Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IFI16 is a member of the HIN-200 family (hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats) that contains a DNA binding domain, a transcriptional regulatory domain, and DAPIN/PAAD, a protein domain associated with interferon response. It can function as a transcription repressor and directly binds p53. Although the structural and biochemical properties of IFI16 are known, the physiological relevance of these properties in the cellular context is still elusive. Here we report that the inhibition of endogenous IFI16 expression by small interfering RNA (siRNA) induces p21Waf1 mRNA and protein expression through p53 but does not induce pro-apoptotic p53 target genes. This rapid induction of p21 was wild-type p53-dependent and resulted in cell cycle arrest along with a marked reduction of phosphorylated Rb in normally growing cells. We also showed that the repression of IFI16 affects p53 transcriptional activity at the p21 promoter as well as the protein stability of p53 and p21. Our findings identified a new role for IFI16 in modulating p53 function and its target gene regulation in the control of cell cycle regulation.
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PMID:IFI16 as a negative regulator in the regulation of p53 and p21(Waf1). 1292 27

We identified IFI16 as a BRCA1-associated protein involved in p53-mediated apoptosis. IFI16 contains the Pyrin/PAAD/DAPIN domain, commonly found in cell death-associated proteins. BRCA1 (aa 502-802) interacted with the IFI16 Pyrin domain (aa 1-130). We found that IFI16 was localized in the nucleoplasm and nucleoli. Clear nucleolar IFI16 localization was not observed in HCC1937 BRCA1 mutant cells, but reintroduction of wild-type BRCA1 restored IFI16 nuclear relocalization following IR (ionizing radiation). Coexpression of IFI16 and BRCA1 enhanced DNA damage-induced apoptosis in mouse embryonic fibroblasts from BRCA1 mutant mice expressing wild-type p53, although mutant IFI16 deficient in binding to BRCA1 did not induce apoptosis. Furthermore, tetracycline-induced IFI16 collaborated in inducing apoptosis when adenovirus p53 was expressed in DNA-damaged p53-deficient EJ cells. These results indicate a BRCA1-IFI16 role in p53-mediated transmission of DNA damage signals and apoptosis.
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PMID:A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway. 1465 89

Immunohistochemical analysis has demonstrated that the human IFI16 gene, in addition to the hematopoietic tissues, is highly expressed in endothelial cells and squamous stratified epithelia. In this study, we have developed a reliable HSV-derived replication-defective vector (TO-IFI16) to efficiently transduce IFI16 into primary human umbilical vein endothelial cells (HUVEC), which are usually poorly transfectable. HUVEC infection with TO-IFI16 virus suppressed endothelial migration, invasion and formation of capillary-like structures in vitro. In parallel, sustained IFI16 expression inhibited HUVEC cell cycle progression, accompanied by significant induction of p53, p21, and hypophosphorylated pRb. Further support for the involvement of these pathways in IFI16 activity came from the finding that infection with TO-IFI16 virus does not impair the in vitro angiogenic activity and cell cycle progression of HUVEC immortalized by HPV16 E6/E7 oncogenes, which are known to inactivate both p53 and pRb systems. This use of a reliable viral system for gene delivery into primary human endothelial cells assigns a potent angiostatic activity to an IFN-inducible gene, namely IFI16, and thus throws further light on antiangiogenic therapy employing IFNs.
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PMID:The interferon-inducible IFI16 gene inhibits tube morphogenesis and proliferation of primary, but not HPV16 E6/E7-immortalized human endothelial cells. 1472 71

IFI16 is a member of the PYRIN superfamily that has been implicated in BRCA1-mediated apoptosis and inflammation signaling pathways. Here we report that most breast cancer cell lines examined expressed decreased mRNA and protein levels of IFI16, although IFI16 is expressed in human primary normal mammary epithelial cells. Significantly, immunohistochemical analysis of tissues from 25 breast cancer patients demonstrated that carcinoma cells showed negative or weaker staining of IFI16 compared with positive nuclear staining in normal mammary duct epithelium. si-RNA-mediated reduction of IFI16 resulted in perturbation of p53 activation when treated with ionizing radiation (IR). Expression of IFI16 enhanced p53 transcriptional activity in cells exposed to IR. Adenovirus expression of IFI16 in IFI16-deficient MCF7 induced apoptosis, which was enhanced by radiomimetic neocarcinostatin treatment. Tetracycline-regulated IFI16 also induced apoptosis when coexpressed with p53 in p53-deficient EJ cells subjected to IR, suggesting that IFI16 is involved in p53-mediated transmission of apoptosis signaling. Consistent with these results, expression of IFI16 enhanced activation of the known p53 target genes, including p21, Hdm2, and bax in MCF7 cells. These results suggest that loss of IFI16 results in deregulation of p53-mediated apoptosis, leading to cancer development.
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PMID:Requirement of IFI16 for the maximal activation of p53 induced by ionizing radiation. 1499 May 79

Reactive oxygen species (ROS), including hydrogen peroxide (H2O2), induces injury of endothelium in a variety of pathophysiological conditions, such as inflammation, aging, and cancer. In our study, we characterized the signaling pathway linking oxidative stress induced by sublethal concentrations of H2O2 to p53 in primary human endothelial cells through the interferon (IFN)-inducible gene IFI16. Induction of IFI16 by H2O2 was concentration- and time-dependent (maximum at 50 microM, 6 h after treatment) and down-regulated by pretreatment with N-acetyl-L-cysteine, which acts as an antioxidant. This pathway is a general response to ROS and not specific to H2O2 treatment, as two other ROS-generating compounds, i.e., S-nitroso-N-acetylpenicillamine and tert-butyl hydroperoxide, were equally capable to induce IFI16. Moreover, IFI16 up-regulation is a result of protein accumulation, as expression of corresponding mRNA, assessed by real-time polymerase chain reaction, was not affected. To investigate the mechanism of IFI16 accumulation, cells were incubated for 6 h in the presence of H2O2 or IFN-beta, and then cycloheximide was added to inhibit further protein synthesis. The half-life of IFI16 protein was found to be significantly increased in H2O2-treated cells compared with IFN-beta-treated cells (t1/2 = 120 min vs. > 30 min in H2O2- vs. IFN-beta-treated cells, respectively). An increase of IFI16 was accompanied by interaction with p53 phosphorylated at its N terminus, as shown by immunoprecipitation experiments. Moreover, binding to IFI16 resulted in its transcriptional activation as shown by an increase in the activity of a reporter gene driven by p53-responsive sequences derived from the p21(WAF1) promoter, along with an increase in the p21 mRNA and protein levels. Altogether, these results demonstrate a novel role of IFI16 in the signal transduction pathway that leads to p53 activation by oxidative stress in endothelial cells.
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PMID:Up-regulation of the interferon-inducible IFI16 gene by oxidative stress triggers p53 transcriptional activity in endothelial cells. 1572 46

The effect of methionine deprivation (methionine stress) on the proliferation, survival, resistance to chemotherapy, and regulation of gene and protein expression in pancreatic tumor lines is examined. Methionine stress prevents successful mitosis and promotes cell cycle arrest and accumulation of cells with multiple micronuclei with decondensed chromatin. Inhibition of mitosis correlates with CDK1 down-regulation and/or inhibition of its function by Tyr(15) phosphorylation or Thr(161) dephosphorylation. Inhibition of cell cycle progression correlates with loss of hyperphosphorylated Rb and up-regulation of p21 via p53 and/or transforming growth factor-beta (TGF-beta) activation depending on p53 status. Although methionine stress-induced toxicity is not solely dependent on p53, the gain in p21 and loss in CDK1 transcription are more enhanced in wild-type p53 tumors. Up-regulation of SMAD7, a TGF-beta signaling inhibitor, suggests that SMAD7 does not restrict the TGF-beta-mediated induction of p21, although it may prevent up-regulation of p27. cDNA oligoarray analysis indicated a pleiotropic response to methionine stress. Cell cycle and mitotic arrest is in agreement with up-regulation of NF2, ETS2, CLU, GADD45alpha, GADD45beta, and GADD45gamma and down-regulation of AURKB, TOP2A, CCNA, CCNB, PRC1, BUB1, NuSAP, IFI16, and BRCA1. Down-regulation of AREG, AGTR1, M-CSF, and EGF, IGF, and VEGF receptors and up-regulation of GNA11 and IGFBP4 signify loss of growth factor support. PIN1, FEN1, and cABL up-regulation and LMNB1, AREG, RhoB, CCNG, TYMS, F3, and MGMT down-regulation suggest that methionine stress sensitizes the tumor cells to DNA-alkylating drugs, 5-fluorouracil, and radiation. Increased sensitivity of pancreatic tumor cell lines to temozolomide is shown under methionine stress conditions and is attributed in part to diminished O(6)-methylguanine-DNA methyltransferase and possibly to inhibition of the cell cycle progression.
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PMID:Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma. 1617 25

IFI16 is a member of the HIN-200 family (hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeat) that contains a DNA binding domain, a transcriptional regulatory domain, DAPIN/PAAD domain associated with interferon (IFN) response and a binding domain for BRCA1, breast cancer tumor suppressor protein. IFI16 has been identified as a target of IFNa and g and is a member of the HIN-200 family. Although series of initial studies have demonstrated a potential activity of IFI16, a physiological role of the protein was largely unknown. A novel insight of the function of IFI16 stemmed from the observation that IFI16 constitutively binds to BRCA1 breast cancer tumor suppressor. Furthermore, it has been demonstrated that IFI16 is involved in p53-mediated regulation of cell growth and apoptosis. Immunocytochemical and immunohistological analyses of breast cancer cell lines and specimens revealed that levels of IFI16 are frequently decreased, supporting the notion that loss of IFI16 is closely associated with tumor development. Finally, siRNA-mediated depletion of IFI16 induces levels of NBS1, nijmegen breakage syndrome protein 1, leading to activation of DNA-PK (DNA-dependent kinase), phosphorylation of p53 Ser37 and accumulation of p21WAF1. Localization of IFI16 is determined by the status of BRCA1 protein under conditions of DNA damage, such as ionizing radiation (IR). More recently, it has been shown that levels of IFI16 are increased by oxidative stress. Together, these results illustrate that IFI16 is involved in DNA damage signaling and cell cycle checkpoint.
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PMID:Role of IFI16 in DNA damage and checkpoint. 1798 41

Our previous results that IFI16 is involved in p53 transcription activity under conditions of ionizing radiation (IR), and that the protein is frequently lost in human breast cancer cell lines and breast adenocarcinoma tissues suggesting that IFI16 plays a crucial role in controlling cell growth. Here, we show that loss of IFI16 by RNA interference in cell culture causes elevated phosphorylation of p53 Ser37 and accumulated NBS1 (nibrin) and p21WAF1, leading to growth retardation. Consistent with these observations, doxycyclin-induced NBS1 caused accumulation of p21WAF1 and increased phosphorylation of p53 Ser37, leading to cell cycle arrest in G1 phase. Wortmannin treatment was found to decrease p53 Ser37 phosphorylation in NBS-induced cells. These results suggest that loss of IFI16 activates p53 checkpoint through NBS1-DNA-PKcs pathway.
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PMID:Loss of p53-regulatory protein IFI16 induces NBS1 leading to activation of p53-mediated checkpoint by phosphorylation of p53 SER37. 1798 42

IFN-inducible IFI16 protein (encoded by IFI16 gene at 1q23.1) is the human member of the IFN-inducible structurally related p200 family proteins. Increased expression of the IFI16 protein, a positive modulator of p53-mediated transcription, in normal old human diploid fibroblasts (HDF) is associated with cellular senescence-mediated cell growth arrest. However, the underlying mechanisms that contribute to transcriptional activation of the IFI16 gene in old HDFs remain to be elucidated. Here, we reported that functional activation of p53 in normal young HDFs and p53-null Saos2 cell line resulted in transcriptional activation of the IFI16 gene. We identified a potential p53 DNA-binding site (indicated as IFI16-p53-BS) in the 5'-regulatory region of the IFI16 gene. Importantly, p53 bound to IFI16-p53-BS in a sequence-specific manner in gel-mobility shift assays. Furthermore, p53 associated with the 5'-regulatory region of the IFI16 gene in chromatin immunoprecipitation assays. Interestingly, p53 associated with the regulatory region of the IFI16 gene only on treatment of cells with DNA-damaging agents or in the old, but not in the young, HDFs. Importantly, our promoter-reporter assays, which were coupled with site-directed mutagenesis of IFI16-p53-BS, showed that p53 activates transcription of the IFI16 gene in HDFs through the p53 DNA-binding site. Together, our observations provide support for the idea that up-regulation of IFI16 expression by p53 and functional interactions between IFI16 protein and p53 contribute to cellular senescence.
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PMID:Expression of an IFN-inducible cellular senescence gene, IFI16, is up-regulated by p53. 1897 96

Cellular senescence is a stress-response phenomenon in which cells lose the ability to proliferate; it is induced by telomere shortening, activation of oncogenes or tumor suppressor genes, or exposure to a sub-lethal dose of DNA damaging agents or oxidative stresses. cDNA microarray analysis reveals that the levels of interferons (IFNs) and IFN-inducible genes were altered during replicative senescence in human umbilical vascular endothelial cells (HUVECs). However, the role of IFNs in cellular senescence of HUVECs remains unidentified. This study demonstrated that prolonged treatment with IFN-gamma induced cellular senescence in HUVECs, as confirmed by G0/G1 cell cycle arrest, up-regulation of p53 and p21 protein levels, increased SA-beta-gal staining, and the accumulation of phospho-H(2)AX foci. IFN-gamma-induced cellular senescence was observed only in p16-knockdown cells or p16-null mouse embryonic fibroblasts (MEFs), but not in p53-knockdown cells or p53-null MEFs. IFN-gamma treatment increased ROS production, and an antioxidant, N-acetylcysteine, inhibited IFN-gamma-induced cellular senescence. Knockdown of ATM kinase or IFI16 rescued IFN-gamma-induced cellular senescence. Therefore, these results suggest that IFN-gamma might play an important role in cellular senescence through a p53-dependent DNA damage pathway and contribute to the pathogenesis of atherosclerosis via its pro-senescent activity.
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PMID:Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells. 1907 Nov 56


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