Targeted disruption of the mouse ing1 locus results in reduced body size, hypersensitivity to radiation and elevated incidence of lymphomas

Kichina, Julia V.; Zeremski, Marija; Aris, L; Gurova, Katerina V.; Walker, Emma C; Franks, Roberta; Nikitin, A Y; Kiyokawa, Hiroaki; Gudkov, Andrei V.

doi:10.1038/sj.onc.1209118

Cited by 63 publications

(96 citation statements)

References 41 publications

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“…MEFs double knock-out for p53 and Mdm2 (DKO) treated with adriamycin were used as a negative control. Phosphorylated p53 was detected by Western blot on CM5 p53 immunoprecipitates using a specific antibody against p53 phosphorylated in system, in agreement with observations in a different animal model of Ing1 loss of function (36). A role for ING1 as a regulator of p53 function has been suggested previously, based on overexpression experiments.…”

Section: Discussionsupporting

confidence: 66%

Ing1 Mediates p53 Accumulation and Chromatin Modification in Response to Oncogenic Stress

Abad

Menéndez

Füchtbauer

et al. 2007

Journal of Biological Chemistry

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ING proteins are putative tumor suppressor proteins linked to the p53 pathway and to the chromatin modification machinery. Here we have analyzed the role of the products of the murine Ing1 locus in cellular tumor-protective responses, using mouse primary fibroblasts where the Ing1 locus has been inactivated by the integration of a ␤geo cassette. We show that Ing1-deficient mouse embryonic fibroblasts display a defective senescence-like antiproliferative response against oncogenic Ras, affecting several senescence-specific markers. This phenotype is accompanied by a reduced accumulation of p53, which can be explained by the reduced basal p53 protein stability in the Ing1-deficient background. Ing1 deficiency also results in defects in the appearance of heterochromatic marks upon expression of oncogenic Ras, suggestive of impaired heterochromatin formation during oncogene-induced senescence. Our results support an important role for the Ing1 locus in protection against oncogenic stress in vivo, both as a mediator of p53 activation and as a regulator of chromatin remodeling processes.

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Section: Discussionsupporting

confidence: 66%

Ing1 Mediates p53 Accumulation and Chromatin Modification in Response to Oncogenic Stress

Abad

Menéndez

Füchtbauer

et al. 2007

Journal of Biological Chemistry

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“…The only reported knockout, ING1, is viable, but animals have an increased incidence of B-cell lymphomas and sensitivity to g-radiation (Kichina et al 2006;Coles et al 2007), consistent with ING1 being a type II tumor suppressor. However, although previous cell culture results clearly indicate that ING proteins interact both physically and genetically with p53 (Garkavtsev et al 1998;Shinoura et al 1999;Shiseki et al 2003;reviewed in Soliman and Riabowol 2007), neither ING1 deletion mice nor their derived cell lines demonstrated that ING1 function depends upon p53 or that p53 function is perturbed in ING1 knockouts (Coles et al 2007).…”

mentioning

confidence: 89%

TheCaenorhabditis elegans ing-3Gene Regulates Ionizing Radiation-Induced Germ-Cell Apoptosis in a p53-Associated Pathway

Luo¹,

Shah²,

Riabowol³

et al. 2009

Genetics

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The inhibitor of growth (ING) family of type II tumor suppressors are encoded by five genes in mammals and by three genes in Caenorhabditis elegans. All ING proteins contain a highly conserved plant homeodomain (PHD) zinc finger. ING proteins are activated by stresses, including ionizing radiation, leading to the activation of p53. ING proteins in mammals and yeast have recently been shown to read the histone code in a methylation-sensitive manner to regulate gene expression. Here we identify and characterize ing-3, the C. elegans gene with the highest sequence identity to the human ING3 gene. ING-3 colocalizes with chromatin in embryos, the germline, and somatic cells. The ing-3 gene is part of an operon but is also transcribed from its own promoter. Both ing-3(RNAi) and ing-3 mutant strains demonstrate that the gene likely functions in concert with the C. elegans p53 homolog, cep-1, to induce germ-cell apoptosis in response to ionizing radiation. Somatically, the ing-3 mutant has a weak kinker uncoordinated (kinker Unc) phenotype, indicating a possible neuronal function.

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“…Not only human ING1b, but also both mouse Ing1 proteins (p31 Ing1a/c and p37 Ing1b ) (Zeremski et al 1999;Kichina et al 2006) synergized with mouse Gadd45a in reporter reactivation (Supplemental Fig. S1D,E).…”

Section: Gadd45a Requires Ing1b For Dna Demethylationmentioning

confidence: 99%

“…We next analyzed Mageb2 regulation genetically in primary mouse embryonic fibroblasts (MEFs), which we generated from mice single mutant (Hollander et al 1999; Kichina et al 2006) or double mutant (double knockout [DKO]) (this study) for Gadd45a and Ing1. Gadd45a and Ing1 are UV-inducible stress response genes (Fornace et al 1988;Hollander et al 1999;Cheung et al 2001).…”

Section: Gadd45a and Ing1 Mediate Mageb2 Demethylationmentioning

confidence: 99%

“…Like Gadd45a, ING1 is induced by stress or UV irradiation, inhibits cell growth by interacting with p21 waf1 , and promotes NER (Cheung et al 2001). Furthermore, Ing1 mouse mutants are radiation-sensitive and tumor-prone, like Gadd45a mutants (Hollander et al 1999;Kichina et al 2006). ING proteins are found in complex with histone acetyl transferases (HATs) (Vieyra et al 2002) and histone deacetylases (HDACs) (Skowyra et al 2001;Kuzmichev et al 2002).…”

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confidence: 99%

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Ing1 functions in DNA demethylation by directing Gadd45a to H3K4me3

et al. 2013

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Active DNA demethylation regulates epigenetic gene activation in numerous processes, but how the target site specificity of DNA demethylation is determined and what factors are involved are still poorly understood. Here we show that the tumor suppressor inhibitor of growth protein 1 (Ing1) is required for targeting active DNA demethylation. Ing1 functions by recruiting the regulator of DNA demethylation growth arrest and DNA damage protein 45a (Gadd45a) to histone H3 trimethylated at Lys 4 (H3K4me3). We show that reduced H3K4 methylation impairs recruitment of Gadd45a/Ing1 and gene-specific DNA demethylation. Our results indicate that histone methylation directs DNA demethylation.

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Targeted disruption of the mouse ing1 locus results in reduced body size, hypersensitivity to radiation and elevated incidence of lymphomas

Cited by 63 publications

References 41 publications

Ing1 Mediates p53 Accumulation and Chromatin Modification in Response to Oncogenic Stress

Ing1 Mediates p53 Accumulation and Chromatin Modification in Response to Oncogenic Stress

TheCaenorhabditis elegans ing-3Gene Regulates Ionizing Radiation-Induced Germ-Cell Apoptosis in a p53-Associated Pathway

Ing1 functions in DNA demethylation by directing Gadd45a to H3K4me3

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