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ING2 (inhibitor of growth family, member 2)

Written2009-05Susanne Jennek, Aria Baniahmad
Institute of Human Genetics, Anthropology, Jena University Hospital, Kollegiengasse 10, 07743 Jena, Germany

(Note : for Links provided by Atlas : click)

Identity

Alias_namesING1L
inhibitor of growth family
Alias_symbol (synonym)p33ING2
Other aliasING1Lp
p32
HGNC (Hugo) ING2
LocusID (NCBI) 3622
Atlas_Id 40975
Location 4q35.1  [Link to chromosome band 4q35]
Location_base_pair Starts at 183506082 and ends at 183512428 bp from pter ( according to hg19-Feb_2009)  [Mapping ING2.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ING2 (4q35.1) / ING2 (4q35.1)

DNA/RNA

 
  Gene structure of ING2a and ING2b (modified according to Unoki et al., 2008).
Description The two isoforms share exon 2 but have different exon 1. The exon 1a of ING2a encodes 58 amino acids. Exon 1b of ING2b encodes 18 amino acids. There is no significant homology between the N-terminal part of ING2b and the N-terminal regions of ING1 isoforms (Unoki et al., 2008).
Transcription The promoter region of ING2a possesses two p53 binding sites in contrast to the promoter of ING2b. Binding of p53 to these sites suppresses the ING2a expression. The promoter region of ING2b harbors a HSF1 and HSF2 binding site, a c-Rel, a SP1 and five MZF1 binding sites (Unoki et al., 2008).

Protein

Description
  • p33ING2a: 280 amino acids; 33kDa protein; harbor, listed from the N-terminal to the C-terminal region, a leucine-zipper-like-region (LZL), a novel conserved region (NCR), a nuclear localization signal (NLS), a plant homeo domain (PHD) finger motif and a poly basic region (PBR);
  • p28ING2b: 240 aa; 28 kDa protein; lacks leucine-zipper-like-domain (LZL) is distinct to the N-terminal part to ING2a (Unoki et al., 2008).
  • Expression ING2 is widely expressed in normal tissues (Shimada et al., 1998).
    Localisation ING2 is predominantly localized in the nucleus to chromatin and the nuclear matrix (Gozani et al., 2003). Through reduced levels of phosphoinositide PtdIns5P, ING2 might be released from chromatin and translocates partially to the cytoplasm (Gozani et al., 2003).
    Function The tumor suppressor protein ING2 has been described to regulate cell cycle, cellular senescence and gene regulation including chromatin level. In response to DNA damage ING2 enhances the acetylation of p53, which negatively regulates cell proliferation (Nagashima et al., 2001). In addition the level of ING2 expression directly regulates the onset of replicative senescence through the induction of p300-dependent acetylation of p53 (Pedeux et al., 2005). ING2 also induces the global histone H4 acetylation and chromatin relaxation and thereby enhances the nucleotide excision repair (Wang et al., 2006). Furthermore, ING2 is also a part of two related mSin3/HDAC1/HDAC2 corepressor complexes (Doyon et al., 2006). Further, chromatin association of ING2 is linked to ING2 ability to bind to trimethylated K4 of histone 3 (H3K4me3) via its plant homeodomain (PHD) region (Shi et al., 2006). p33ING2 is also associated with histone methyltranferase (HMT-) activity in vitro and in vivo, methylating specifically histone H3 and histone H1 (Goeman et al., 2008). In addition, ING2, as a transcriptional repressor, directly interacts with the corepressor Alien and enhances the Alien-mediated gene silencing (Fegers et al., 2007). Furthermore, ING2 interacts with the Smad-interaction transcriptional modulator SnoN mediating TGF-beta-induced Smad-dependent transcription and cellular responses (Sarker et al., 2008). The activity of ING2, as a nuclear phosphatidylinositol receptor can be modulated by phosphoinositides (Gozani et al., 2003).
    Homology The PHD-finger motif is highly-conserved among all ING genes. There are five human ING genes (ING1, ING2, ING3, ING4, ING5) which encode multiple isoforms via splicing. So far known ING2 gene encodes two isoforms (ING2a: 33kDa; ING2b: 28kDA).

    Mutations

    Note So far natural occurring point mutations of ING2 in association with cancer were not yet described. However, loss of heterozygosity (LOH) and aberrant ING2-mRNA levels were associated with cancer.

    Implicated in

    Note
      
    Entity Colon cancer
    Oncogenesis ING2 expression level in human colon tumors is significantly higher than in normal colon tissue. In conclusion, ING2 might be involved in colon cancers (Shimada et al., 1998).
      
      
    Entity Hepatocellular carcinoma (HCC)
    Oncogenesis ING2 transcription and post-transcription level is downregulated in the majority of HCC tumors compared with non-tumors liver tissue. Furthermore, ING2 expression level is reduced in 44 of 84 (52.4%) HCC cases and the ING2 expression level correlated with tumor size, histopathologic classification and serum AFP (Zhang et al., 2008). It is also shown that HCC patients with reduced ING2 expression have a significantly increased risk exhibiting a shorter survival time. In conclusion, ING2 may be involved in the progression of HCC (Zhang et al., 2008).
      
      
    Entity Head and neck squamous cell carcinoma (HNSCC)
    Oncogenesis There is a loss of heterozygosity (LOH) in the region 4q32 in the long arm of the chromosome 4 in 20% of the cases (Borkovsky et. al., 2008). This region includes ING2 and SAP30 genes that are parts of the two related mSin3/ HDAC1/2 corepressor complexes. LOH on region 4q35.1 was detected in 30 (54.6%) out of 55 informative cases (Borkovsky et. al., 2008). High LOH frequency is associated with advanced tumor stages, therefore, ING2 LOH is likely to be a late event in HNSCC.
      
      
    Entity Lung cancer
    Oncogenesis Although, there are no ING2 mutations identified in 30 human lung cancer cell lines and 31 primary lung cancer tumors. The ING2 mRNA expression is reduced in 6 out of 7 lung cancer cell lines (Okano et al., 2006).
      
      
    Entity Cutaneous melanomas
    Oncogenesis The nuclear expression level of ING2 is significantly reduced in human melanomas compared to dysplastic nevi. It is suggested that reduced ING2 expression may be involved in the initiation of melanoma (Lu et al., 2006; Ythier et al., 2008).
      

    Bibliography

    Frequent deletion of ING2 locus at 4q35.1 associates with advanced tumor stage in head and neck squamous cell carcinoma.
    Borkosky SS, Gunduz M, Nagatsuka H, Beder LB, Gunduz E, Ali MA, Rodriguez AP, Cilek MZ, Tominaga S, Yamanaka N, Shimizu K, Nagai N.
    J Cancer Res Clin Oncol. 2009 May;135(5):703-13. Epub 2008 Nov 8.
    PMID 18998165
     
    Biological functions of the ING family tumor suppressors.
    Campos EI, Chin MY, Kuo WH, Li G.
    Cell Mol Life Sci. 2004 Oct;61(19-20):2597-613. (REVIEW)
    PMID 15526165
     
    ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation.
    Doyon Y, Cayrou C, Ullah M, Landry AJ, Cote V, Selleck W, Lane WS, Tan S, Yang XJ, Cote J.
    Mol Cell. 2006 Jan 6;21(1):51-64.
    PMID 16387653
     
    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 Nov;6(11):4182-8. Epub 2007 Oct 11.
    PMID 17929852
     
    ING2 recruits histone methyltransferase activity with methylation site specificity distinct from histone H3 lysines 4 and 9.
    Goeman F, Otto K, Kyrylenko S, Schmidt O, Baniahmad A.
    Biochim Biophys Acta. 2008 Oct;1783(10):1673-80. Epub 2008 May 10.
    PMID 18513492
     
    The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor.
    Gozani O, Karuman P, Jones DR, Ivanov D, Cha J, Lugovskoy AA, Baird CL, Zhu H, Field SJ, Lessnick SL, Villasenor J, Mehrotra B, Chen J, Rao VR, Brugge JS, Ferguson CG, Payrastre B, Myszka DG, Cantley LC, Wagner G, Divecha N, Prestwich GD, Yuan J.
    Cell. 2003 Jul 11;114(1):99-111.
    PMID 12859901
     
    Nuclear ING2 expression is reduced in human cutaneous melanomas.
    Lu F, Dai DL, Martinka M, Ho V, Li G.
    Br J Cancer. 2006 Jul 3;95(1):80-6. Epub 2006 Jun 6.
    PMID 16755297
     
    DNA damage-inducible gene p33ING2 negatively regulates cell proliferation through acetylation of p53.
    Nagashima M, Shiseki M, Miura K, Hagiwara K, Linke SP, Pedeux R, Wang XW, Yokota J, Riabowol K, Harris CC.
    Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9671-6. Epub 2001 Jul 31.
    PMID 11481424
     
    Alterations in novel candidate tumor suppressor genes, ING1 and ING2 in human lung cancer.
    Okano T, Gemma A, Hosoya Y, Hosomi Y, Nara M, Kokubo Y, Yoshimura A, Shibuya M, Nagashima M, Harris CC, Kudoh S.
    Oncol Rep. 2006 Mar;15(3):545-9.
    PMID 16465410
     
    ING2 regulates the onset of replicative senescence by induction of p300-dependent p53 acetylation.
    Pedeux R, Sengupta S, Shen JC, Demidov ON, Saito S, Onogi H, Kumamoto K, Wincovitch S, Garfield SH, McMenamin M, Nagashima M, Grossman SR, Appella E, Harris CC.
    Mol Cell Biol. 2005 Aug;25(15):6639-48.
    PMID 16024799
     
    Molecular biology of squamous cell carcinoma of the head and neck.
    Perez-Ordonez B, Beauchemin M, Jordan RC.
    J Clin Pathol. 2006 May;59(5):445-53. (REVIEW)
    PMID 16644882
     
    ING2 as a novel mediator of transforming growth factor-beta-dependent responses in epithelial cells.
    Sarker KP, Kataoka H, Chan A, Netherton SJ, Pot I, Huynh MA, Feng X, Bonni A, Riabowol K, Bonni S.
    J Biol Chem. 2008 May 9;283(19):13269-79. Epub 2008 Mar 11.
    PMID 18334480
     
    ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression.
    Shi X, Hong T, Walter KL, Ewalt M, Michishita E, Hung T, Carney D, Pena P, Lan F, Kaadige MR, Lacoste N, Cayrou C, Davrazou F, Saha A, Cairns BR, Ayer DE, Kutateladze TG, Shi Y, Cote J, Chua KF, Gozani O.
    Nature. 2006 Jul 6;442(7098):96-9. Epub 2006 May 21.
    PMID 16728974
     
    Cloning of a novel gene (ING1L) homologous to ING1, a candidate tumor suppressor.
    Shimada Y, Saito A, Suzuki M, Takahashi E, Horie M.
    Cytogenet Cell Genet. 1998;83(3-4):232-5.
    PMID 10072587
     
    After a decade of study-ING, a PHD for a versatile family of proteins.
    Soliman MA, Riabowol K.
    Trends Biochem Sci. 2007 Nov;32(11):509-19. Epub 2007 Oct 18. (REVIEW)
    PMID 17949986
     
    A novel ING2 isoform, ING2b, synergizes with ING2a to prevent cell cycle arrest and apoptosis.
    Unoki M, Kumamoto K, Robles AI, Shen JC, Zheng ZM, Harris CC.
    FEBS Lett. 2008 Nov 26;582(28):3868-74. Epub 2008 Oct 23.
    PMID 18951897
     
    The novel tumor suppressor p33ING2 enhances nucleotide excision repair via inducement of histone H4 acetylation and chromatin relaxation.
    Wang J, Chin MY, Li G.
    Cancer Res. 2006 Feb 15;66(4):1906-11.
    PMID 16488987
     
    The new tumor suppressor genes ING: genomic structure and status in cancer.
    Ythier D, Larrieu D, Brambilla C, Brambilla E, Pedeux R.
    Int J Cancer. 2008 Oct 1;123(7):1483-90. (REVIEW)
    PMID 18636562
     
    Decreased expression of ING2 gene and its clinicopathological significance in hepatocellular carcinoma.
    Zhang HK, Pan K, Wang H, Weng DS, Song HF, Zhou J, Huang W, Li JJ, Chen MS, Xia JC.
    Cancer Lett. 2008 Mar 18;261(2):183-92. Epub 2007 Dec 21.
    PMID 18160212
     

    Citation

    This paper should be referenced as such :
    Jennek, S ; Baniahmad, A
    ING2 (inhibitor of growth family, member 2)
    Atlas Genet Cytogenet Oncol Haematol. 2010;14(4):386-388.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/ING2ID40975ch4q35.html


    External links

    Nomenclature
    HGNC (Hugo)ING2   6063
    Cards
    AtlasING2ID40975ch4q35
    Entrez_Gene (NCBI)ING2  3622  inhibitor of growth family member 2
    AliasesING1L; p33ING2
    GeneCards (Weizmann)ING2
    Ensembl hg19 (Hinxton)ENSG00000168556 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000168556 [Gene_View]  chr4:183506082-183512428 [Contig_View]  ING2 [Vega]
    ICGC DataPortalENSG00000168556
    TCGA cBioPortalING2
    AceView (NCBI)ING2
    Genatlas (Paris)ING2
    WikiGenes3622
    SOURCE (Princeton)ING2
    Genetics Home Reference (NIH)ING2
    Genomic and cartography
    GoldenPath hg38 (UCSC)ING2  -     chr4:183506082-183512428 +  4q35.1   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)ING2  -     4q35.1   [Description]    (hg19-Feb_2009)
    EnsemblING2 - 4q35.1 [CytoView hg19]  ING2 - 4q35.1 [CytoView hg38]
    Mapping of homologs : NCBIING2 [Mapview hg19]  ING2 [Mapview hg38]
    OMIM604215   
    Gene and transcription
    Genbank (Entrez)AB012853 AB196793 AF053537 AJ006851 AK294310
    RefSeq transcript (Entrez)NM_001291959 NM_001564
    RefSeq genomic (Entrez)
    Consensus coding sequences : CCDS (NCBI)ING2
    Cluster EST : UnigeneHs.107153 [ NCBI ]
    CGAP (NCI)Hs.107153
    Alternative Splicing GalleryENSG00000168556
    Gene ExpressionING2 [ NCBI-GEO ]   ING2 [ EBI - ARRAY_EXPRESS ]   ING2 [ SEEK ]   ING2 [ MEM ]
    Gene Expression Viewer (FireBrowse)ING2 [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)3622
    GTEX Portal (Tissue expression)ING2
    Human Protein AtlasENSG00000168556-ING2 [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ9H160   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtQ9H160  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProQ9H160
    Splice isoforms : SwissVarQ9H160
    PhosPhoSitePlusQ9H160
    Domaine pattern : Prosite (Expaxy)ZF_PHD_1 (PS01359)    ZF_PHD_2 (PS50016)   
    Domains : Interpro (EBI)ING2    ING_fam    ING_N_histone_binding    Zinc_finger_PHD-type_CS    Znf_FYVE_PHD    Znf_PHD    Znf_PHD-finger    Znf_RING/FYVE/PHD   
    Domain families : Pfam (Sanger)ING (PF12998)   
    Domain families : Pfam (NCBI)pfam12998   
    Domain families : Smart (EMBL)ING (SM01408)  PHD (SM00249)  
    Conserved Domain (NCBI)ING2
    DMDM Disease mutations3622
    Blocks (Seattle)ING2
    SuperfamilyQ9H160
    Human Protein Atlas [tissue]ENSG00000168556-ING2 [tissue]
    Peptide AtlasQ9H160
    HPRD05021
    IPIIPI00016930   IPI00879214   
    Protein Interaction databases
    DIP (DOE-UCLA)Q9H160
    IntAct (EBI)Q9H160
    FunCoupENSG00000168556
    BioGRIDING2
    STRING (EMBL)ING2
    ZODIACING2
    Ontologies - Pathways
    QuickGOQ9H160
    Ontology : AmiGODNA binding  chromatin binding  protein binding  nucleus  nucleus  nucleoplasm  nucleoplasm  Golgi apparatus  cytosol  plasma membrane  transcription, DNA-templated  regulation of transcription, DNA-templated  male meiosis I  signal transduction  spermatogenesis  spermatid development  zinc ion binding  negative regulation of cell proliferation  covalent chromatin modification  Sin3 complex  CCAAT-binding factor complex  flagellated sperm motility  positive regulation of transforming growth factor beta receptor signaling pathway  positive regulation of histone deacetylation  protein complex binding  methylated histone binding  phosphatidylinositol binding  regulation of growth  positive regulation of transcription, DNA-templated  male germ-line stem cell asymmetric division  seminiferous tubule development  negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  regulation of cellular senescence  regulation of response to DNA damage stimulus  
    Ontology : EGO-EBIDNA binding  chromatin binding  protein binding  nucleus  nucleus  nucleoplasm  nucleoplasm  Golgi apparatus  cytosol  plasma membrane  transcription, DNA-templated  regulation of transcription, DNA-templated  male meiosis I  signal transduction  spermatogenesis  spermatid development  zinc ion binding  negative regulation of cell proliferation  covalent chromatin modification  Sin3 complex  CCAAT-binding factor complex  flagellated sperm motility  positive regulation of transforming growth factor beta receptor signaling pathway  positive regulation of histone deacetylation  protein complex binding  methylated histone binding  phosphatidylinositol binding  regulation of growth  positive regulation of transcription, DNA-templated  male germ-line stem cell asymmetric division  seminiferous tubule development  negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  regulation of cellular senescence  regulation of response to DNA damage stimulus  
    REACTOMEQ9H160 [protein]
    REACTOME PathwaysR-HSA-6811555 [pathway]   
    NDEx NetworkING2
    Atlas of Cancer Signalling NetworkING2
    Wikipedia pathwaysING2
    Orthology - Evolution
    OrthoDB3622
    GeneTree (enSembl)ENSG00000168556
    Phylogenetic Trees/Animal Genes : TreeFamING2
    HOVERGENQ9H160
    HOGENOMQ9H160
    Homologs : HomoloGeneING2
    Homology/Alignments : Family Browser (UCSC)ING2
    Gene fusions - Rearrangements
    Tumor Fusion PortalING2
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerING2 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)ING2
    dbVarING2
    ClinVarING2
    1000_GenomesING2 
    Exome Variant ServerING2
    ExAC (Exome Aggregation Consortium)ENSG00000168556
    GNOMAD BrowserENSG00000168556
    Genetic variants : HAPMAP3622
    Genomic Variants (DGV)ING2 [DGVbeta]
    DECIPHERING2 [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisING2 
    Mutations
    ICGC Data PortalING2 
    TCGA Data PortalING2 
    Broad Tumor PortalING2
    OASIS PortalING2 [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICING2  [overview]  [genome browser]  [tissue]  [distribution]  
    Mutations and Diseases : HGMDING2
    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 ING2
    DgiDB (Drug Gene Interaction Database)ING2
    DoCM (Curated mutations)ING2 (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)ING2 (select a term)
    intoGenING2
    NCG5 (London)ING2
    Cancer3DING2(select the gene name)
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Diseases
    OMIM604215   
    Orphanet
    DisGeNETING2
    MedgenING2
    Genetic Testing Registry ING2
    NextProtQ9H160 [Medical]
    TSGene3622
    GENETestsING2
    Target ValidationING2
    Huge Navigator ING2 [HugePedia]
    snp3D : Map Gene to Disease3622
    BioCentury BCIQING2
    ClinGenING2
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD3622
    Chemical/Pharm GKB GenePA29873
    Clinical trialING2
    Miscellaneous
    canSAR (ICR)ING2 (select the gene name)
    Probes
    Litterature
    PubMed56 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineING2
    EVEXING2
    GoPubMedING2
    iHOPING2
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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