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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The novel ING tumor-suppressor family proteins (ING1-5) have been discovered during the past decade and are recognized as the regulators of transcription, cell cycle checkpoints, DNA repair, apoptosis, cellular senescence, angiogenesis, and nuclear phosphoinositide signaling. ING proteins contain a few conserved domains, including plant homeodomain motif, nuclear localization signal, and potential chromatin regulatory domain, suggesting that the ING family proteins may share common biological functions. ING3 has been shown to modulate p53-mediated transcription, cell cycle control, and apoptosis, possibly by modulating the NuA4 complex histone acetyltransferase activity. Because ING1b and ING2 have been shown to be involved in cellular stress responses such as nucleotide excision repair and apoptosis after UV irradiation, we investigated whether ING3 also mediated UV-induced apoptosis. We found that ING3 expression was rapidly induced by UV irradiation at both mRNA and protein levels. Using the stable clones of melanoma cells overexpressing ING3, we showed that overexpression of ING3 significantly promoted UV-induced apoptosis. Unlike its homologues ING1b and ING2, ING3-increased apoptosis was independent of functional p53. Furthermore, ING3 did not affect the expression of mitochondrial proteins but increased the cleavage of Bid and caspases-8, -9, and -3. Moreover, ING3-mediated apoptosis was blocked by inhibition of caspase-8 or Fas activation. In addition, ING3 up-regulated Fas expression at both mRNA and protein levels. Knock down of ING3 decreased UV-induced apoptosis remarkably. These data indicate that ING3 plays an important role in cellular response to UV irradiation by enhancing UV-induced apoptosis through the activation of Fas/caspase-8 pathway.
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PMID:ING3 promotes UV-induced apoptosis via Fas/caspase-8 pathway in melanoma cells. 1652 Mar 80

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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PMID:A functional link between the tumour suppressors ARF and p33ING1. 1660 80

SWI/SNF is a multiprotein chromatin remodeling complex important for gene regulation. BRG1 and its close relative BRM, have ATPase activity necessary for transcriptional regulation by conformational change of nucleosomes. Due to this role on gene expression, several members of SWI/SNF complex including BRG1 and BRM function as a tumor suppressor or negative regulator of cellular proliferation. On the other hand, the shuttling of proteins between nucleus and cytoplasm is strongly involved in the regulation of cell cycle and proliferation. Many of tumor suppressor gene (TSG)s including p53, BRCA1, ING1 play some of their functions through nucleocytoplasmic shuttling. Abnormalities related with this process abrogate the subcellular localization of the TSGs and lead to cancer development. We recently demonstrated BRG1 as a TSG in oral cancer. Our analysis also revealed an interesting finding that one of the splicing forms of BRG1 is selectively lost in cancer tissue as compared to normal counterparts. Our further analysis revealed a putative nuclear retention signal domain for this splicing form. In this article, we speculate the possible mechanism for the inactivation of BRG1 gene in oral cancer through an abnormality in its subcellular localization.
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PMID:Epigenetic alterations of BRG1 leads to cancer development through its nuclear-cytoplasmic shuttling abnormalities. 1682 95

ING proteins affect apoptosis, growth, and DNA repair by transducing stress signals such as DNA damage, binding histones, and subsequently regulating chromatin structure and p53 activity. p53 target genes, including the p21 cyclin-dependent kinase inhibitor and Bax, an inducer of apoptosis, are regulated by ING proteins. To identify additional targets downstream of p33ING1 and p32ING2, cDNA microarrays were performed on phenotypically normal human primary fibroblasts. The 0.36% of genes affected by ING proteins in primary fibroblasts were distinct from targets seen in established cells and included the HSP70 heat shock gene, whose promoter was specifically induced >10-fold. ING1-induced expression of HSP70 shifted cells from survival to a death pathway in response to tumor necrosis factor alpha (TNF-alpha), and p33ING1b protein showed synergy with TNF-alpha in inducing apoptosis, which correlated with reduced NF-kappaB-dependent transcription. These findings are consistent with previous reports that HSP70 promotes TNF-alpha-mediated apoptosis by binding I-kappaBeta kinase gamma and impairing NF-kappaB survival signaling. Induction of HSP70 required the amino terminus of ING1b but not the plant homeodomain region that was recently identified as a histone binding domain. Regulation of HSP70 gene expression by the ING tumor suppressors provides a novel link between the INGs and the stress-regulated NF-kappaB survival pathway important in hypoxia and angiogenesis.
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PMID:HSP70 induction by ING proteins sensitizes cells to tumor necrosis factor alpha receptor-mediated apoptosis. 1703 Jun 16

ING proteins have been proposed to alter chromatin structure and gene transcription to regulate numerous aspects of cell physiology, including cell growth, senescence, stress response, apoptosis, and transformation. ING1, the founding member of the inhibitor of growth family, encodes p37(Ing1), a plant homeodomain (PHD) protein that interacts with the p53 tumor suppressor protein and seems to be a critical cofactor in p53-mediated regulation of cell growth and apoptosis. In this study, we have generated and analyzed p37(Ing1)-deficient mice and primary cells to further explore the role of Ing1 in the regulation of cell growth and p53 activity. The results show that endogenous levels of p37(Ing1) inhibit the proliferation of p53-wild-type and p53-deficient fibroblasts, and that p53 functions are unperturbed in p37(Ing1)-deficient cells. In addition, loss of p37(Ing1) induces Bax expression and increases DNA damage-induced apoptosis in primary cells and mice irrespective of p53 status. Finally, p37(Ing1) suppresses the formation of spontaneous follicular B-cell lymphomas in mice. These results indicate that p53 does not require p37(Ing1) to negatively regulate cell growth and offers genetic proof that Ing1 suppresses cell growth and tumorigenesis. Furthermore, these data reveal that p37(Ing1) can negatively regulate cell growth and apoptosis in a p53-independent manner.
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PMID:Deletion of p37Ing1 in mice reveals a p53-independent role for Ing1 in the suppression of cell proliferation, apoptosis, and tumorigenesis. 1733 34

The INhibitor of Growth (ING) family of type II tumour suppressors are encoded by five genes in mammals (ING1-ING5), most of which encode multiple isoforms via splicing, and all of which contain a highly conserved plant homeodomain (PHD) finger motif. Since their discovery approximately ten years ago, significant progress has been made in understanding their subcellular targeting, their relationship to p53, their activation by bioactive phospholipids, and their key role in reading the histone code via PHD fingers, with subsequent effects on histone acetylation and transcriptional regulation. In the past year, we have begun to understand how ING proteins integrate stress signals with interpretation and modification of the histone epigenetic code to function as tumour suppressors.
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PMID:After a decade of study-ING, a PHD for a versatile family of proteins. 1794 86

p33ING2 belongs to the ING-gene family that is involved in tumor suppression, DNA repair, cell cycle regulation, and cellular senescence. Most functions are dependent on the tumor suppressor p53. p33ING2 was also shown to bind to trimethylated lysine 4 of histone H3. Here, we show that p33ING2 contains a transferable silencing function, which is independent of p53. p33ING2-mediated gene silencing is resistant to the HDAC-inhibitor trichostatin A indicating that p33ING2 uses a non-HDAC class I or II pathway for gene repression in reporter assays. In line with that we show that p33ING2 is associated with histone methyltransferase (HMT) activity in vitro and in vivo, methylating specifically histone H3. Interestingly, the specificity is distinct from the MeCP2-recruited HMT. Mutation or methylation of lysine 9, a mark well known for repression, abrogates histone methylation by MeCP2 but not by the p33ING2 complex. Instead, the ING2-associated HMT shows an increased methylation activity if lysine 9 is methylated. In contrast, mutation or methylation of lysine 4, a methylation preferentially detected at active genes, led to a reduction of the ING2-associated HMT. Notably, also p33ING1 recruits HMT activity suggesting a more general biochemical interaction between members of p33ING family and HMT activity. Deletion analyses revealed that the ING2 C-terminus recruits HMT activity, which correlates with silencing function.
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PMID:ING2 recruits histone methyltransferase activity with methylation site specificity distinct from histone H3 lysines 4 and 9. 1851 92

The Inhibitor of Growth (ING) gene family encodes structurally related proteins that alter chromatin to regulate gene expression and cell growth. The initial member, ING1, has also been proposed to function as a tumor suppressor in human cancer based on its ability to suppress cell growth and transformation in vitro. Mouse Ing1 produces two proteins (p31 and p37) from differentially spliced transcripts. We have recently generated p37(Ing1b)-null mice and observed spontaneous follicular B-cell lymphomagenesis in this model to show that ING proteins can function in vivo as tumor suppressors. In this present report, we examine the role of p37(Ing1b) in the regulation of B-cell growth and explore the relationship between p37(Ing1b) and p53-mediated tumor suppression. Our results indicate that p37(Ing1b) inhibits the proliferation of B cells and follicular B cells regardless of p53 status, and loss of p53 greatly accelerates the rate of B-cell lymphomagenesis in p37(Ing1b)-null mice. However, in contrast to the highly penetrant follicular B-cell lymphomas observed in p37(Ing1b)-null mice, mice lacking both p37(Ing1b) and p53 typically present with aggressive diffuse large B-cell lymphomas (DLBL). Analysis of marker gene expression in p37(Ing1b)/p53 null tumors indicates that the double-null mice develop both nongerminal center and germinal center B-cell-like DLBL, and also documents up-regulation of nuclear factor-kappaB activity in p37(Ing1b)/p53-null B cells and B-cell tumors. These results confirm that p53 mutation is an important mechanistic step in the formation of diffuse large B-cell lymphomas and reveals a p53-independent role for Ing1b in suppressing B-cell tumorigenesis.
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PMID:p37Ing1b regulates B-cell proliferation and cooperates with p53 to suppress diffuse large B-cell lymphomagenesis. 1897 12

Increasing evidence has been gathered for p53-dependent apoptosis, but it is still unclear how p53 initiates apoptosis by employing its transcriptional program. Pair-wise interactions of p53 with expression of other genes fail to predict p53 levels or rate of apoptosis. A more sophisticated approach, using neural networks, permits prediction of interaction among three or more genes (p53, bax, and ING1). These interactions are decidedly nonlinear. Careful measurements and advanced mathematical treatments will permit us not only to understand how expression of pro- and anti-apoptotic genes is regulated, but also to integrate cross-platform and cross-experimental data for the validation of predicted interactions.
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PMID:Nonlinear cooperation of p53-ING1-induced bax expression and protein S-nitrosylation in GSNO-induced thymocyte apoptosis: a quantitative approach with cross-platform validation. 1908 96

Cellular senescence is an effective anti-tumor barrier that acts by restraining the uncontrolled proliferation of cells carrying potentially oncogenic alterations. ING proteins are putative tumor suppressor proteins functionally linked to the p53 pathway and to chromatin regulation. ING proteins exert their tumor-protective action through different types of responses. Here, we review the evidence on the participation of ING proteins, mainly ING1 and ING2, in the implementation of the senescent response. The currently available data support an important role of ING proteins as regulators of senescence, in connection with the p53 pathway and chromatin organization.
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PMID:ING proteins in cellular senescence. 1944 13


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