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)

Constitutive activation of the telomerase is a key step in the development of human cancers. Interferon-gamma (IFN-gamma) signaling induces growth arrest in many tumors through multiple regulatory mechanisms. In this study, we show that IFN-gamma signaling represses telomerase activity and human telomerase reverse transcriptase (hTERT) transcription, and suggest that this signaling is mediated by IRF-1. Ectopic expression of IRF-1 attenuated hTERT promoter activity. Murine embryonic fibroblasts (MEFs) genetically deficient in IRF-1 (IRF-1(-/-)) showed an elevated level (>15 times) of hTERT promoter activity as compared to the hTERT promoter activity of wild-type MEFs. The telomerase activity and hTERT expression in IRF-1(-/-) MEFs were downregulated by IRF-1 transfection. Interestingly, less extent of telomerase repression was observed in HPV E6 and E7 negative, p53 mutant HT-3 cells than in HPV 18 E6 and E7 positive HeLa cells (intact p53). These findings provide evidence that IRF-1 is a potential mediator of IFN-gamma-induced attenuation of telomerase activity and hTERT expression.
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PMID:Interferon regulatory factor-1 (IRF-1) is a mediator for interferon-gamma induced attenuation of telomerase activity and human telomerase reverse transcriptase (hTERT) expression. 1254 59

Interferon-gamma (IFN-gamma) induces cell-cycle arrest and p53-independent apoptosis in primary cultured hepatocytes. However, the detailed mechanism, including regulating molecules, is still unclear. In this study, we found that IFN-gamma induced generation of reactive oxygen species (ROS) in primary hepatocytes and that pyrrolidinedithiocarbamate (PDTC), an anti-oxidant reagent, completely suppressed IFN-gamma-induced hepatic apoptosis. PDTC blocked apoptosis downstream from IRF-1 and upstream from caspase activation, suggesting that the generation of ROS occurred between these stages. However, IFN-gamma also induced the generation of ROS in IRF-1-deficient hepatocytes, cells insensitive to IFN-gamma-induced apoptosis. Moreover, a general cyclooxygenase (COX) inhibitor, indomethacin (but not the cyclooxygenase 2-specific inhibitor, NS-398) also inhibited the apoptosis without blocking the generation of ROS. Both PDTC and indomethacin also blocked IFN-gamma-induced release of cytochrome c from mitochondria. These results suggest that ROS are not the only or sufficient mediators of IFN-gamma-induced hepatic apoptosis. In contrast, we also found that IFN-gamma induced endoplasmic reticulum (ER) stress proteins, CHOP/GADD153 and caspase 12, in wild-type primary hepatocytes, but induced only caspase 12 and not CHOP/GADD153 protein in IRF-1-deficient hepatocytes. These results suggest that IFN-gamma induces ER stress in primary hepatocytes. Both the ROS and ER stress induced by IFN-gamma may be complementary mediators that induce apoptosis in primary hepatocytes.
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PMID:Interferon-gamma induces reactive oxygen species and endoplasmic reticulum stress at the hepatic apoptosis. 1270 88

Cell growth control by interferons (IFNs) involves up-regulation of the tumor suppressor interferon regulatory factor 1 (IRF1). To exert its anti-proliferative effects, this factor must ultimately control transcription of several key genes that regulate cell cycle progression. Here we show that the G1/S phase-related cyclin-dependent kinase 2 (CDK2) gene is a novel proliferation-related downstream target of IRF1. We find that IRF1, but not IRF2, IRF3, or IRF7, selectively represses CDK2 gene transcription in a dose- and time-dependent manner. We delineate the IRF1-responsive repressor element between nt -68 to -31 of the CDK2 promoter. For comparison, the tumor suppressor p53 represses CDK2 promoter activity independently of IRF1 through sequences upstream of nt -68, and the CDP/cut/Cux1 homeodomain protein represses transcription down-stream of -31. Thus, IRF1 repression represents one of three distinct mechanisms to attenuate CDK2 levels. The -68/-31 segment lacks a canonical IRF responsive element but contains a single SP1 binding site. Mutation of this element abrogates SP1-dependent enhancement of CDK2 promoter activity as expected but also abolishes IRF1-mediated repression. Forced elevation of SP1 levels increases endogenous CDK2 levels, whereas IRF1 reduces both endogenous SP1 and CDK2 protein levels. Hence, IRF1 represses CDK2 gene expression by interfering with SP1-dependent transcriptional activation. Our findings establish a causal series of events that functionally connect the anti-proliferative effects of interferons with the IRF1-dependent suppression of the CDK2 gene, which encodes a key regulator of the G1/S phase transition.
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PMID:The tumor suppressor interferon regulatory factor 1 interferes with SP1 activation to repress the human CDK2 promoter. 1273 45

The growth arrest and DNA damage-inducible protein 45alpha (GADD45a) gene is responsive to a variety of DNA-damaging agents. It is known that induction of the GADD45a gene is regulated in a p53-dependent manner after ionizing irradiation. Our previous study showed that X-ray irradiation increased the transcription rate of the GADD45a gene much earlier than the maximum accumulation of stabilized p53 protein in human myeloblastic leukemia ML-1 cells. We hypothesized that some transcription factor(s) may cooperate with p53 in regulating the GADD45a gene early after the irradiation of ML-1 cells. This idea is supported by recent studies showing that the p53-dependent activation of several genes in human and mouse cells requires some additional transcription factors, such as Sp1, GKLF, Ets1, and IRF-1. To examine the possible involvement of cooperating factors in transcriptional regulation of the GADD45a gene by ionizing radiation, we comprehensively searched for the X-ray-inducible binding locus of the nuclear factor throughout the upstream region (-2244 bp/+89 bp) and the third intron (+1389 bp/+2488 bp) of the GADD45a gene by EMSA using 136 probes. The X-ray-responsive binding of nuclear factors was detected at eight loci. Oct, NF-kappaB, HNF, NF-AT, and KLF family transcription factors were identified by a competition assay. It is possible that some of these factors cooperate with p53 to mediate transcriptional regulation of the GADD45a gene after ionizing irradiation.
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PMID:Comprehensive search for X-ray-responsive elements and binding factors in the regulatory region of the GADD45a gene. 1503 57

Growth inhibition by transforming growth factor (TGF)-beta 1 has been attributed to the induction of cyclin-dependent kinase inhibitors, among which p21/Waf1 plays a major role in many biological contexts. In the present study, two new intracellular mediators for the induction of p21/Waf1 by TGF-beta 1 were identified in a human hepatocellular carcinoma cell line (JHH-5) expressing mutant-type p53. After addition of TGF-beta 1 to JHH-5 cells, a marked increase of the p21/Waf1 expression preceded the inhibition of DNA synthesis. Expression of IFN regulatory factor (IRF)-1, a known transacting factor for p21/Waf1 promoter, was elevated just before or in parallel with the increase of p21/Waf1. Transduction of antisense IRF-1 inhibited the increase in p21/Waf1 in JHH-5 cells treated with TGF-beta 1 and partially released the cells from the growth arrest by TGF-beta 1. Expression of S100C/A11, a member of the Ca(2+)-binding S100 protein family, also markedly increased after addition of TGF-beta 1. S100C/A11 protein was translocated to and accumulated in nuclei of TGF-beta 1-treated JHH-5 cells, where p21/Waf1 was concomitantly accumulated. When a recombinant S100C/A11 protein was introduced into nuclei of JHH-5 cells, DNA synthesis was markedly inhibited in a dose-dependent manner in the absence of TGF-beta 1. Prior transfection of p21/Waf1-targeted small interfering RNA efficiently blocked decrease of DNA synthesis in JHH-5 cells caused by TAT-S100C/A11 or TGF-beta 1 and markedly inhibited expression of p21/Waf1 protein in the cells. These results indicate that IRF-1 and S100C/A11 mediate growth inhibition by TGF-beta 1 via induction of p21/Waf1.
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PMID:Involvement of interferon regulatory factor 1 and S100C/A11 in growth inhibition by transforming growth factor beta 1 in human hepatocellular carcinoma cells. 1520 26

Two high affinity Ser-20-phospho-LXXLL p53-binding domains of p300 map to the C-terminal interferon-binding domain (IBiD) and N-terminal IBiD homology domain (IHD) regions. Purified fractions of a recombinant IHD miniprotein are active in a set of in vitro assays highlighting its affinity to the N-terminal LXXLL domain of p53 including (i) dose-dependent binding to Ser-20-phosphorylated p53 tetramers; (ii) DNA-stimulated binding to p53 tetramers; and (iii) inhibition of MDM2-mediated p53 ubiquitination. The active component of the IHD miniprotein was localized to a 75-amino-acid fragment corresponding to amino acids 401-475 on human p300. This minimal IHD miniprotein can function in vivo as a p53-binding polypeptide in assays including: (i) complex formation with VP16-LXXLL peptide motifs in the two-hybrid assay; (ii) action as a dominant negative inhibitor of p53 from p21 luciferase templates; and (iii) attenuation of endogenous p21 protein levels. Further, we show here that the IRF-1-dependent stabilization and reactivation of p53DeltaPRO protein (LXXLL+/PXXP-) can be neutralized by the minimal IHD miniprotein, suggesting that IHD can bind to the p53 LXXLL domain in vivo. Phage-peptide display to the IHD miniprotein gave rise to an LSQXTFSXLXXLL consensus binding site that displays significant homology to the LXXLL transactivation domain of p53. These data validate the IHD scaffold as an independent LXXLL peptide-binding domain within the p300 protein, complementing the known peptide-binding domains including IBiD, C/H1, and C/H3.
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PMID:The N-terminal interferon-binding domain (IBiD) homology domain of p300 binds to peptides with homology to the p53 transactivation domain. 1533 67

Interleukin (IL)-4 inhibits proliferation of several human cancer cell lines in vitro. Although IL-4 is known to regulate proliferation of lymphocytes by modulating p27KIP1 expression, the mechanism involved in the IL-4-induced growth inhibition of nonhematopoietic cancer cells has not been fully elucidated. Previously, we reported that IL-4 suppressed proliferation of human renal cell carcinoma (RCC) cell lines in vitro. Here, we show that IL-4 inhibits cell cycle progression at the G1 phase in Caki-1 cells by increasing the expression of p21WAF1 and interferon regulatory factor (IRF)-1, and decreasing the cyclin dependent kinase (CDK) 2 activity. Up-regulation of p21WAF1 and IRF-1 expression is transcriptional, but independent of p53. The levels of p21WAF1 and IRF-1 proteins were enhanced as early as 1 h after IL-4 treatment. CDK2 activity started to decline at 4 h after IL-4 treatment, and by 24 h, was approximately 50% of the control. Neither the protein expressions of p27KIP1 and p16INK4a, nor the phosphorylation level of pRb was changed. The importance of p21WAF1 and IRF-1 in the growth inhibition induced by IL-4 was confirmed by antisense oligonucleotide transfection. Both of p21WAF1 and IRF-1 antisense oligonucleotides prevented IL-4-mediated growth inhibition by approximately 30% compared to the respective sense oligonucleotides. In summary, our study indicated that p21WAF1 and IRF-1 mediate the growth inhibitory effect of IL-4 in human RCC cells.
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PMID:IL-4 inhibits proliferation of renal carcinoma cells by increasing the expression of p21WAF1 and IRF-1. 1536 57

The overexpression of the inhibitor of apoptosis protein, survivin, may provide tumor cells with a distinct survival advantage in situ; hence, therapeutic strategies have been designed to inhibit its expression. In this study, we ectopically expressed the interferon regulatory factor (IRF)-1 protein in the breast carcinoma cell lines MDA-MB-468 and SK-BR-3 using a recombinant adenovirus (Ad-IRF-1). By screening microarray analysis of cDNA from the human breast cancer cell line MDA-MB-468 infected with Ad-IRF-1, we observed a 15-fold down-regulation of the survivin gene when compared with uninfected cells. Consequently, we tested survivin expression in Ad-IRF-1-infected MDA-MB-468 and SK-BR-3 breast cancer cell lines. Immunoblotting analyses supported the contention that ectopic expression of the IRF-1 protein results in down-regulation of survivin protein expression that is independent of p53. In addition, Ad-IRF-1 infection of these human breast cancer cell lines induces the expression of p21. We also report that increased apoptosis is observed in tumor cells infected with Ad-IRF-1 compared with Ad-Psi5 mock-infected cells and that cell death is further augmented when the IRF-1-infected cells are cultured with Adriamycin. Moreover, in a xenogeneic mouse model of breast carcinoma, in vivo treatment of tumor-bearing mice with intratumoral Ad-IRF-1 injections results in tumor growth inhibition. In resected tumors from mice that had been treated with Ad-IRF-1, tumor cells that express the IRF-1 transgene have a predominant IRF-1-positive, survivin-negative phenotype. Collectively, these observations suggest that therapies designed to enhance IRF-1 expression within tumor cells may represent novel treatment strategies for breast cancer.
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PMID:Ectopic expression of interferon regulatory factor-1 promotes human breast cancer cell death and results in reduced expression of survivin. 1554 8

Antiestrogens have been the therapeutic agents of choice for breast cancer patients whose tumors express estrogen receptors, regardless of menopausal status. Unfortunately, many patients will eventually develop resistance to these drugs. Antiestrogens primarily act by preventing endogenous estrogen from activating estrogen receptors and promoting cell growth, which can ultimately lead to tumor cell death. Understanding the mechanisms by which antiestrogens cause cell death or apoptosis is critical to our efforts to develop ways to circumvent resistance. This article focuses on antiestrogen-induced apoptosis both in vitro and in vivo. We review the clinical utility of both antiestrogens and aromatase inhibitors and their apoptogenic mechanisms in cell culture models. Among the key signaling components discussed are the roles of Bcl-2 family members, several cytokines, and their receptors, p53, nuclear factor kappa B (NFkappaB), IRF-1, phosphatidylinositol 3-kinase (PI3K)/Akt, and specific caspases. Finally, we discuss the evidence supporting a role for apoptotic defects in acquired and de novo antiestrogen resistance.
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PMID:Antiestrogens, aromatase inhibitors, and apoptosis in breast cancer. 1611 69

Caspase-1, a cysteine protease is primarily involved in proteolytic activation of proinflammatory cytokines such as interleukin-1beta. It is also involved in some forms of apoptosis. Here we have analyzed the role of p73, a homolog of tumor suppressor p53, in regulating human caspase-1 gene transcription. The caspase-1 promoter was strongly activated by p73alpha and p73beta primarily through a p53/p73 responsive site. Overexpression of p73 by transient transfection increased the caspase-1 mRNA level. Treatment of cells with cisplatin (which increases p73 protein level) resulted in increased caspase-1 promoter activity and its mRNA level. Blocking of p73 function by a dominant negative mutant reduced basal as well as cisplatin-induced caspase-1 promoter activity. Mutation of the p73 responsive site abolished cisplatin-induced activation of the promoter. Interferon-gamma induced caspase-1 promoter activity and this was reduced by p73-directed small hairpin RNA and also by a dominant negative mutant of p73. Abrogation of the p73 responsive site partially inhibited interferon-gamma-induced activation of the caspase-1 promoter. Treatment of HeLa cells with interferon-gamma resulted in an increase in p73 protein as well as its activity. Mutation of the IRF-1 binding site abolished interferon-gamma-induced caspase-1 promoter activity but p73-induced activation was only marginally reduced. IRF-1 cooperated with p73 and cisplatin cooperated with interferon-gamma in the activation of the caspase-1 promoter. Our results show that p73 is a regulator of caspase-1 gene transcription, and is required for optimal activation of the caspase-1 promoter by interferon-gamma.
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PMID:Role of p73 in regulating human caspase-1 gene transcription induced by interferon-{gamma} and cisplatin. 1613 20


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