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

Human papillomaviruses (HPVs) infect keratinocytes and induce proliferative lesions. In infected cells, viral gene products alter the activities of cellular proteins, such as Rb and p53, resulting in altered cell cycle response. It is likely that HPV gene products also alter expression of cellular genes. In this study we used microarray analysis to examine the global changes in gene expression induced by high-risk HPV type 31 (HPV31). Among 7,075 known genes and ESTs (expressed sequence tags) tested, we found that 178 were upregulated and 150 were downregulated twofold or more in HPV31 cells compared to normal human keratinocytes. While no specific pattern could be deduced from the list of genes that were upregulated, downregulated genes could be classified to three groups: genes that are involved in the regulation of cell growth, genes that are specifically expressed in keratinocytes, and genes whose expression is increased in response to interferon stimulation. The basal level of expression of several interferon-responsive genes was found to be downregulated in HPV31 cells by both microarray analysis and Northern blot analysis in different HPV31 cell lines. When cells were treated with alpha or gamma interferon, expression of interferon-inducible genes was impaired. At high doses of interferon, the effects were less pronounced. Among the genes repressed by HPV31 was the signal transducer and activator of transcription (Stat-1), which plays a major role in mediating the interferon response. Suppression of Stat-1 expression may contribute to a suppressed response to interferon as well as immune evasion.
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PMID:Microarray analysis identifies interferon-inducible genes and Stat-1 as major transcriptional targets of human papillomavirus type 31. 1075 30

A thymic stromal cell line, TFGD, was established from a thymic tumor mass developed spontaneously in p53 knock out mouse, and was found to produce cytokines that could induce bone marrow hematopoietic stem cells (HSCs) to differentiate into macrophages. The cytokines produced by the TFGD line were assessed by immunoassays. High level of macrophage-colony stimulating factor (M-CSF) and interleukin (IL)-6 was detected in the TFGD-culture supernatant, whereas granulocyte/macrophage-colony stimulating factor (GM-CSF), IL-3, IL-4, IL-5, IL-13, or interferon (IFN)-gamma was undetectable. Blocking experiments showed that anti-M-CSF monoclonal antibody could neutralize the differentiation-inducing activity shown by the TFGD-culture supernatant. Dot blot analysis of the total RNA isolated from the cultured fetal thymic stromal cells showed that M-CSF transcripts were expressed in the normal thymus. These observations, together with the earlier finding that M-CSF plus IL-6 is the optimal combination of cytokines for the induction of macrophage differentiation from HSCs in vitro, may indicate that thymic macrophages could be generated within the thymus by cytokines involving M-CSF.
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PMID:A mouse thymic stromal cell line producing macrophage-colony stimulating factor and interleukin-6. 1089 58

Four human cell lines derived from Ewing's sarcoma, EW-7, EW-1, COH and ORS, were investigated to establish the effects of human recombinant interferon-alpha2a and human recombinant interferon-beta on cell proliferation and apoptosis. All four cell lines were much more sensitive to the antiproliferative effects of IFN-beta than of IFN-alpha. Analysis of the early signals triggered by IFN-alpha and IFN-beta demonstrated that the two IFNs were similarly effective in inducing tyrosine phosphorylation of the Jak-1 and Tyk-2 kinases and the transcription factors Stat-1 and Stat-2. Interestingly, an additional rapid phosphorylation of Stat-1 on serine was observed after IFN-beta treatment, with concomitant activation of p38 mitogen-activated protein kinase. In these cells, Stat-1 Ser727 phosphorylation in response to IFN-beta was found to be impaired by p38 MAPkinase inhibitor (SB203580). IFN-beta induced the formation of the Interferon Stimulated Gene Factor 3 complex more efficiently than IFN-alpha, as well as sustained induction of IRF-1, which may account for its greater induction of 2'5'oligo(A)synthetase and greater inhibition of cell proliferation. IFN-beta, but not IFN-alpha, induced apoptosis in wild-type p53 EW-7 and COH cell lines, but not in the mutated p53 EW-1 or ORS cell lines. The apoptosis induced by IFN-beta in EW-7 and COH cell lines appeared to be mediated by IRF-1 and involved the activation of caspase-7. Ectopic expression of IRF-1 induced apoptosis in all four cell lines which correlated with the activation of caspase-7 and with the downregulation of the Bcl-2 oncoprotein, as observed for IFN-beta-induced apoptosis in parental EW-7 and COH cell lines.
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PMID:IFN-beta induces serine phosphorylation of Stat-1 in Ewing's sarcoma cells and mediates apoptosis via induction of IRF-1 and activation of caspase-7. 1091 94

Systematic forward genetics, so powerful for analyzing pathways in haploid organisms, has contributed much less to our understanding of diploid mammalian cells. With Ian Kerr, we have used regulated expression of selectable markers in heavily mutagenized cells to isolate mutant mammalian cell lines defective in eight different proteins required for interferon signaling. These cells have been valuable in studying the roles of the deleted Janus Kinase (JAK), signal transducer and activator of transcription (STAT), and receptor proteins in interferon and other signaling pathways. Mutant cells defective in the induction of class II major histocompatibility complex (MHC) antigens by interferon-gamma or in repressing interferon-regulated genes have also been obtained. More recently, mutant cells unresponsive to double-stranded RNA, tumor necrosis factor alpha (TNF-alpha), or interleukin-1 (IL-1) have been isolated and characterized and a mutant line defective in expressing the tumor suppressor protein p53 has also been obtained. Systematic forward genetics can now be applied more easily to mammalian cells, to help elucidate signaling pathways.
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PMID:Genetic analysis of interferon and other mammalian signaling pathways. 1094 15

Human T-cell lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature activated T cells resistant to conventional chemotherapy. The viral transactivator protein Tax plays a critical role in HTLV-I-induced transformation and apoptosis resistance by inducing I kappa B-alpha degradation, resulting in the activation of the NF-kappa Bpathway. In these HTLV-I-transformed cells, arsenic trioxide (As) and interferon (IFN)-alpha synergize to induce cell cycle arrest and apoptosis. We demonstrate that cell death induction is only partly dependent upon caspase activation and is not associated with modulation of bcl-2, bax, or p53 expression. However, combined As and IFN induce the degradation of Tax, associated with an up-regulation of I kappa B-alpha resulting in a sharp decrease in RelA DNA binding nuclear factor (NF)-kappa B complexes because of the cytoplasmic retention of RelA. Taken the role of Tax in HTLV-I-induced transformation, its down-regulation probably accounts for cell death induction through inactivation of the NF-kappa B pathway. Such specific targeting of the viral oncoprotein by As-IFN treatment, reminiscent of As targeting of promyelocytic leukemia/retinoic acid receptor-alpha in acute promyelocytic leukemia, provides strong rational for combined As-IFN therapy in ATL patients. (Blood. 2000;96:2849-2855)
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PMID:Arsenic-interferon-alpha-triggered apoptosis in HTLV-I transformed cells is associated with tax down-regulation and reversal of NF-kappa B activation. 1102 21

Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, is associated with three proliferative diseases ranging from viral cytokine-induced hyperplasia to monoclonal neoplasia: multicentric Castleman's disease (CD), Kaposi's sarcoma (KS), and primary effusion lymphoma (PEL). Here we report a new latency-associated 1,704-bp KSHV spliced gene belonging to a cluster of KSHV sequences having homology to the interferon regulatory factor (IRF) family of transcription factors. ORFK10.5 encodes a protein, latency-associated nuclear antigen 2 (LANA2), which is expressed in KSHV-infected hematopoietic tissues, including PEL and CD but not KS lesions. LANA2 is abundantly expressed in the nuclei of cultured KSHV-infected B cells. Transcription of K10.5 in PEL cell cultures is not inhibited by DNA polymerase inhibitors nor significantly induced by phorbol ester treatment. Unlike LANA1, LANA2 does not elicit a serologic response from patients with KS, PEL, or CD as measured by Western blot hybridization. Both KSHV vIRF1 (ORFK9) and LANA2 (ORFK10.5) appear to have arisen through gene duplication of a captured cellular IRF gene. LANA2 is a potent inhibitor of p53-induced transcription in reporter assays. LANA2 antagonizes apoptosis due to p53 overexpression in p53-null SAOS-2 cells and apoptosis due to doxorubicin treatment of wild-type p53 U2OS cells. While LANA2 specifically interacts with amino acids 290 to 393 of p53 in glutathione S-transferase pull-down assays, we were unable to demonstrate LANA2-p53 interaction in vivo by immunoprecipitation. These findings show that KSHV has tissue-specific latent gene expression programs and identify a new latent protein which may contribute to KSHV tumorigenesis in hematopoietic tissues via p53 inhibition.
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PMID:Kaposi's sarcoma-associated herpesvirus LANA2 is a B-cell-specific latent viral protein that inhibits p53. 1111 11

Interferons are important in regulating cell growth and differentiation, immune function and initiating anti-viral responses. While the pleotrophic actions of interferons have been well documented, the molecular mechanisms underpinning their biological effects have not been fully characterized. IFI 16 is a member of the interferon-inducible HIN-200 family of nuclear proteins, which we have recently shown can function as a potent transcriptional repressor. A murine member of the HIN-200 family, p202, can indirectly interact with p53 via the p53 binding protein (p53bp) and inhibit p53-mediated transcriptional activation. The binding activity of p202 to p53bp was shown to require the conserved MFHATVAT motif present in all 200 amino acid repeat regions of HIN-200 proteins. Given that IFI 16 contains two MFHATVAT motifs, we sought to determine whether IFI 16 may form a complex with p53 and if so to ascertain the functional significance of this interaction. We demonstrate that IFI 16 can directly bind to the C-terminal region of p53 and augment p53-mediated transcriptional activation without altering the steady state levels of p53. Thus, in addition to its ability to directly regulate gene expression, IFI 16 can also modulate the transcription function of other cellular transcription factors. These findings demonstrate a possible link between gene induction following interferon stimulation and p53-mediated cellular events.
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PMID:Functional interaction between p53 and the interferon-inducible nucleoprotein IFI 16. 1114 55

An apoptotic cellular defense mechanism is triggered in response to viral dsRNA generated during the course of infection by many DNA and RNA viruses. We demonstrate that apoptosis induced by dsRNA or a paramyxovirus is independent of the action of interferon as it can proceed in a variety of cell lines and primary cells deficient in an interferon response. Initiation of apoptosis appears to be triggered by activation of a cellular transcription factor, the dsRNA-activated factor (DRAF1). DRAF1 is composed of interferon regulatory factor 3 (IRF-3) and the transcriptional coactivators CREB binding protein (CBP) or p300. We find that activation of IRF-3 in the absence of viral infection stimulates apoptosis. In addition, a negative interfering mutant blocks both target gene induction and apoptosis, demonstrating a requirement for gene expression by IRF-3/DRAF1 to promote apoptosis. IRF-3/DRAF1 target gene expression is also induced in response to a distinct apoptotic stimulus, the DNA damaging agent etoposide. The activity of the p53 tumor suppressor does not appear to be required for IRF-3/DRAF1-mediated apoptosis.
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PMID:Apoptosis is promoted by the dsRNA-activated factor (DRAF1) during viral infection independent of the action of interferon or p53. 1115 66

Vesicular stomatitis virus (VSV) is an essentially nonpathogenic negative-stranded RNA virus, the replication of which is extremely sensitive to the antiviral effects of interferon (IFN). We demonstrate here that VSV selectively induces the cytolysis of numerous transformed human cell lines in vitro, with all the morphological characteristics of apoptotic cell death. Importantly, VSV can also potently inhibit the growth of p53-null C6 glioblastoma tumors in vivo without infecting and replicating in normal tissue. With our previous findings demonstrating that primary cells containing the double-stranded RNA-activated protein kinase PKR and a functional IFN system are not permissive to VSV replication, these results suggest that signaling by IFN may be defective in many malignancies. Thus VSV might be useful in novel therapeutic strategies for targeting neoplastic disease.
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PMID:Vesicular stomatitis virus (VSV) therapy of tumors. 1118 59

Type I interferon (IFN)-dependent inhibition of cell growth can occur either in the absence or presence of apoptosis. The mechanisms that determine whether or not cells undergo apoptosis after exposure to IFN-alpha are not clear. This study shows that a variety of cell lines that display growth inhibition but not apoptosis in response to IFN-alpha will undergo programmed cell death when low concentrations of the protein-tyrosine phosphatase inhibitor vanadate are added with IFN-alpha. In contrast, the combination of tumor necrosis factor-alpha with vanadate did not trigger apoptosis in these cells. Caspase-3 activity was detected only in cells exposed to IFN-alpha and vanadate but not to IFN-alpha or vanadate alone. The ability of IFN-alpha and vanadate to induce apoptosis did not require expression of p53 and was blocked by N-acetyl-l-cysteine. Activation of the Jak/Stat pathway and expression of IFN-inducible genes was not altered by incubation of cells with IFN-alpha and vanadate compared with IFN-alpha alone. However, mutant cells lacking Stat1, Stat2, Jak1, or Tyk2, or cells expressing kinase inactive Jak1 or Tyk2 did not undergo apoptosis in the presence of IFN-alpha and vanadate. These results suggest that IFN-alpha stimulation of Stat-dependent genes is necessary, but not sufficient, for this cytokine to induce apoptosis. Another signaling cascade that involves the activity of a protein-tyrosine phosphatase and/or the generation of reactive oxygen species may play an important role in promoting IFN-alpha-induced apoptosis.
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PMID:Vanadate facilitates interferon alpha-mediated apoptosis that is dependent on the Jak/Stat pathway. 1127 70


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