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ING3 (inhibitor of growth family, member 3)

Written2014-11Audrey Mouche, Katherine Yaacoub, Thierry Guillaudeux, Rémy Pedeux
INSERM U917, Microenvironnement et Cancer, Rennes, France, Universite de Rennes 1, Rennes, France (AM, KY, RP, TG); Etablissement Francais du Sang, Rennes, France (RP); UMS Biosit 3480 CNRS/018 INSERM (TG)

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)p47ING3
FLJ20089
Eaf4
MEAF4
Other aliasING2
HGNC (Hugo) ING3
LocusID (NCBI) 54556
Atlas_Id 40977
Location 7q31.31  [Link to chromosome band 7q31]
Location_base_pair Starts at 120590817 and ends at 120615711 bp from pter ( according to hg19-Feb_2009)  [Mapping ING3.png]
 
  Figure 1. Chromosomal localization of the ING3 gene in Homo sapiens.
Fusion genes
(updated 2016)
ARID4B (1q42.3) / ING3 (7q31.31)ING3 (7q31.31) / CHMP1A (16q24.3)ING3 (7q31.31) / IVNS1ABP (1q25.3)
YTHDC1 (4q13.2) / ING3 (7q31.31)

DNA/RNA

 
  Figure 2. Structure and transcripts of Human ING3 genes. Coding regions are in dark blue and non-coding regions are represented in light blue.
Description In 1996, Karl Riabowol's group identified a new Tumor Suppressor Gene (TSG) by using subtractive hybridization between cDNAs from normal mammary epithelial cells and mammary epithelial cells from tumor. This experiment was followed by an in vivo screen for tumourigenesis. Using this method, the authors identified a new candidate TSG that they named ING1 for INhibitor of Growth 1 (Garkavtsev et al., 1996). Few years later, ING2, ING3, ING4 and ING5 were identified by homology search. ING3 was identified through bioinformatic analyses in order to find human EST clone showing a high homology with the p33ING1b and p33ING2 cDNAs (Nagashima et al., 2003).
Transcription The ING3 gene has been mapped to chromosome 7 at locus 7q31. Interestingly, unlike ING1, 2, 4 and 5, ING3 is located far from telomeric regions and is evolutionarily distinct from the other (Fig.1) (He et al., 2005). Human ING3 is made of twelve exons, resulting in 2 transcribed variants (ING3v1a, ING3v3) (Fig.2).
Pseudogene INGX is the pseudogene of ING (He et al., 2005).

Protein

 
  Figure 3. Schematic representation of ING3 proteins structure. In the C-terminal part: Nuclear Localization Signal (NLS), Plant Homeo Domain (PHD). In the N-terminal part: Leucine Zipper-Like domain (LZL), Novel Conserved Region (NCR).
Description The ING proteins are characterized by the presence of a highly conserved PHD in their C-terminal part. This domain is commonly found in proteins involved in chromatin modification (Bienz, 2006; Mellor, 2006). The C-terminal part of ING3 isoform contains a Leucine Zipper-Like domain (LZL) and a Novel Conserved Region (NCR) (Fig.3).
Expression ING3 is ubiquitously expressed in mammalian tissues. Moreover, ING3 expression is increased in oocytes from Human, Rhesus monkey and mice (Awe and Byrne, 2013).
Localisation ING3 contains an NLS domain, so it is mainly located in the nucleus.
Function ING3 is a candidate tumor suppressor gene. ING3 regulates apoptosis in a p53 dependent and independent manner. Indeed, ING3 activates bax transcription through p53 and promotes apoptosis via Fas/caspase 8 pathway in melanoma cells (Nagashima et al., 2003; Wang and Li, 2006). Moreover, ING3 is a member of the human NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of genes through acetylation of histones H4 and H2A (Doyon et al., 2004). ING3 through its involvement in the NuA4 HAT complex regulates the expression of mTOR. Consequently, ING3 regulates oocyte polarization and asymmetric division during oocyte mice maturation through the mTOR pathway (Suzuki et al., 2013).

Implicated in

Note
  
Entity Ameloblastoma
Note The analysis of LOH (loss of heterozygosity) for ING genes family, in 33 samples of ameloblastoma cases, showed a high percentage of allelic loss (48.5%) for ING3 gene. Moreover, there is a strong correlation between the inactivation of ING3 gene and tumor aggressiveness (Borkosky et al., 2010).
  
  
Entity Breast cancer
Note The analysis of ING3 status in 9 breast cancer cell lines revealed a downregulation of ING3v1 and v3 mRNA in 2 of these cell lines. However, their mRNA abundances were increased in seven other cell lines compared to normal breast epithelial cells (Walzak et al., 2008).
  
  
Entity Colorectal carcinoma
Note In colorectal carcinoma, the ING3 mRNA expression was reduced compared to colorectal non-neoplastic mucosa (NNM). In addition, the expression of ING3 protein has been detected in the cytoplasm but not in the nucleus. Moreover, there is no difference of ING3 protein level between NNM and carcinomas tissues. However, the expression of ING3 was not correlated to the prognosis of patients with colorectal cancer. These results suggest that downregulation of ING3 may have a significant role in colorectal carcinogenesis (Gou et al., 2014).
  
  
Entity Cutaneous melanoma
Note In malignant melanoma, nuclear expression of ING3 was reduced compared to dysplastic nevi, while an increase of cytoplasmic expression is found, in 24%, 39%, and 62% of the dysplastic nevi, primary melanoma, and metastases, respectively. In addition, the location of primary melanomas and the upregulated ING3 cytoplasmic expression are not correlated. In patients with strong nuclear ING3 staining, the survival rate reached 93%, whereas in patients with negative-to-moderate nuclear ING3 staining, the survival rate was just 44%. These findings suggest that ING3 is an important factor for melanoma prognosis and progression (Wang et al., 2007).
  
  
Entity Head and neck squamous carcinoma
Note The analysis of loss of heterozygosity in 49 head and neck squamous cell carcinoma (HNSCC) showed that 48% had an allelic deletion detected in 2 regions on chromosome 7q31 where ING3 is mapped. In addition, only one sample showed a missense mutation manifested by nucleotide change from GAC to GGC at codon 20 which leads to an amino acid substitution from aspartic acid to glycine. A silent mutation from GAC to GAT has been detected in three samples at codon 356 with no amino acid change. Moreover, 50% of primary tumor tissues and 75% of tumor derived cell lines showed a decreased expression of ING3 mRNA. In one case, a complete loss of ING3 mRNA has been detected in 2 primary tissues. In this study, a significant decrease of ING3 mRNA expression but rare mutation found, suggests that a transcriptional mechanism, such as promoter methylation, may contribute to the HNSCC development (Gunduz et al., 2002).
  
  
Entity Hepatocellular carcinoma
Note In the case of hepatocellular carcinoma (HCC), the analysis of ING3 mRNA expression revealed that in all the 49 tumor samples, ING3 was downregulated compared to normal livers. In addition, the expression of ING3 mRNA is reduced in 18 HCC cell lines compared to noncancerous cell lines. Moreover, in 64/112 samples of HCC, a downregulation of ING3 protein expression was found, while 24/112 samples had an upregulation of ING3 and 24/112 exhibited the same expression of ING3 protein. However, the overexpression of ING3 suppresses cell proliferation in Hep3B cell line, thus confirming that ING3 may be tumor suppressor gene (Lu et al., 2012). Another study showed that 16/20 patients with HCC exhibited a downregulation of ING3 protein and ING3 mRNA expression. In addition, in 4/6 hepatic cell lines, there is a downregulation of ING3 protein and ING3 mRNA expression (Yang et al., 2012).
  
  
Entity Lung cancer
Note In two lung cancer cell lines, a downregulation of ING3v1 and v3 transcripts has been detected (Walzak et al., 2008).
  
  
Entity Ovarian cancer
Note ING3v1 and ING3v3 showed a weak decrease of mRNA expression, in 1/1 ovarian cancer cell line GI-102 (Walzak et al., 2008).
  
  
Entity Pancreatic cancer
Note In GI-103 pancreatic cell line, mRNA expression of ING3v3 transcript is downregulated but, surprisingly, ING3v1 is upregulated (Walzak et al., 2008).
  
  
Entity Prostate cancer
Note In PC3 prostate cancer cell line, mRNA expression levels of ING3v1 and v3 are decreased (Walzak et al., 2008).
  

Bibliography

Identifying candidate oocyte reprogramming factors using cross-species global transcriptional analysis.
Awe JP, Byrne JA.
Cell Reprogram. 2013 Apr;15(2):126-33. doi: 10.1089/cell.2012.0060. Epub 2013 Mar 4.
PMID 23458164
 
The PHD finger, a nuclear protein-interaction domain.
Bienz M.
Trends Biochem Sci. 2006 Jan;31(1):35-40. Epub 2005 Nov 16. (REVIEW)
PMID 16297627
 
Allelic loss of the ING gene family loci is a frequent event in ameloblastoma.
Borkosky SS, Gunduz M, Beder L, Tsujigiwa H, Tamamura R, Gunduz E, Katase N, Rodriguez AP, Sasaki A, Nagai N, Nagatsuka H.
Oncol Res. 2010;18(10):509-18.
PMID 20681410
 
Structural and functional conservation of the NuA4 histone acetyltransferase complex from yeast to humans.
Doyon Y, Selleck W, Lane WS, Tan S, Cote J.
Mol Cell Biol. 2004 Mar;24(5):1884-96.
PMID 14966270
 
Suppression of the novel growth inhibitor p33ING1 promotes neoplastic transformation.
Garkavtsev I, Kazarov A, Gudkov A, Riabowol K.
Nat Genet. 1996 Dec;14(4):415-20.
PMID 8944021
 
Downregulated inhibitor of growth 3 (ING3) expression during colorectal carcinogenesis.
Gou WF, Sun HZ, Zhao S, Niu ZF, Mao XY, Takano Y, Zheng HC.
Indian J Med Res. 2014 Apr;139(4):561-7.
PMID 24927342
 
Allelic loss and reduced expression of the ING3, a candidate tumor suppressor gene at 7q31, in human head and neck cancers.
Gunduz M, Ouchida M, Fukushima K, Ito S, Jitsumori Y, Nakashima T, Nagai N, Nishizaki K, Shimizu K.
Oncogene. 2002 Jun 27;21(28):4462-70.
PMID 12080476
 
Phylogenetic analysis of the ING family of PHD finger proteins.
He GH, Helbing CC, Wagner MJ, Sensen CW, Riabowol K.
Mol Biol Evol. 2005 Jan;22(1):104-16. Epub 2004 Sep 8.
PMID 15356280
 
Downregulation of inhibitor of growth 3 is correlated with tumorigenesis and progression of hepatocellular carcinoma.
Lu M, Chen F, Wang Q, Wang K, Pan Q, Zhang X.
Oncol Lett. 2012 Jul;4(1):47-52. Epub 2012 Apr 19.
PMID 22807958
 
It takes a PHD to read the histone code.
Mellor J.
Cell. 2006 Jul 14;126(1):22-4. (REVIEW)
PMID 16839870
 
A novel PHD-finger motif protein, p47ING3, modulates p53-mediated transcription, cell cycle control, and apoptosis.
Nagashima M, Shiseki M, Pedeux RM, Okamura S, Kitahama-Shiseki M, Miura K, Yokota J, Harris CC.
Oncogene. 2003 Jan 23;22(3):343-50.
PMID 12545155
 
ING3 is essential for asymmetric cell division during mouse oocyte maturation.
Suzuki S, Nozawa Y, Tsukamoto S, Kaneko T, Imai H, Minami N.
PLoS One. 2013 Sep 16;8(9):e74749. doi: 10.1371/journal.pone.0074749. eCollection 2013.
PMID 24066152
 
Expression profiles of mRNA transcript variants encoding the human inhibitor of growth tumor suppressor gene family in normal and neoplastic tissues.
Walzak AA, Veldhoen N, Feng X, Riabowol K, Helbing CC.
Exp Cell Res. 2008 Jan 15;314(2):273-85. Epub 2007 Aug 2.
PMID 17720155
 
Prognostic significance of nuclear ING3 expression in human cutaneous melanoma.
Wang Y, Dai DL, Martinka M, Li G.
Clin Cancer Res. 2007 Jul 15;13(14):4111-6.
PMID 17634537
 
ING3 promotes UV-induced apoptosis via Fas/caspase-8 pathway in melanoma cells.
Wang Y, Li G.
J Biol Chem. 2006 Apr 28;281(17):11887-93. Epub 2006 Mar 6.
PMID 16520380
 
Expression and prognostic value of ING3 in human primary hepatocellular carcinoma.
Yang HY, Liu HL, Tian LT, Song RP, Song X, Yin DL, Liang YJ, Qu LD, Jiang HC, Liu JR, Liu LX.
Exp Biol Med (Maywood). 2012 Apr;237(4):352-61. doi: 10.1258/ebm.2011.011346.
PMID 22550337
 

Citation

This paper should be referenced as such :
Mouche A, Yaacoub K, Guillaudeux T, Pedeux R
ING3 (inhibitor of growth family, member 3);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/ING3ID40977ch7q31.html


External links

Nomenclature
HGNC (Hugo)ING3   14587
Cards
AtlasING3ID40977ch7q31
Entrez_Gene (NCBI)ING3  54556  inhibitor of growth family member 3
AliasesEaf4; ING2; MEAF4; p47ING3
GeneCards (Weizmann)ING3
Ensembl hg19 (Hinxton)ENSG00000071243 [Gene_View]  chr7:120590817-120615711 [Contig_View]  ING3 [Vega]
Ensembl hg38 (Hinxton)ENSG00000071243 [Gene_View]  chr7:120590817-120615711 [Contig_View]  ING3 [Vega]
ICGC DataPortalENSG00000071243
TCGA cBioPortalING3
AceView (NCBI)ING3
Genatlas (Paris)ING3
WikiGenes54556
SOURCE (Princeton)ING3
Genetics Home Reference (NIH)ING3
Genomic and cartography
GoldenPath hg19 (UCSC)ING3  -     chr7:120590817-120615711 +  7q31   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)ING3  -     7q31   [Description]    (hg38-Dec_2013)
EnsemblING3 - 7q31 [CytoView hg19]  ING3 - 7q31 [CytoView hg38]
Mapping of homologs : NCBIING3 [Mapview hg19]  ING3 [Mapview hg38]
OMIM607493   
Gene and transcription
Genbank (Entrez)AF074968 AF161419 AF180298 AK000096 AK291905
RefSeq transcript (Entrez)NM_019071 NM_198266 NM_198267
RefSeq genomic (Entrez)NC_000007 NC_018918 NG_023322 NT_007933 NW_004929332
Consensus coding sequences : CCDS (NCBI)ING3
Cluster EST : UnigeneHs.489811 [ NCBI ]
CGAP (NCI)Hs.489811
Alternative Splicing GalleryENSG00000071243
Gene ExpressionING3 [ NCBI-GEO ]   ING3 [ EBI - ARRAY_EXPRESS ]   ING3 [ SEEK ]   ING3 [ MEM ]
Gene Expression Viewer (FireBrowse)ING3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)54556
GTEX Portal (Tissue expression)ING3
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9NXR8   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9NXR8  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9NXR8
Splice isoforms : SwissVarQ9NXR8
PhosPhoSitePlusQ9NXR8
Domaine pattern : Prosite (Expaxy)ZF_PHD_1 (PS01359)    ZF_PHD_2 (PS50016)   
Domains : Interpro (EBI)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)PHD (SM00249)  
Conserved Domain (NCBI)ING3
DMDM Disease mutations54556
Blocks (Seattle)ING3
PDB (SRS)1X4I   
PDB (PDBSum)1X4I   
PDB (IMB)1X4I   
PDB (RSDB)1X4I   
Structural Biology KnowledgeBase1X4I   
SCOP (Structural Classification of Proteins)1X4I   
CATH (Classification of proteins structures)1X4I   
SuperfamilyQ9NXR8
Human Protein AtlasENSG00000071243
Peptide AtlasQ9NXR8
HPRD06321
IPIIPI00387159   IPI00413787   IPI00478624   IPI00927032   IPI00925545   
Protein Interaction databases
DIP (DOE-UCLA)Q9NXR8
IntAct (EBI)Q9NXR8
FunCoupENSG00000071243
BioGRIDING3
STRING (EMBL)ING3
ZODIACING3
Ontologies - Pathways
QuickGOQ9NXR8
Ontology : AmiGOSwr1 complex  histone acetyltransferase activity  nucleus  nucleoplasm  nucleolus  cytoplasm  transcription, DNA-templated  regulation of transcription, DNA-templated  zinc ion binding  Piccolo NuA4 histone acetyltransferase complex  methylated histone binding  NuA4 histone acetyltransferase complex  regulation of growth  positive regulation of apoptotic process  histone H4 acetylation  histone H2A acetylation  
Ontology : EGO-EBISwr1 complex  histone acetyltransferase activity  nucleus  nucleoplasm  nucleolus  cytoplasm  transcription, DNA-templated  regulation of transcription, DNA-templated  zinc ion binding  Piccolo NuA4 histone acetyltransferase complex  methylated histone binding  NuA4 histone acetyltransferase complex  regulation of growth  positive regulation of apoptotic process  histone H4 acetylation  histone H2A acetylation  
REACTOMEQ9NXR8 [protein]
REACTOME Pathways3214847 [pathway]   
NDEx NetworkING3
Atlas of Cancer Signalling NetworkING3
Wikipedia pathwaysING3
Orthology - Evolution
OrthoDB54556
GeneTree (enSembl)ENSG00000071243
Phylogenetic Trees/Animal Genes : TreeFamING3
HOVERGENQ9NXR8
HOGENOMQ9NXR8
Homologs : HomoloGeneING3
Homology/Alignments : Family Browser (UCSC)ING3
Gene fusions - Rearrangements
Fusion : MitelmanARID4B/ING3 [1q42.3/7q31.31]  [t(1;7)(q42;q31)]  
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerING3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ING3
dbVarING3
ClinVarING3
1000_GenomesING3 
Exome Variant ServerING3
ExAC (Exome Aggregation Consortium)ING3 (select the gene name)
Genetic variants : HAPMAP54556
Genomic Variants (DGV)ING3 [DGVbeta]
DECIPHER (Syndromes)7:120590817-120615711  ENSG00000071243
CONAN: Copy Number AnalysisING3 
Mutations
ICGC Data PortalING3 
TCGA Data PortalING3 
Broad Tumor PortalING3
OASIS PortalING3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICING3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDING3
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 ING3
DgiDB (Drug Gene Interaction Database)ING3
DoCM (Curated mutations)ING3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ING3 (select a term)
intoGenING3
NCG5 (London)ING3
Cancer3DING3(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM607493   
Orphanet
MedgenING3
Genetic Testing Registry ING3
NextProtQ9NXR8 [Medical]
TSGene54556
GENETestsING3
Huge Navigator ING3 [HugePedia]
snp3D : Map Gene to Disease54556
BioCentury BCIQING3
ClinGenING3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD54556
Chemical/Pharm GKB GenePA29875
Clinical trialING3
Miscellaneous
canSAR (ICR)ING3 (select the gene name)
Probes
Litterature
PubMed33 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineING3
EVEXING3
GoPubMedING3
iHOPING3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Apr 12 11:33:39 CEST 2017

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