318
    GeneTree (enSembl)ENSG00000166200
    Phylogenetic Trees/Animal Genes : TreeFamCOPS2
    HOVERGENP61201
    HOGENOMP61201
    Homologs : HomoloGeneCOPS2
    Homology/Alignments : Family Browser (UCSC)COPS2
    Gene fusions - Rearrangements
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerCOPS2 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)COPS2
    dbVarCOPS2
    ClinVarCOPS2
    1000_GenomesCOPS2 
    Exome Variant ServerCOPS2
    ExAC (Exome Aggregation Consortium)COPS2 (select the gene name)
    Genetic variants : HAPMAP9318
    Genomic Variants (DGV)COPS2 [DGVbeta]
    DECIPHERCOPS2 [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisCOPS2 
    Mutations
    ICGC Data PortalCOPS2 
    TCGA Data PortalCOPS2 
    Broad Tumor PortalCOPS2
    OASIS PortalCOPS2 [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICCOPS2  [overview]  [genome browser]  [tissue]  [distribution]  
    Mutations and Diseases : HGMDCOPS2
    intOGen PortalCOPS2
    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 COPS2
    DgiDB (Drug Gene Interaction Database)COPS2
    DoCM (Curated mutations)COPS2 (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)COPS2 (select a term)
    intoGenCOPS2
    NCG5 (London)COPS2
    Cancer3DCOPS2(select the gene name)
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Diseases
    OMIM604508   
    Orphanet
    MedgenCOPS2
    Genetic Testing Registry COPS2
    NextProtP61201 [Medical]
    TSGene9318
    GENETestsCOPS2
    Target ValidationCOPS2
    Huge Navigator COPS2 [HugePedia]
    snp3D : Map Gene to Disease9318
    BioCentury BCIQCOPS2
    ClinGenCOPS2
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD9318
    Chemical/Pharm GKB GenePA134952445
    Clinical trialCOPS2
    Miscellaneous
    canSAR (ICR)COPS2 (select the gene name)
    Probes
    Litterature
    PubMed88 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineCOPS2
    EVEXCOPS2
    GoPubMedCOPS2
    iHOPCOPS2
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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