ING2 (inhibitor of growth family, member 2)

2009-05-01   Susanne Jennek , Aria Baniahmad 

Institute of Human Genetics, Anthropology, Jena University Hospital, Kollegiengasse 10, 07743 Jena, Germany




Atlas Image
Gene structure of ING2a and ING2b (modified according to Unoki et al., 2008).


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).


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).



  • 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).


    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).


    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).


    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).



    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

    Entity name
    Colon cancer
    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 name
    Hepatocellular carcinoma (HCC)
    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 name
    Head and neck squamous cell carcinoma (HNSCC)
    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 name
    Lung cancer
    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 name
    Cutaneous melanomas
    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).


    Pubmed IDLast YearTitleAuthors
    189981652009Frequent deletion of ING2 locus at 4q35.1 associates with advanced tumor stage in head and neck squamous cell carcinoma.Borkosky SS et al
    155261652004Biological functions of the ING family tumor suppressors.Campos EI et al
    163876532006ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation.Doyon Y et al
    179298522007The tumor suppressors p33ING1 and p33ING2 interact with alien in vivo and enhance alien-mediated gene silencing.Fegers I et al
    185134922008ING2 recruits histone methyltransferase activity with methylation site specificity distinct from histone H3 lysines 4 and 9.Goeman F et al
    128599012003The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor.Gozani O et al
    167552972006Nuclear ING2 expression is reduced in human cutaneous melanomas.Lu F et al
    114814242001DNA damage-inducible gene p33ING2 negatively regulates cell proliferation through acetylation of p53.Nagashima M et al
    164654102006Alterations in novel candidate tumor suppressor genes, ING1 and ING2 in human lung cancer.Okano T et al
    160247992005ING2 regulates the onset of replicative senescence by induction of p300-dependent p53 acetylation.Pedeux R et al
    166448822006Molecular biology of squamous cell carcinoma of the head and neck.Perez-Ordoñez B et al
    183344802008ING2 as a novel mediator of transforming growth factor-beta-dependent responses in epithelial cells.Sarker KP et al
    167289742006ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression.Shi X et al
    100725871998Cloning of a novel gene (ING1L) homologous to ING1, a candidate tumor suppressor.Shimada Y et al
    179499862007After a decade of study-ING, a PHD for a versatile family of proteins.Soliman MA et al
    189518972008A novel ING2 isoform, ING2b, synergizes with ING2a to prevent cell cycle arrest and apoptosis.Unoki M et al
    164889872006The novel tumor suppressor p33ING2 enhances nucleotide excision repair via inducement of histone H4 acetylation and chromatin relaxation.Wang J et al
    186365622008The new tumor suppressor genes ING: genomic structure and status in cancer.Ythier D et al
    181602122008Decreased expression of ING2 gene and its clinicopathological significance in hepatocellular carcinoma.Zhang HK et al

    Other Information

    Locus ID:

    NCBI: 3622
    MIM: 604215
    HGNC: 6063
    Ensembl: ENSG00000168556


    dbSNP: 3622
    ClinVar: 3622
    TCGA: ENSG00000168556


    Gene IDTranscript IDUniprot

    Expression (GTEx)



    PathwaySourceExternal ID
    Gene ExpressionREACTOMER-HSA-74160
    Generic Transcription PathwayREACTOMER-HSA-212436
    Transcriptional Regulation by TP53REACTOMER-HSA-3700989
    Regulation of TP53 ActivityREACTOMER-HSA-5633007
    Regulation of TP53 Activity through AcetylationREACTOMER-HSA-6804758
    PI5P Regulates TP53 AcetylationREACTOMER-HSA-6811555

    Protein levels (Protein atlas)

    Not detected


    Pubmed IDYearTitleCitations
    184511452008Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence.84
    114814242001DNA damage-inducible gene p33ING2 negatively regulates cell proliferation through acetylation of p53.65
    160247992005ING2 regulates the onset of replicative senescence by induction of p300-dependent p53 acetylation.41
    183344802008ING2 as a novel mediator of transforming growth factor-beta-dependent responses in epithelial cells.25
    164889872006The novel tumor suppressor p33ING2 enhances nucleotide excision repair via inducement of histone H4 acetylation and chromatin relaxation.23
    238238702013Nuclear phosphatidylinositol-5-phosphate regulates ING2 stability at discrete chromatin targets in response to DNA damage.18
    211249652010Targeted disruption of Ing2 results in defective spermatogenesis and development of soft-tissue sarcomas.17
    174698222007Stabilized phosphatidylinositol-5-phosphate analogues as ligands for the nuclear protein ING2: chemistry, biology, and molecular modeling.15
    167820912006Leucine zipper-like domain is required for tumor suppressor ING2-mediated nucleotide excision repair and apoptosis.14
    194375362009ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression.14


    Susanne Jennek ; Aria Baniahmad

    ING2 (inhibitor of growth family, member 2)

    Atlas Genet Cytogenet Oncol Haematol. 2009-05-01

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