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

Interleukin (IL)-6 is an autocrine growth factor for renal cell carcinoma (RCC). We sought to determine whether p53 regulates constitutive IL-6 production. RCC cell lines containing mutant (mut) p53 produced higher levels of IL-6 than those containing wild-type (wt) p53 (P < 0.05). Transfection of wt p53 into RCC cell lines bearing mut p53 (UOK 121LN) or wt p53 (A498 and ACHN) resulted in repression of IL-6 promoter chloramphenicol acetyltransferase activity (P < 0.05). Mutant p53 was either less effective at repressing IL-6 promoter activity (ACHN cells) or enhanced IL-6 promoter activity (A498 cells). A498 cells stably transfected with mut p53 produced higher levels of IL-6 than A498 cells transfected with an empty expression vector (P < 0.05). Electrophoretic mobility shift assays showed decreased binding of CAAT enhancer binding protein, cyclic AMP responsive element binding protein, +/- nuclear factor-kappaB transcription factors to the IL-6 promoter in various RCC cell lines transfected with wt p53 (P < 0.05) but not in those transfected with mut p53. These data suggest that: (a) mutation of p53 contributes to the overexpression of IL-6 in RCC; and (b) wt p53 represses IL-6 expression, at least in part, by interfering with specific transcription factor binding to the IL-6 promoter.
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PMID:Autocrine interleukin-6 production in renal cell carcinoma: evidence for the involvement of p53. 1183 May 54

Infection with the human immunodeficiency virus (HIV) invariably leads to the development of acquired immunodeficiency syndrome (AIDS) in most infected humans, yet does so rarely, if at all, in HIV-infected chimpanzees. The differences between the two species are not due to differences in cellular receptors or an inability of the chimpanzee to be infected, but rather to the lack of pan-immune activation in the infected primate. This results in reduced apoptotic death in CD4+ T-helper lymphocytes and a lower viral load. In humans the degree of chronic immune activation correlates with virus load and clinical outcome with high immune activation leading to high viral loads and the more rapid progression to AIDS and death. The type of immune perturbation seen in HIV-associated AIDS is similar to that of chronic graft-versus-host disease (GVHD) where reduced cell-mediated immune (CMI) responses occur early in the course of the disease and where humoral responses (HI) predominate. A reduced CMI response occurs in a number of chronic infectious diseases, including tuberculosis and leishmaniasis. More recently, it has become increasingly apparent that the CMI response is suppressed in virtually all malignant diseases, including melanoma and colorectal and prostate cancer. This raises the possibility that, as the malignant process develops, the cancer cells evolve to subvert the CMI response. Moreover, the reduced CMI response seen in colorectal cancer (CRC) patients is completely reversed following curative surgery strongly supporting the hypothesis that CRC can suppress the systemic immune response. Wound healing, ovulation, embryo implantation, and fetal growth are all associated with suppressed CMI and neovascularization (the formation of new blood vessels) or angiogenesis (the formation of new blood vessels from an existing vasculature). If unresolved, wound healing results in chronic inflammation, which can give rise to the phenomenon of "scar cancers." Indeed all the chronic inflammatory conditions known to be associated with the subsequent development of malignant disease, including chronic obstructive airway disease (COPD), ulcerative colitis (UC), and asbestosis, give rise to similar proangiogenic, suppressed CMI, and HI-predominant environments. In keeping with this CMI-associated cytokines such as interleukin (IL)-2 and interferon (IFN)-gamma tend to be antiangiogenic, whereas HI cytokines such as IL-6 tend to be proangiogenic. Furthermore, chronic immune activation leads to the synthesis and release of factors such as macrophage inflammatory protein (MIP)-1 that inhibit apoptosis through suppression of p53 activity. The "Golden Triangle" of suppressed CMI, angiogenesis, and reduced apoptosis would provide the ideal environment for the serial mutations to occur that are required for the development of malignant disease. If the observed association is relevant to carcinogenesis, then treatments aimed at reducing the components of these inflammatory conditions may be useful both in the setting of chemoprevention and the therapeutic management of established disease.
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PMID:Chronic immune activation and inflammation in the pathogenesis of AIDS and cancer. 1188 29

The tumor suppressor wild-type p53 can induce apoptosis. M1-t-p53 myeloid leukemic cells have a temperature-sensitive p53 protein that changes its conformation to wild-type p53 after transfer from 37 degrees C to 32 degrees C. We have now found that these cells showed an early lysosomal rupture after transfer to 32 degrees C. Mitochondrial damage, including decreased membrane potential and release of cytochrome c, and the appearance of apoptotic cells occurred later. Lysosomal rupture, mitochondrial damage, and apoptosis were all inhibited by the cytokine IL-6. Some other compounds can also inhibit apoptosis induced by p53. The protease inhibitor N-tosyl-l-phenylalanine chloromethyl ketone inhibited the decrease in mitochondrial membrane potential and cytochrome c release, the Ca(2+)-ATPase inhibitor thapsigargin inhibited only cytochrome c release, and the antioxidant butylated hydroxyanisole inhibited only the decrease in mitochondrial membrane potential. In contrast to IL-6, these other compounds that inhibited some of the later occurring mitochondrial damage did not inhibit the earlier p53-induced lysosomal damage. The results indicate that apoptosis is induced by p53 through a lysosomal-mitochondrial pathway that is initiated by lysosomal destabilization, and that this pathway can be dissected by using different apoptosis inhibitors. These findings on the induction of p53-induced lysosomal destabilization can also help to formulate new therapies for diseases with apoptotic disorders.
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PMID:Lysosomal destabilization in p53-induced apoptosis. 1195 17

The p53 tumor suppressor protein plays a central role in cell cycle regulation, DNA repair, and apoptosis. Recent studies indicate that DNA damage and somatic mutations in the p53 gene can occur because of genotoxic stress in many tissues, including the skin, colon, and synovium. Although somatic mutations in the p53 gene have been demonstrated in rheumatoid arthritis (RA) synovial tissue and synoviocytes, no information is available on the location or extent of p53 mutations. Using microdissected RA synovial tissue sections, we observed abundant p53 transition mutations, which are characteristic DNA damage caused by oxidative stress. p53 mutations, as well as p53 mRNA expression, were located mainly in the synovial intimal lining rather than the sublining (P < 0.01). Clusters of p53 mutant subclones were observed in some microdissected regions, suggesting oligoclonal expansion. Because IL-6 gene expression is regulated by wild-type p53, IL-6 mRNA expression in microdissected tissues was quantified by using real-time PCR. The regions with high rates of p53 mutations contained significantly greater amounts of IL-6 mRNA compared with the low mutation samples (P < 0.02). The microdissection findings suggest that p53 mutations are induced in RA synovial tissues by inflammatory oxidative stress. This process, as in sun-exposed skin and inflamed colonic epithelium, provides some of the mutant clones with a selective growth advantage. A relatively low percentage of cells containing p53 mutations can potentially affect neighboring cells and enhance inflammation through the elaboration of proinflammatory cytokines.
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PMID:Regional analysis of p53 mutations in rheumatoid arthritis synovium. 1211 14

This paper lists the genotype frequencies of 50 polymorphisms of 37 genes (ALDH2, ADRB2, ADRB3, COMT, CD36, CXCR2, CCND1, COX2, CYP2A6, CYP17, CYP19, IGF1, IL-1A, IL-1B, IL-1RN, IL-1R1, IL-6, IL-8, IL-10, LEP, Le, L-myc, MPO, MTR, MTHFR, MAO-A, NQO1, OGG1, p53, p73, Se, SRD5A2, TGF-B, TNF-A, TNF-B, XPD, and XRCC1) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients. Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers, 15 polymorphisms (CD36 A52C, CXCR2 C785T, CCND1 G870A, IGF1 C/T at intron 2 and G2502T, IL-1A 46-bp VNTR, IL-1R1 C-116T, IL-6 Ins/Del 17C, IL-8 A-278T and C74T, IL- 10 T-819C, LEP A-2548G, SRD5A2 2-bp VNTR, XPD Lys751Gln, and XRCC1 Arg399Gln) and six sets of combined genotype frequencies (IL-1B C-31T and IL-1A C-889T, IL-1B C-31T and IL-1RN 86-bp VNTR, IL-1B C-31T and IL-1R1 C-116T, TNF-A G-308A and TNF-B A252G, SRD5A2 Val89Leu and 2-bp VNTR, and XRCC1 Arg399Gln and XPD Lys751Gln) were reported in this paper for the first time for Japanese. Although microarray technology will produce this kind of information in near future, this is the first document that reports the genotype/allele frequencies among Japanese for an archival purpose.
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PMID:Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients. 1216 25

Antigen-presenting cells (APCs) are crucial for the generation of a functional immune response to pathogens. Furthermore, there is abundant evidence for their importance in primary T-cell activation, B-cell maturation and maintenance of an ongoing immune response. In the present study, we have analysed phenotypic characteristics and functionality of a p53-deficient APC cell line (JawsII) derived from mouse bone marrow culture. We show that unstimulated JawsII cells express low surface levels of major histocompatibility complex (MHC) and costimulatory molecules, both of which can be upregulated upon treatment with cytokines in vitro. Cytokine stimulation also leads to an enhanced T-cell activation capacity but has only little effect on cytokine release by the JawsII cells themselves. On the contrary, stimulation of the JawsII cells with lipopolysaccharide (LPS) leads to the production and secretion of high amounts of interleukin-1 (IL-1), IL-6 and tumour necrosis factor-alpha (TNF-alpha) but no increase in the surface levels of MHC and costimulatory molecules, and has only little effect on the T-cell activation capacity. Our data suggest that the effects observed upon treatment with cytokines or LPSs are complementary, and that both stimuli are needed for mediating a strong and efficient JawsII cell-dependent T-cell activation.
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PMID:Treatment of an immortalized APC cell line with both cytokines and LPS ensures effective T-cell activation in vitro. 1241 Jul 99

Global gene expression patterns in breast cancer cells after treatment with oxidants (hydrogen peroxide, menadione, and t-butyl hydroperoxide) were investigated in three replicate experiments. RNA collected after treatment (at 1, 3, 7, and 24 h) rather than after a single time point, enabled an analysis of gene expression patterns. Using a 17,000 microarray, template-based clustering and multidimensional scaling analysis of the gene expression over the entire time course identified 421 genes as being either up- or down-regulated by the three oxidants. In contrast, only 127 genes were identified for any single time point and a 2-fold change criteria. Surprisingly, the patterns of gene induction were highly similar among the three oxidants; however, differences were observed, particularly with respect to p53, IL-6, and heat-shock related genes. Replicate experiments increased the statistical confidence of the study, whereas changes in gene expression patterns over a time course demonstrated significant additional information versus a single time point. Analyzing the three oxidants simultaneously by template cluster analysis identified genes that heretofore have not been associated with oxidative stress.
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PMID:Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. 1241 54

Multiple myeloma is a malignant proliferation of plasma cells which fail to undergo apoptosis. To understand events associated with lack of apoptosis in these cells, we studied effect of antisense p53 gene transduction in a multiple myeloma cell line, ARH77. Adeno-associated virus was used as a vector to introduce p53 cDNA in an antisense orientation driven by a herpes virus thymidine kinase promoter. We observed, that an antisense p53 (p53as) transduced cell line showed marked reduction in p53 mRNA and protein expression and increased growth when compared to the control cell lines transduced with neomycin-resistance gene or untransduced cells. There was a concomitant up-regulation of bcl-2 expression by over five-fold in p53as-transduced cells compared with controls; while there was no significant change in expression of c-myc and IL-6, genes implicated in myeloma growth. We measured apoptosis in the transduced cells by DNA end-labeling reaction which revealed decrease in apoptosis from 15.6% in control cells to 1.6% in p53as-transduced cells. Additionally, the p53as cells over expressing bcl-2 also showed resistance to killing by dexamethasone. In summary, our data demonstrates that loss of p53 function leads to myeloma cell progression and resistant phenotype through bcl-2-related mechanisms.
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PMID:Antisense p53 transduction leads to overexpression of bcl-2 and dexamethasone resistance in multiple myeloma. 1247 55

The role of p53, a pro-apoptotic protein, in experimental autoimmune encephalomyelitis (EAE) was investigated using p53-deficient C57BL/6J mice. p53-deficient mice immunised with myelin oligodendrocyte glycoprotein (MOG) exhibited a more severe clinical course of EAE with more severe inflammation in the central nervous system (CNS) compared to wild-type littermates. While T and B cell responses of p53-deficient mice to MOG were comparable to those of wild-type littermates, significantly higher production of IL-6, granulocyte macrophage colony-stimulating factor and IL-10 was observed in lymphocytes exposed to MOG from p53-deficient mice than those from wild-type littermates. Furthermore, a flow cytometric analysis of Annexin V staining showed that apoptosis of CNS-infiltrating cells was less in p53-deficient mice with EAE compared to wild-type littermates. These results suggest that p53 may be involved in the regulatory process of EAE through the control of cytokine production and/or the apoptotic elimination of inflammatory cells.
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PMID:Regulatory role of p53 in experimental autoimmune encephalomyelitis. 1257 21

A number of studies have demonstrated that the STAT pathway is an important signaling cascade utilized by the IL-6 cytokine family to regulate a variety of cell functions. However, the downstream target genes of STAT activation that mediate the cytokine-induced cellular responses are largely uncharacterized. The aims of the current study are to determine whether the STAT signaling pathway is critically involved in the oncostatin M (OM)-induced growth inhibition and morphological changes of MCF-7 cells and to identify STAT3-target genes that are utilized by OM to regulate cell growth and morphology. We show that expression of a dominant negative (DN) mutant of STAT3 in MCF-7 cells completely eliminated the antiproliferative activity of OM, whereas expression of DN STAT1 had no effect. The growth inhibition of breast cancer cells was achieved through a concerted action of OM on cell cycle components. We have identified four cell cycle regulators including c-myc, cyclin D1, c/EBPdelta, and p53 as downstream effectors of the OM-activated STAT3 signaling cascade. The expression of these genes is differentially regulated by OM in MCF-7 cells, but is unaffected by OM in MCF-7-dnStat3 stable clones. We also demonstrate that the OM-induced morphological changes are correlated with increased cell motility in a STAT3-dependent manner. Expression analysis of extracellular matrix (ECM) proteins leads to the identification of fibronectin as a novel OM-regulated ECM component. Our studies further reveal that STAT3 plays a key role in the robust induction of fibronectin expression by OM in MCF-7 and T47D cells. These new findings provide a molecular basis for the mechanistic understanding of the effects of OM on cell growth and migration.
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PMID:Delineating an oncostatin M-activated STAT3 signaling pathway that coordinates the expression of genes involved in cell cycle regulation and extracellular matrix deposition of MCF-7 cells. 1258 69


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