| Written | 2009-05 | Susanne Jennek, Aria Baniahmad |
| Institute of Human Genetics, Anthropology, Jena University Hospital, Kollegiengasse 10, 07743 Jena, Germany |
| Identity |
| Alias_names | ING1L |
| inhibitor of growth family | |
| Alias_symbol (synonym) | p33ING2 |
| Other alias | ING1Lp |
| p32 | |
| HGNC (Hugo) | ING2 |
| LocusID (NCBI) | 3622 |
| Atlas_Id | 40975 |
| Location | 4q35.1 [Link to chromosome band 4q35] |
| Location_base_pair | Starts at 183505050 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 | |
| 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 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Mon Sep 3 15:54:36 CEST 2018 |
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