Human ING1 Proteins Differentially Regulate Histone Acetylation

Vieyra, Diego; Loewith, Robbie; Scott, Michelle S.; Bonnefin, Paul; Boisvert, François‐Michel; Cheema, Parneet K.; Pastyryeva, Svitlana; Meijer, Maria; Johnston, Randal N.; Bazett-Jones, David P.; McMahon, Steven B.; Cole, Michael; Young, Dallan; Riabowol, Karl

doi:10.1074/jbc.m200197200

Cited by 101 publications

(119 citation statements)

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“…Interestingly, it has been proposed previously that p33 ING1 could play a role in HP1 deposition during formation of nascent constitutive heterochromatin (39). One possible explanation for our observation is linked to the reported ability of p33 ING1 to modulate histone acetylation (7,9,39). There is clear pharmacological and genetic evidence indicating that histone deacetylation is needed for the tethering of HP1 proteins to chromatin (40 -43).…”

Section: Discussionmentioning

confidence: 76%

“…Several ING proteins have been shown to act as upstream regulators of p53 in overexpression experiments, either increasing p53 protein stability (4) or promoting the acetylation of Lys residues at the C terminus of p53 (5,6). The latter effect is likely mediated by the association of ING proteins to acetyltransferases such as CBP/p300 or PCAF (7) or deacetylases such as Sir2 (6). ING proteins also participate in the regulation of chromatin dynamics.…”

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confidence: 99%

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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: Discussionmentioning

confidence: 76%

mentioning

confidence: 99%

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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“…Of these interactions, endogenous ING1 and ING2 co-immunoprecipitate CBP and p300, respectively, suggesting that ING1-CBP and ING2-p300 complexes might be present in vivo [Vieyra et al, 2002a;Pedeux et al, 2005]. With respect to ING4-p300/CBP and ING5-p300/CBP interactions, the association was demonstrated via transient overexpression strategies ; whether the endogenous proteins interact physiologically remains to be determined.…”

Section: Chromatin Regulation: Mammalian Ingsmentioning

confidence: 99%

The fellowships of the INGs

Shi

Gozani

2005

J of Cellular Biochemistry

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The inhibitor of growth (ING) family of proteins is an evolutionarily conserved family, with members present from yeast to humans. The mammalian ING proteins are candidate tumor suppressor proteins and accordingly can cooperate with p53 to arrest proliferation and induce apoptosis. ING proteins are also reported to function in the promotion of cellular senescence, the regulation of DNA damage responses and the inhibition of angiogenesis. At the molecular level, ING proteins are thought to function as chromatin regulatory molecules, acting as co-factors for distinct histone and factor acetyl-transferase (H/FAT) and deacetylase (HDAC) enzyme complexes. Further, ING proteins interact with a number of additional proteins involved in the regulation of critical nuclear processes, such as gene expression and DNA replication, and also function as nuclear phosphoinositide (PtdInsP) [He et al., 2005]. The bestcharacterized members include the five human members (INGs1-5) and three S. cerevisiae members (Yng1, Yng2, and Pho23.) The founding member of the family, ING1, was identified using an approach designed for discovery of genes whose expression was suppressed in cancer cells [Garkavtsev et al., 1996]. Accordingly, ING1 was subsequently shown to cooperate with p53 to induce apoptosis and cellular senescence, activities consistent with the notion that ING1 is a tumor suppressor [Garkavtsev and Riabowol, 1997;Garkavtsev et al., 1998]. Since the discovery of ING1, studies from multiple groups have implicated ING1 as well as other family members in negative regulation of cell proliferation, promotion of apoptosis and cellular senescence, contact inhibition, DNA damage repair, and inhibition of angiogenesis (for review see [Nouman et al., 2003;Campos et al., 2004; Gong etal., 2005; Kim,2005]andreferencestherein).In this context, multiple tumors have been found to either (i) harbor mutations within ING genes, (ii) have reduced expression of ING proteins, or (iii) have altered ING protein sub-cellular localization. Based on these collective findings, mammalian INGs are now thought to function as type II tumor suppressors (reviewed in [Gong et al., 2005]).Studies in both yeast and human cells suggest that ING proteins exert their biological functions through their associations with specific molecular partners. For the purpose of this Prospect, we divide these interacting partners of ING proteins into three groups: (i) components of HAT or HDAC complexes, (ii) other proteins involved in nuclear regulatory functions (e.g., p53 and NFkB), and (iii) the signaling lipids, PtdInsPs. Below we review these interactions and discuss the possibility that ING proteins function by integrating stress-induced PtdInsP signaling to (i) facilitate the assembly and (ii) regulate the sub-nuclear localization of distinct complexes consisting of different combinations of group (i) and (ii) interactors.

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“…ING proteins have been linked functionally to the p53 pathway at different levels, including the control of p53 protein stability, as transcriptional cofactors, or through post-translational modifications of p53 (Nagashima et al, 2001;Nourani et al, 2001;Gozani et al, 2003). ING proteins also participate in chromatin remodelling through their association with histone deacetylases and histone acetyltransferases (Nourani et al, 2001;Feng et al, 2002;Kuzmichev et al, 2002;Vieyra et al, 2002;Xin et al, 2004;Goeman et al, 2005). The most extensively studied member of the ING family is p33ING1, one of the products of the ING1 locus (also referred to as p33ING1b, or ING1b elsewhere; Feng et al, 2002).…”

mentioning

confidence: 99%

“…More importantly, there is ample evidence, both in mammals and yeast, showing that ING proteins can form complexes with histone deacetylases and histone acetyltransferases. Based on this, it has been suggested that ING proteins could play a role in transcriptional control, through chromatin remodelling (Nourani et al, 2001;Skowyra et al, 2001;Feng et al, 2002;Kuzmichev et al, 2002;Vieyra et al, 2002;Xin et al, 2004;Goeman et al, 2005). An increasing number of evidences indicate that ARF can have a direct role in transcriptional control (Kamijo et al, 1998;Rocha et al, 2003Rocha et al, , 2005Calabro et al, 2004;D'Amico et al, 2004;Datta et al, 2004;Kalinichenko et al, 2004;Qi et al, 2004) and, therefore, it is feasible that ARF might cooperate with p33ING1 in transcriptional regulation, through chromatin remodelling processes.…”

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confidence: 99%

A functional link between the tumour suppressors ARF and p33ING1

et al. 2006

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The ARF tumour suppressor protein plays a critical role in the activation of p53 in response to oncogenic stress. ARF can activate p53 through nucleolar sequestration of Mdm2. However, several lines of evidence indicate that this is not the only way of action of ARF, and alternative mechanisms must exist. p33ING1 is a putative tumour suppresor, which induces cell-cycle arrest and apoptosis in a p53-dependent manner. Here, we describe that ARF and p33ING1 can interact in vivo. We also show that the subcellular localization of ING1 can be modulated by ARF protein levels, causing a displacement from nuclear to nucleolar localization. Finally, the ability of p33ING1 to cause cell-cycle arrest and induction of p21CIP1, or Mdm2, is impaired in ARF-deficient primary mouse fibroblasts. Based on these observations, we propose that the interaction with p33ING1 represents a novel mechanism for the tumour suppression function of ARF.

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Human ING1 Proteins Differentially Regulate Histone Acetylation

Cited by 101 publications

References 36 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

The fellowships of the INGs

A functional link between the tumour suppressors ARF and p33ING1

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