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

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.

The nuclear to cytoplasmic shift of ING5 protein during colorectal carcinogenesis with their distinct links to pathologic behaviors of carcinomas

“…A large body of research has shown evidence for alteration or down-regulation of the ING genes in malignancies [2][3][4]. ING2 was shown to be down-regulated at both the transcriptional and posttranslational levels and was closely associated with a poor survival rate in hepatocellular carcinoma [27].…”

“…Among them, ING5 is localized to human chromosome 2q37.3, contains 8 exons and 7 introns, and encodes 5233-bp cDNA, whose 1068 nucleotides are translated into 28-kDa protein of 240 amino acids [2]. The encoding product, a tumor suppressor protein, can inhibit cell growth and induce apoptosis [3,4].…”

“…Among them, chromosomal deletion, mutation, or hypermethylation, which can lead to loss (class I) or inactivation (class II) of tumor suppressor genes causing immortality of cancer cells, has provided clues to the identification of genes critical for initiation, promotion, and development of tumors, such as the inhibitor of growth (ING) family [2].…”

“…Loss or down-regulation of ING protein function is frequently observed in different tumor types, many of which are resistant to apoptosis, thus warranting their classification as type II tumor suppressors [2][3][4][10][11][12][13][14][15][16]. Several different in vitro and in vivo models have explored the role of ING proteins in regulating apoptosis [2,4,17].…”

“…Several different in vitro and in vivo models have explored the role of ING proteins in regulating apoptosis [2,4,17]. ING5 overexpression can result in a diminished colony-forming efficiency, a decreased cell population in S phase, and the induction of apoptosis in a p53-dependent manner [9].…”