Comparative Assessment Expression of the Inhibitor of Growth 1 Gene (<i>ING1</i>) in Normal and Neoplastic Tissues

Nouman, G S; Angus, Brian; Lunec, John; Crosier, S; Lodge, Andrew J.; Anderson, James

doi:10.1089/15368590252917584

Cited by 31 publications

(38 citation statements)

References 22 publications

(26 reference statements)

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“…Based on reports of malignancies in the stomach [7], esophagus [8], brain [9], breast [10], blood [11,12], lung [13], liver [14], head and neck [15], lymphoid system [16], thyroid [17], and ovary [18], it can be deduced that the expression of p33…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-mediated expression of p33ING1b induces apoptosis and inhibits proliferation in gastric adenocarcinoma cells in vitro

Purbey

Huang

et al. 2012

Gastric Cancer

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Background Inhibitor of growth 1b (ING1b) is considered to be a class II tumor suppressor gene. Although reduced expression of p33ING1b has been reported in many human malignancies, including gastric cancers, the effect of p33ING1b on gastric cancer cells has yet to be investigated. Methods Expression of p33ING1b in gastric adenocarcinoma tissues and their adjacent non-malignant gastric mucosa, as well as in gastric adenocarcinoma cell lines and normal gastric epithelial cells, was detected by using Western blotting. Recombinant adenoviruses were prepared to mediate the ectopic expression of p33 ING1b(Ad-ING1b) and green fluorescent protein (GFP)(Ad-GFP) in the gastric adenocarcinoma cell lines, SGC-7901, MKN28, and MKN45 and the normal gastric epithelial cell line GES-1. Alterations in the proliferation and apoptosis of the cells after adenoviral infection were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively, and cell cycle distribution was analyzed in a fluorescenceactivated cell sorter. Results Western blotting confirmed the reduced expression of p33ING1b in gastric adenocarcinoma tissues and gastric adenocarcinoma cell lines. The ectopic expression of p33ING1b mediated by Ad-ING1b resulted in decreased growth, increased apoptosis, and cell cycle arrest at the G1 phase in both benign and malignant gastric epithelial cells regardless of their p53 status. Addition of a p53 inhibitor, pifithrin-a, did not abolish the pro-apoptotic and cell cyclearresting effects of p33ING1b in p53 wild-type cells. Conclusions Down-regulation of p33ING1b might play an important role in the development of gastric adenocarcinoma. Targeted local expression of p33ING1b may offer a promising alternative therapeutic measure for gastric cancer.

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Section: Introductionmentioning

confidence: 99%

Adenovirus-mediated expression of p33ING1b induces apoptosis and inhibits proliferation in gastric adenocarcinoma cells in vitro

Purbey

Huang

et al. 2012

Gastric Cancer

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“…Additionally, a loss of nuclear localization and an increase of cytoplasmic localization of ING1 has been observed in melanoma, ductal breast and papillary thyroid carcinomas and lymphoblastic leukaemia. [37][38][39] To understand the molecular basis of histone recognition by the ING1 PHD finger and to further our knowledge of tumorigenic mechanisms, we determined a 2.1 Å resolution crystal structure of the PHD finger of human ING1 in complex with a H3K4me3 peptide and elucidated the role of cancer specific mutations in the histone binding and function of ING1.…”

Section: Introductionmentioning

confidence: 99%

Histone H3K4me3 Binding Is Required for the DNA Repair and Apoptotic Activities of ING1 Tumor Suppressor

Peña

Hom

Hung

et al. 2008

Journal of Molecular Biology

115

111

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SummaryInhibitor of growth 1 (ING1) is implicated in oncogenesis, DNA damage repair and apoptosis. Mutations within the ING1 gene and altered expression levels of ING1 are found in multiple human cancers. Here, we show that both DNA repair and apoptotic activities of ING1 require the interaction of the C-terminal plant homeodomain (PHD) finger with trimethylated at Lys 4 histone H3 (H3K4me3). The ING1 PHD finger recognizes methylated H3K4 but not other histone modifications as revealed by the peptide microarrays. The molecular mechanism of the histone recognition is elucidated based on a 2.1 Å resolution crystal structure of the PHD-H3K4me3 complex. The K4me3 occupies a deep hydrophobic pocket formed by the conserved Y212 and W235 residues that make cation-π contacts with the trimethylammonium group. Both aromatic residues are essential in the H3K4me3 recognition, as substitution of these residues with Ala disrupts the interaction. Unlike the wild type ING1, the W235A mutant, overexpressed in the stable clones of melanoma cells or in HT1080 cells, was unable to stimulate DNA repair after UV irradiation or promote DNA-damage induced apoptosis, indicating that H3K4me3 binding is necessary for these biological functions of ING1. Furthermore, N216S, V218I and G221V mutations, found in human malignances, impair the ability of ING1 to associate with H3K4me3 or to induce nucleotide repair and cell death, linking the tumorigenic activity of ING1 with epigenetic regulation. Together, our findings reveal the critical role of the H3K4me3 interaction in mediating cellular responses to genotoxic stresses and offer new insight into the molecular mechanism underlying the tumor suppressive activity of ING1.

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“…Although ING1 mutations are infrequent, most of them were found in the NLS and PHD domains (Gong et al, 2005). ING1 downregulation was observed in different tumor types (breast, gastric, esophageal, blood, lung and brain) (Gong et al, 2005), whereas protein mislocalization was described in tumors of different origin (Nouman et al, 2002). ING2 expression was reduced in colorectal, hepatocellular carcinoma, prostate, pancreatic, lung cancer and cutaneous melanoma (Nagashima et al, 2001;Lu et al, 2006;Okano et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Detection of novel mRNA splice variants of human ING4 tumor suppressor gene

et al. 2007

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Inhibitor of growth (ING)4, member of a gene family encoding potential tumor suppressors, is implicated as a repressor of angiogenesis and tumor growth and suppresses loss of contact inhibition in vitro. Here, we report that ING4 undergoes alternative splicing. Expression analysis identified novel ING4 spliced variant mRNAs encoding proteins devoid of different portions. The ING4 variants were detected in both normal and tumor tissues. The existence of ING4 variants was confirmed by several approaches, including reverse transcriptase-polymerase chain reaction, real-time PCR and in silico experiments. To investigate the functional consequences of alternative splicing the ING4 variant cDNAs were expressed in mammalian cells. Our studies indicated that (i) the ING4 variants do not differ from wild-type in their nuclear localization, interaction with p53 and association to HBO1 complex; and (ii) the ING4-DEx6A variant, devoid of the C-terminal portion, loses the capability to inhibit NF-jB. On the whole our data suggest that alternative splicing could modulate the activity of ING4 tumor suppressor protein.

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Comparative Assessment Expression of the Inhibitor of Growth 1 Gene (ING1) in Normal and Neoplastic Tissues

Cited by 31 publications

References 22 publications

Adenovirus-mediated expression of p33ING1b induces apoptosis and inhibits proliferation in gastric adenocarcinoma cells in vitro

Adenovirus-mediated expression of p33ING1b induces apoptosis and inhibits proliferation in gastric adenocarcinoma cells in vitro

Histone H3K4me3 Binding Is Required for the DNA Repair and Apoptotic Activities of ING1 Tumor Suppressor

Detection of novel mRNA splice variants of human ING4 tumor suppressor gene

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