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

HPV-16 E6 and E7 oncoproteins impair the cell cycle in human uterine cervix carcinoma cells (HUCC) by acting on p53 and retinoblastoma proteins, respectively. We recently reported that E7 related into the extracellular compartment by HUCC SiHa cells could inhibit immune T-cell response to recall and alloantigens by a mechanism involving an overproduction of the immunosuppressive IFN alpha by antigen presenting cells (APCs). In this study, we found that besides E7, E6 protein and the vascular endothelium growth factor (VEGF) were released into the SiHa cell supernatants, and we further showed that extracellular E7 but not E6 oncoprotein 1) inhibits the immune cell response to recall and alloantigens, and 2) enhances the release of angiogenic cytokines, including TNF alpha, IL-1 beta and IL-6 by macrophages and/or dendritic cells. VEGF unexpectedly released by cancer cells could also contribute to angiogenesis. Thus in HUCC the same E7 oncoprotein which contributes to controlling the cancer cell cycle has the means in its extracellular configuration to contribute to microenvironmental immunosuppressive and angiogenic processes. Neutralizing anti-E7 antibodies either passively administered or induced by active immunization could represent a new immunotherapeutic endeavour to combat the immunosuppression and/or neoangiogenesis effects of extracellular E7 protein.
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PMID:HPV-16 E7 but not E6 oncogenic protein triggers both cellular immunosuppression and angiogenic processes. 1055 78

The presence of interleukin (IL)-6 in peritoneal carcinomatous fluid (PCF) and its effect on immune cells composition in PCF in patients with advanced ovarian carcinoma was studied. In 21 out of 30 ovarian carcinoma patients, PCF IL-6 levels were found to exceed those seen in PCFs of patients with gastrointestinal cancer. IL-6 activity was higher in serous/mucinous than in endometrioid and undifferentiated ovarian carcinoma PCF (P = 0.05). Ovarian carcinoma PCF IL-6 activities were correlated with serum C-reactive protein levels (r = 0.65, P = 0.0000, n = 25). Ovarian carcinoma PCF leucocyte profile differed from that in blood with respect to: (i) lower percentage of NK and CD8+ and (ii) higher percentage of B and CD45RO+, CD14+ and HLA-DR+ cells. The proportions of CD45RO+ in blood were correlated with IL-6 levels in PCF. Corresponding to PCF ovarian carcinoma tumours were stained for the presence of Ki-67 antigen and p53. The highest proportions of Ki-67+ cells and cells showing accumulation of p53 were seen in undifferentiated tumours. A low grade of p53 staining was seen in tumours associated with high IL-6 levels in PCF. It was evident that IL-6 production (i) depended on the histiotype of the tumour, (ii) influenced the local immune system in favour of accumulation of B, and T memory cells, and (iii) was higher in patients lacking p53 accumulation.
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PMID:IL-6 production in ovarian carcinoma is associated with histiotype and biological characteristics of the tumour and influences local immunity. 1068 75

BACKGROUND: Approximately 25% of patients with monoclonal gammopathy of undetermined significance (MGUS) eventually develop multiple myeloma (MM) or a related plasma cell disorder that is universally fatal. In this report, we examine the changes that occur in the clonal plasma cell that are likely to be important in the progression of MGUS to active myeloma. METHODS: Studies that investigate the mechanisms involved in the multistep pathogenesis of monoclonal gammopathies are reviewed. Cytokines such as IL-6 and IL-1-beta, adhesion molecules, viruses, and oncogenes including ras, bcl-2, Rb, and p53 are discussed. RESULTS: IL-1-beta is produced by plasma cells from virtually all MM patients but is undetectable in most MGUS patients. IL-1-beta has potent osteoclast activating factor activity, can increase the expression of adhesion molecules, and can induce paracrine IL-6 production. The increased production of adhesion molecules could explain why myeloma cells are found predominantly in the bone marrow. Subsequently, these "fixed" monoclonal plasma cells could now stimulate osteoclasts through the production of IL-1-beta and paracrine generation of IL-6 resulting in osteolytic disease. With continued progression of the myeloma, the monoclonal plasma cells may later acquire the ability to produce IL-6 in an autocrine fashion that will be manifested clinically by an elevated labeling index. CONCLUSIONS: A better understanding of the progression of MGUS to myeloma may lead to novel therapeutic strategies to prevent the development of MM.
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PMID:Biology of the Transition of Monoclonal Gammopathy of Undetermined Significance (MGUS) to Multiple Myeloma. 1076 Oct 54

DM650, a soluble human IL-6Ralpha mutant with mutation of C277D/H280I, was previously shown to exhibit an antagonism to IL-6, which resulted in growth-inhibition of human multiple myeloma cell line AF-10 autocrining as the growth-stimulating factor. We investigated here the nature of the growth inhibition by examining cell apoptosis. Flow-cytometric analysis of the DNA fragmentation demonstrated that 7.2% of the AF-10 cells were apoptotic after 24 h of treatment with DM650. The constitutive gene expression of bcl-2 in AF-10 cells indicated that apoptosis suppressed by IL-6 was independent of bcl-2 regulation. The altered gene expression of c-myc and p53 suggested that a novel apoptosis pathway, other than that suppressed by IL-6, might be triggered by a complex of DM650 and IL-6.
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PMID:Study on the growth inhibition of human multiple myeloma cells by an IL-6Ralpha mutant. 1077 37

Increasing lines of evidence suggest a role of apoptosis in the neurodegeneration associated with Alzheimer's disease, in which it has been implicated in increasing the expression of p53 and Fas. On the other hand, inflammatory cytokines have also been implicated as important factors in the progression of neuronal damage in this disease. In an attempt to investigate the possible in vivo relationship between programmed cell death and the inflammatory response in patients with dementia of the Alzheimer type (DAT), we measured the levels of soluble Fas, interleukin-1beta (IL-lbeta) and IL-6 in cerebrospinal fluid (CSF) from ten DAT patients and ten age-matched controls. Our results show a significant increase in IL-6 and soluble Fas concentrations in the CSF of DAT patients compared with those from nondemented controls. Moreover, linear regression analysis demonstrated a significant correlation (r=0.703; P<0.05) between soluble Fas and IL-6 levels in the CSF in DAT patients. These results suggest that Fas is implicated in the inflammatory response observed in Alzheimer's brains.
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PMID:Increased cerebrospinal fluid fas (Apo-1) levels in Alzheimer's disease. Relationship with IL-6 concentrations. 1086 77

Previously we have shown that deregulated expression of c-myc in M1 myeloid leukemic cells blocked IL-6-induced differentiation and its associated growth arrest; however, the cells proliferated at a significantly reduced rate compared to untreated cells. The basis for the increased doubling time of IL-6-treated M1myc cells was found to be due to the induction of a p53-independent apoptotic pathway. The apoptotic response was not completely penetrant; in the same population of cells both proliferation and apoptosis were continuously ongoing. Down-regulation of Bcl-2 was insufficient to account for the apoptotic response, since deregulated expression of Bcl-2 delayed, but did not block, the onset of apoptosis. Furthermore, our results indicated that the IL-6-induced partial hypophosphorylation of the retinoblastoma gene product (Rb), observed in M1myc cells, was not responsible for the apoptotic response. Finally, the findings in M1 cells were extended to myeloid cells derived from the bone marrow of wild type and p53-deficient mice, where the deregulated expression of c-myc was also shown to block terminal differentiation and induce apoptosis independent of p53. These findings provide new insights into how myc participates in the neoplastic process, and how additional mutations can promote more aggressive tumors. Oncogene (2000) 19, 2967 - 2977
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PMID:p53-independent apoptosis associated with c-Myc-mediated block in myeloid cell differentiation. 1087 48

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

Because there is no known genetic abnormality common to all patients with myeloma, it is important to understand how genetic heterogeneity may lead to differences in signal transduction, cell cycle, and response to therapy. Model cell lines have been used to study the effect that mutations in p53 and ras can have on growth properties and responses of myeloma cells. The U266 cell line has a single mutant p53 allele. Stable expression of wild-type (wt) p53 in U266 cells results in a significant suppression of interleukin (IL)-6 gene expression and in the concomitant suppression of cell growth that could be restored by the addition of exogenous IL-6. Expression of wt p53 also leads to cell cycle arrest and protection from doxorubicin (Dox)- and melphalan (Mel)-induced apoptosis. The addition of IL-6 resulted in cell cycle progression and blocked p53-mediated protection from apoptosis. ANBL6 is an IL-6-dependent cell line that is sensitive to dexamethasone (Dex), Dox, and Mel. IL-6 is able to protect ANBL6 cells from Dex- and Mel- but not Dox-induced apoptosis. To study the effect of an activating mutation in ras, the ANBL6 cell line transfected with either a constitutively activated N- or K-ras gene was used. Both N-ras12 and K-ras12 genes were able to protect ANBL6 cells from apoptosis induced by Dex, Dox, and Mel. These data show that changes in ras or p53 can alter the myeloma cell response to IL-6 and demonstrate that the genetic background can alter therapeutic responses.
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PMID:Heterogeneity in therapeutic response of genetically altered myeloma cell lines to interleukin 6, dexamethasone, doxorubicin, and melphalan. 1105

Human herpesvirus 8 ([HHV-8], Kaposi's sarcoma-associated herpesvirus [KSHV]) is a novel human oncovirus classified as a gamma-herpesvirus. HHV-8 is associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and some cases of multicentric Castleman's disease (MCD). Antibodies against HHV-8 are detected in the sera of almost all KS patients, about 30% of HIV-infected homosexual males in the world and 1.4% of the Japanese population. In HHV-8-associated malignancies such as KS and PEL, HHV-8 latently infects these tumor cells. Unlike other viruses, HHV-8 encodes several human homologues including cytokines (IL-6, MIPs, IRFs) and regulatory proteins (cyclin D, G-protein coupled receptor [GPCR]). These proteins may play significant roles in the pathogenesis of HHV-8-associated diseases. It has been demonstrated in vitro that the functions of retinoblastoma and p53 proteins were inhibited by viral cyclin D and latency-associated nuclear antigen, respectively. Mice transgenic for GPCR have a KS-like region in the skin. These data suggest the full oncogenecity of HHV-8. On the other hand, many cells expressing lytic proteins are found in MCD tissues, suggesting that the pathogenesis of MCD is different from that of HHV-8-associated malignancies.
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PMID:Human herpesvirus 8 virology, epidemiology and related diseases. 1105 56

Epidemiological evidence implicates ultraviolet radiation and genetic changes (e.g., p53 mutations) as important factors in the etiology of nonmelanoma skin cancer. Little is known about a possible role of cutaneous papillomaviruses in these tumors. We previously reported both positive and negative regulation of the promoter activity of a number of HPV types by UV irradiation. To determine the underlying mechanism, we examined the influence of pro-inflammatory cytokines and MAP-kinases induced by UV irradiation by transfecting the HPV 20-URR and the HPV 27-URR into the RKO, HaCaT and H1299 cell lines expressing wild-type or mutated p53 or lacking p53, respectively. IL-1alpha, IL-1beta, IL-6, IL-17, TNF-alpha, as well as interferon-alpha, -beta and -gamma activated the promoter in the HPV 20-URR but inhibited the HPV 27-URR promoter. The effect of IL-1alpha and UV light was abolished by the addition of IL-1 receptor antagonist. UV irradiation induced a prolonged activation of JNK in HaCaT and H1299 but not in RKO cells, and its dephosphorylation was enhanced in the presence of p53 and the HPV-URRs.
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PMID:Opposite regulation of the HPV 20-URR and HPV 27-URR promoters by ultraviolet irradiation and cytokines. 1127 87


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