Inhibitor of Growth (ING) Family: An Emerging Molecular Target for Cancer Therapy

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  • Gunduz Esra
    Department of Oral Pathology and Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Molecular Genetics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
  • Gunduz Mehmet
    Department of Oral Pathology and Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Department of Otolaryngology Head and Neck Surgery, Wakayama Medical University
  • Beder Levent Bekir
    Department of Otolaryngology Head and Neck Surgery, Wakayama Medical University
  • Tamamura Ryo
    Department of Oral Pathology and Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
  • Nagatsuka Hitoshi
    Department of Oral Pathology and Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
  • Nagai Noriyuki
    Department of Oral Pathology and Medicine, Dentistry and Pharmaceutical Sciences, Okayama University

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Abstract

ING1 gene, the founding member of the ING tumor suppressor family, was originally identified through subtractive hybridization between normal mammary epithelial cells and breast cancer cell lines, and subsequent in vivo selection of genetic suppressor element that displayed oncogenic features. Soon after identification of ING1, four additional members of the ING family (ING2-5) were cloned and all the gene products contain a highly conserved plant homeodomain (PHD) finger motif in the carboxy (C)-terminal end, that plays important role for their function. Furthermore, ING family members contain nuclear localization signals and N-terminal sequences important in the interaction with histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) that regulate gene promoter activity within chromatin. Although exact functions of ING family genes have not been clarified, the gene products are involved in transcriptional regulation, apoptosis, cell cyle, angiogenesis and DNA repair through p53-dependent and -independent pathways. Chromosomal deletion and decreased expression of each ING family member gene in various cancer types strongly suggested products of these genes as tumor suppressor factors. Rare mutation but frequent allelic loss and epigenetic changes have been shown in ING family genes, suggesting them as a class II tumor suppressor gene. This review summarizes the known biological functions of the ING tumor suppressors and signaling related pathways.

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