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ING1 and ING2: multifaceted tumor suppressor genes

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Abstract

Inhibitor of Growth 1 (ING1) was identified and characterized as a “candidate” tumor suppressor gene in 1996. Subsequently, four more genes, also characterized as “candidate” tumor suppressor genes, were identified by homology search: ING2, ING3, ING4, and ING5. The ING proteins are characterized by a high homology in their C-terminal domain, which contains a Nuclear Localization Sequence and a Plant HomeoDomain (PHD), which has a high affinity to Histone 3 tri-methylated on lysine 4 (H3K4Me3). The ING proteins have been involved in the control of cell growth, senescence, apoptosis, chromatin remodeling, and DNA repair. Within the ING family, ING1 and ING2 form a subgroup since they are evolutionarily and functionally close. In yeast, only one gene, Pho23, is related to ING1 and ING2 and possesses also a PHD. Recently, the ING1 and ING2 tumor suppressor status has been fully established since several studies have described the loss of ING1 and ING2 protein expression in human tumors and both ING1 and ING2 knockout mice were reported to have spontaneously developed tumors, B cell lymphomas, and soft tissue sarcomas, respectively. In this review, we will describe for the first time what is known about the ING1 and ING2 genes, proteins, their regulations in both human and mice, and their status in human tumors. Furthermore, we explore the current knowledge about identified functions involving ING1 and ING2 in tumor suppression pathways especially in the control of cell cycle and in genome stability.

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Acknowledgments

We thank Dr. D. Ythier for critical reading of this manuscript and H. Symington for careful reading of the English. R.P. is supported by INSERM (Institut National de la Santé et de la Recherche Medicale), C.G. is a recipient of a doctoral fellowship from the French Ministry of Education and Research, D.L. is recipient of a post-doctoral EMBO fellowship (ALTF 834-2011), and the work was supported by La Ligue Contre le Cancer (Grand Ouest), Association pour la Recherche sur le Cancer (ARC), Rennes Métropole (AIS) and Leucémie Espoir grants.

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Authors and Affiliations

  1. INSERM U917, Faculté de Médecine de Rennes, Microenvironnement et Cancer, Building 2, Room 117, 2 avenue du Professeur Léon Bernard, 35043, Rennes, France

    Claire Guérillon & Rémy Pedeux

  2. Université de Rennes 1, Rennes, France

    Claire Guérillon & Rémy Pedeux

  3. Etablissement Français du Sang, Rennes, France

    Rémy Pedeux

  4. The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK

    Delphine Larrieu

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  1. Claire Guérillon
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Correspondence to Rémy Pedeux.

Electronic supplementary material

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18_2013_1270_MOESM1_ESM.pdf

Supplementary Figure S1: Structure of Human ING1, mouse ING1, and ING2 genes, mRNAs and proteins. A. ING1 human gene. E1c, E1d, E1a, E1b, E1balt, E2 are respectively Exon 1c, Exon 1d, Exon 1a, Exon 1b, Exon 1balt, and Exon 2. Exons E1d and E1balt of ING1v2 and ING1v5 are represented in orange. They both code for the same protein ING1c (ING1v2/v5) as their ATG on E2 is the same. B. ING1 human mRNAs. C. ING1b human protein. All ING1 protein isoforms contain a NCR and a NLS in their central region and a PHD and a PBR in their C-terminal part. ING1b is also composed of a PIP and a PBD in its N-terminal part. D. ING1 mouse gene. E1a, E1b, E2 are respectively Exon 1a, 1b, 1c and Exon 2. E. ING1 mouse mRNAs. F. ING1 mouse proteins. The three mouse ING1 isoforms possess a NCR, a NLS, a PHD and a PBR. In addition, mouse ING1b contains a PIP and a PBD in its N-terminal domain. G. ING2 mouse gene. E1a, E1b, E2 are respectively Exon 1a, 1b and Exon 2. H. ING2 mouse mRNAs. I. ING2 mouse proteins. ING2a contains a LZL in its C terminal part. ING2a possesses a NCR and ING2b is truncated of a part of the NCR domain. Both ING2a and ING2b are composed of a NLS containing three NTS, a PHD zinc finger motif and a PBR. On genes and mRNAs, none coding regions are in yellow and coding region are represented in purple. Each mRNA variant is represented with its name on the left and its GenBank accession number on the right. Each protein is represented with its characterized domains with its name on the right and with its molecular weight, and its GenBank accession number on the left (PDF 51 kb)

18_2013_1270_MOESM2_ESM.pdf

Supplementary Figure S2: Sequences comparison between human and mouse ING1b or ING2 cDNAs and proteins. A. Human ING1b and mouse ING1 cDNA sequences alignment. B. Human ING1b and mouse ING1 protein sequences alignment. C. Human and mouse ING2 cDNA sequences alignment. D. Human and mouse ING2a and ING2b proteins alignment. For all alignments, the PIP is colored in pinked purple; the LZL amino acid sequence is colored in green the PBD is colored in blue; the NCR is colored in purple; the NLS is highlighted in blue; the three NTS are colored in blue; the REASP amino acid motif is colored in pink; the PHD is colored in red; the PBR is colored in orange. All alignments were carried out using CLUSTAL 2.1 multiple sequence alignment software (PDF 4.49 MB)

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Guérillon, C., Larrieu, D. & Pedeux, R. ING1 and ING2: multifaceted tumor suppressor genes. Cell. Mol. Life Sci. 70, 3753–3772 (2013). https://doi.org/10.1007/s00018-013-1270-z

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