Nuclear to cytoplasmic compartment shift of the p33<sup><i>ING1b</i></sup> tumour suppressor protein is associated with malignancy in melanocytic lesions

Nouman, G S; Anderson, James; Mathers, Marie E.; Leonard, Niamh; Crosier, S; Lunec, Joseph; Angus, Brian

doi:10.1046/j.1365-2559.2002.01369.x

Cited by 38 publications

(47 citation statements)

References 30 publications

(45 reference statements)

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“…In this study, we found that rapid ING3 degradation has an important role in the loss of ING3 expression in advanced melanomas, thereby providing another explanation of aberrant ING3 expression in melanomas in addition to our previous finding that subcellular relocalization of ING3 causes its deregulation in both primary and metastatic melanomas (Wang et al, 2007). Meanwhile, ING1b has been shown to be shifted from the nucleus to the cytoplasm in melanocytic lesions (Nouman et al, 2002), which may be mediated by 14-3-3 proteins (Gong et al, 2006). Both nuclear ING2 and overall ING4 expressions are also downregulated in melanomas, although only the reduced ING4 expression was significantly associated with melanoma progression (Lu et al, 2006;Li et al, 2008).…”

Section: Discussionsupporting

confidence: 68%

The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system

et al. 2009

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The inhibitor of growth family member 3 (ING3) has been shown to modulate transcription, cell cycle control and apoptosis. We previously reported that nuclear ING3 expression was remarkably reduced in melanomas, which correlated with a poorer patient survival, suggesting that decreased ING3 expression may be associated with melanoma progression. However, the mechanism of diminished ING3 expression in melanoma is not clear. Here we show that ING3 level was decreased in metastatic melanoma cells because of a rapid degradation. Furthermore, we showed that ING3 undergoes degradation through the ubiquitinproteasome pathway. ING3 physically interacts with subunits of E3 ligase Skp1-Cullin-F-box protein complex (SCF complex). Knockdown of F-box protein S-phase kinaseassociated protein 2 (Skp2) reduces the ubiquitination of ING3 and significantly stabilizes ING3 in melanoma cells. In addition, lysine 96 residue is essential for ING3 ubiquitination as its mutation to arginine dramatically abrogated ING3 degradation. Disruption of ING3 degradation stimulated ING3-induced G1 cell-cycle arrest and enhanced ultravioletinduced apoptosis. Taken together, our data show that ING3 is degraded by the ubiquitin-proteasome pathway through the SCF Skp2 complex and interruption of ING3 degradation enhances the tumor-suppressive function of ING3, which provides a potential cancer therapeutic approach by interfering ING3 degradation.

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Section: Discussionsupporting

confidence: 68%

The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system

et al. 2009

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“…ING1b exhibited proliferation-inhibitory, apoptosis-promoting, and cell cycle-arrest effects in both benign and malignant cells [20][21][22][23][24][25][26][27][28][29]. These data, along with the results of reduced expression of p33 ING1b in gastric adenocarcinoma tissues, provide substantial evidence that p33…”

Section: P33mentioning

confidence: 76%

“…ING1b expression was down-regulated in the gastric adenocarcinoma cell lines SGC-7901, MKN28, and MKN45 compared with the normal by nucleus-to-cytoplasm translocation in cancer cells [11,22]. Based on these results, it can be concluded that decreased expression of p33 ING1b is a common phenomenon in gastric adenocarcinoma, and this alteration might contribute to the development of gastric adenocarcinoma.…”

Section: P33mentioning

confidence: 77%

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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“…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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Nuclear to cytoplasmic compartment shift of the p33^ING1b tumour suppressor protein is associated with malignancy in melanocytic lesions

Cited by 38 publications

References 30 publications

The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system

The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system

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

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Nuclear to cytoplasmic compartment shift of the p33ING1b tumour suppressor protein is associated with malignancy in melanocytic lesions

Cited by 38 publications

References 30 publications

The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system

The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system

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

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Nuclear to cytoplasmic compartment shift of the p33^ING1b tumour suppressor protein is associated with malignancy in melanocytic lesions