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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)


Alias (NCBI)Eaf4
HGNC (Hugo) ING3
HGNC Alias symbp47ING3
LocusID (NCBI) 54556
Atlas_Id 40977
Location 7q31.31  [Link to chromosome band 7q31]
Location_base_pair Starts at 120950777 and ends at 120956980 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ING3.png]
  Figure 1. Chromosomal localization of the ING3 gene in Homo sapiens.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ARID4B (1q42.3)::ING3 (7q31.31)ING3 (7q31.31)::CHMP1A (16q24.3)ING3 (7q31.31)::IVNS1ABP (1q25.3)
YTHDC1 (4q13.2)::ING3 (7q31.31)


  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).


  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

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).


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


This paper should be referenced as such :
Audrey Mouche, Katherine Yaacoub, Thierry Guillaudeux, Rmy Pedeux
ING3 (inhibitor of growth family, member 3)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(11):662-665.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(1;7)(q42;q31) ARID4B::ING3

External links

HGNC (Hugo)ING3   14587
Atlas Explorer : (Salamanque)ING3
Entrez_Gene (NCBI)ING3    inhibitor of growth family member 3
AliasesEaf4; ING2; MEAF4; p47ING3
GeneCards (Weizmann)ING3
Ensembl hg19 (Hinxton)ENSG00000071243 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000071243 [Gene_View]  ENSG00000071243 [Sequence]  chr7:120950777-120956980 [Contig_View]  ING3 [Vega]
ICGC DataPortalENSG00000071243
TCGA cBioPortalING3
AceView (NCBI)ING3
Genatlas (Paris)ING3
SOURCE (Princeton)ING3
Genetics Home Reference (NIH)ING3
Genomic and cartography
GoldenPath hg38 (UCSC)ING3  -     chr7:120950777-120956980 +  7q31.31   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ING3  -     7q31.31   [Description]    (hg19-Feb_2009)
GoldenPathING3 - 7q31.31 [CytoView hg19]  ING3 - 7q31.31 [CytoView hg38]
Genome Data Viewer NCBIING3 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AF074968 AF161419 AF180298 AK000096 AK291905
RefSeq transcript (Entrez)NM_019071 NM_198266 NM_198267
Consensus coding sequences : CCDS (NCBI)ING3
Gene ExpressionING3 [ NCBI-GEO ]   ING3 [ EBI - ARRAY_EXPRESS ]   ING3 [ SEEK ]   ING3 [ MEM ]
Gene Expression Viewer (FireBrowse)ING3 [ Firebrowse - Broad ]
GenevisibleExpression of ING3 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)54556
GTEX Portal (Tissue expression)ING3
Human Protein AtlasENSG00000071243-ING3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)ING3
Human Protein Atlas [tissue]ENSG00000071243-ING3 [tissue]
Protein Interaction databases
Complex Portal (EBI) CPX-709 Piccolo NuA4 histone acetyltransferase complex
CPX-978 NuA4 histone acetyltransferase complex
Ontologies - Pathways
PubMed57 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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