UNIPROT:P04637 - FACTA Search

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

Keloids are the result of a dysregulated wound-healing process and are characterized by formation of excess scar tissue that proliferates beyond the boundaries of the inciting wound. In this study, we investigated the expression of key proteins involved in regulating apoptosis in keloids. Twenty archival paraffin-embedded keloid samples were randomly selected for an immunoperoxidase assay with antibodies against fas, p53, bcl-2, and bcl-x proteins using the target antigen-retrieval technique. Apoptosis was assessed in keloids and normal skin and in keloid and normal fibroblasts by the TdT-mediated dUTP nick-end labeling (tunel) assay on tissue sections, fibroblast cultures, and by flow cytometry for cell suspensions. We found that 18 of 20 keloids expressed p53 protein; bcl-2 was expressed by keloid fibroblasts in 19 of 20 keloids, and all specimens had prominent fas expression throughout the tissue. The distribution of these three antigens was regional within each lesion and followed a consistent pattern of p53 and bcl-2 expression colocalized to the hypercellular, peripheral areas of each keloid in a perinuclear pattern (p < .001). In contrast, an inverse distribution of fas expression was shown, with staining being more diffuse across the cell surfaces and limited to the central, more hypocellular regions in16 of 17 keloids (p < .001). There was no specific staining pattern in these keloids with antihuman bcl-x. In vitro studies on cultured keloid fibroblasts (derived from six patients) revealed maintenance of the p53+, bcl-2+ phenotype up to passage 10. Neither neonatal nor normal adult skin fibroblasts expressed either antigen but could be induced to express p53 by exposure to adriamycin. Keloid lesions and keloid fibroblasts were found to have lower rates of apoptosis than normal controls. Keloid fibroblasts displayed enhanced apoptosis rates in response to hydrocortisone, gamma interferon, and hypoxia treatment as compared with normal adult fibroblasts. Focal dysregulation of p53 combined with upregulation of bcl-2 may help produce a combination of increased cell proliferation and decreased cell death in the younger, hypercellular areas of the keloid. This phenotype is reversed in the older areas of the keloid and may prevent malignant degeneration, thus favoring normal apoptosis as evidenced by prominent fas expression.
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PMID:p53 and apoptosis alterations in keloids and keloid fibroblasts. 977 48

Nitric oxide (NO) is thought to play an important role in neurotransmission, inflammation, and regulation of cell death in the mammalian brain. Here, we examined the synthesis and biological effects of NO in human malignant glioma cells. Exposure to cytokines such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta and lipopolysaccharide (LPS) induced NO synthesis in rat C6 and A172 human glioma cells, but not in LN-229, T98G or LN-18 human malignant glioma cells. Induced release of NO involved enhanced expression of inducible NO synthase (iNOS). Failure to detect NO release in the latter cell lines was not overcome by neutralization of endogenous TGF-beta or by coexposure to cytokines, LPS, and antioxidants. Apoptosis induced by CD95 ligand (CD95L) did not involve NO formation. Neither NOS inhibitors nor NO donators modulated CD95L-induced apoptosis. Dexamethasone (DEX)-mediated protection of glioma cells from CD95L-induced apoptosis was also independent of DEX effects on NO metabolism. DEX inhibited not only cytokine/LPS-evoked NO release but also attenuated the toxicity of NO in three of five cell lines. Forced expression of temperature-sensitive p53 val135 in C6 cells in either mutant or wild-type conformation inhibited cytokine/LPS-induced NO synthesis. Further, accumulation of p53 in both mutant or wild-type conformation protected glioma cells from the toxicity of exogenous NO, consistent with a gain of p53 function associated with p53 accumulation. We conclude that resistance to NO-dependent immune defense mechanisms may contribute to the malignant progression of human cancers with p53 alterations, notably those associated with the accumulation of mutant p53 protein.
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PMID:Synthesis and biological effects of NO in malignant glioma cells: modulation by cytokines including CD95L and TGF-beta, dexamethasone, and p53 gene transfer. 981 63

A recently identified herpesvirus, human herpesvirus-8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, has been found in nonmalignant bone marrow dendritic cells of patients with multiple myeloma. The virus is also detectable in the peripheral blood of most patients; its absence suggests earlier-stage disease. HHV-8 is not detected in the blood of family members and sexual partners of myeloma patients. Sequencing of HHV-8 open-reading frames (ORFs) shows differences between individual myeloma patients, as well as between myeloma patients and those with other HHV-8-related malignancies. Consistent expression of the viral homolog of both interferon regulatory factor (IRF) and interleukin-8 receptor (IL-8R) suggests a possible role for these transforming viral genes in the pathogenesis of myeloma. Detailed analysis of myeloma cell lines has shown that myeloma is characterized by frequent chromosome translocations involving the switch regions of the immunoglobulin heavy-chain (IgH) locus on 14q32. The three partner chromosomes most commonly involved are 11q13 (cyclin D1), 4p16 (FGFR3), and 16q23 (c-maf). Mutations have also been identified in N- and K-ras and, less frequently, involving p53. Monosomy 13q is common. These findings have implications for immunotherapy. Angiogenesis increases with progressive disease and appears to be a prognostic factor. In at least one patient, this process appears to have been reversed with thalidomide therapy. The underlying mechanisms for the increased vascularization in myeloma have not been identified, and several possibilities have been proposed.
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PMID:Initiation and maintenance of multiple myeloma. 998 83

Effects of drug treatment with antimetabolites on a human colon cancer cell line, SW480, were studied. Cells were treated with 10 microM of 5-fluorouracil (5FU), an inhibitor of pyrimidine synthesis, or 1000 microM of hydroxyurea (HU), an inhibitor of both purine and pyrimidine syntheses, or the combination. Recombinant alpha-2a-interferon (IFN), 500 U/mL, also was employed, as this augments the effects of both antimetabolites in vitro and in vivo. The predominant effect of this combination was to block cells in early S phase as measured by 5-bromo-2'-deoxyuridine (BrdUrd) incorporation. By 24 hr, 86% of the cells had accumulated in S phase, but failed to progress to G2/M. This was accompanied by an early, rapid decline in all four deoxyribonucleoside triphosphates (dNTPs) by 38-86% at 4-24 hr. Despite these effects, expression of the G1/S transition state enzyme, ribonucleotide reductase (RR), increased at 24 hr as measured by a 3 to 5-fold increase in mRNA levels for the M2 subunit, in the absence of a measurable effect on protein levels. The rise in levels of RR mRNA and the continued progression of cells into S phase were associated with a synergistic inhibition of cell cycle proliferation resulting from treatment with the three-drug combination. This suggests that in the presence of antimetabolite-induced depletion of dNTPs, SW480 cells, which lack a normal p53 gene, will proceed into S phase, and that this is associated with a rise in expression of the G1/S transition state enzyme, RR. Cells arrested in S phase by a p53-independent mechanism will undergo a synergistic enhancement of cell death.
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PMID:Effects of perturbations of pools of deoxyribonucleoside triphosphates on expression of ribonucleotide reductase, a G1/S transition state enzyme, in p53-mutated cells. 1007 25

The tumor suppressor p53 plays a key role in inducing G1 arrest and apoptosis following DNA damage. The double-stranded-RNA-activated protein PKR is a serine/threonine interferon (IFN)-inducible kinase which plays an important role in regulation of gene expression at both transcriptional and translational levels. Since a cross talk between IFN-inducible proteins and p53 had already been established, we investigated whether and how p53 function was modulated by PKR. We analyzed p53 function in several cell lines derived from PKR+/+ and PKR-/- mouse embryonic fibroblasts (MEFs) after transfection with the temperature-sensitive (ts) mutant of mouse p53 [p53(Val135)]. Here we report that transactivation of transcription by p53 and G0/G1 arrest were impaired in PKR-/- cells upon conditions that ts p53 acquired a wild-type conformation. Phosphorylation of mouse p53 on Ser18 was defective in PKR-/- cells, consistent with an impaired transcriptional induction of the p53-inducible genes encoding p21(WAF/Cip1) and Mdm2. In addition, Ser18 phosphorylation and transcriptional activation by mouse p53 were diminished in PKR-/- cells after DNA damage induced by the anticancer drug adriamycin or gamma radiation but not by UV radiation. Furthermore, the specific phosphatidylinositol-3 (PI-3) kinase inhibitor LY294002 inhibited the induction of phosphorylation of Ser18 of p53 by adriamycin to a higher degree in PKR+/+ cells than in PKR-/- cells. These novel findings suggest that PKR enhances p53 transcriptional function and implicate PKR in cell signaling elicited by a specific type of DNA damage that leads to p53 phosphorylation, possibly through a PI-3 kinase pathway.
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PMID:Double-stranded-RNA-activated protein kinase PKR enhances transcriptional activation by tumor suppressor p53. 1008 13

Most prostate cancers eventually develop resistance to hormonal therapy and chemotherapies. Many mechanisms for resistance to chemotherapy have been identified. Mutations or inactivation of the p53 suppressor gene and overexpression of bcl-2 are among such mechanisms. Mutations in the p53 gene can lead to resistance to certain chemotherapy agents, and such mutations are seen more often in metastatic than in primary prostate cancers. Thus, agents that are active in the setting of mutated p53 may have some advantage in prostate cancer. Overexpression of bcl-2 occurs frequently in prostate cancer and is associated with both hormonal therapy and chemotherapy resistance. In experimental systems, bcl-2 overexpression occurs after androgen deprivation and transfection of bcl-2 into sensitive cell lines makes them resistant to chemotherapy and hormonal therapies. Bcl-2 can be inactivated by phosphorylation as occurs with taxanes. The retinoids, as a class, can inhibit the growth of resistant cell lines that overexpress bcl-2, and the combination of interferon (IFN) and cis-retinoic acid (CRA) demonstrated increased antitumor activity. In our cell line model the combination of IFN and CRA greatly enhanced the cytotoxicity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). Based on these observations, we conducted a phase I/II trial of CRA and IFN-alpha in patients with biochemical recurrence of prostate cancer. Twenty-six percent achieved a decrease of prostate-specific antigen (PSA), which was correlated to elevated serum transforming growth factor-beta. We then conducted a phase I trial of 13-CRA, IFN-alpha, and escalating doses of paclitaxel. Eighteen patients were treated with 1 mg/kg CRA and 1x10(6) unit IFN on days 1 to 4 and paclitaxel at doses from 100 to 175 mg/m2. Eleven patients received the 175 mg/m2 paclitaxel dose. Two patients in the phase I study achieved partial responses (one cervix and one prostate cancer). We subsequently initiated a phase II study of 13-CRA, IFN-alpha, and paclitaxel in hormone refractory prostate cancer. For entry patients must show progressive disease after androgen ablation. To test the mechanism of action, we are assaying peripheral blood monocytes and, when possible, tumor tissue for bcl-2 expression. As our understanding of the mechanisms of tumor resistance to chemotherapy improves, we will be able to design better approaches in treatment targeted to overcome the mechanisms of resistance.
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PMID:Overcoming bcl-2- and p53-mediated resistance in prostate cancer. 1019 Jul 92

The tumor suppressor p53 is a multifunctional protein that plays a critical role in modulating cellular responses upon DNA damage or other stresses. These functions of p53 are regulated both by protein-protein interactions and phosphorylation. The double-stranded RNA activated protein kinase PKR is a serine/threonine kinase that modulates protein synthesis through the phosphorylation of translation initiation factor eIF-2alpha. PKR is an interferon (IFN)-inducible protein that is thought to mediate the anti-viral and anti-proliferative effects of IFN via its capacity to inhibit protein synthesis. Here we report that PKR physically associates with p53. The interaction of PKR with p53 is enhanced by IFNs and upon conditions that p53 acquires a wild type conformation. PKR/p53 complex formation in vitro requires the N-terminal regulatory domain of PKR and the last 30 amino acids of the C-terminus of human p53. In addition, p53 may function as a substrate of PKR since phosphorylation of human p53 on serine392 is induced by activated PKR in vitro. These novel findings raise the possibility of a functional interaction between PKR and p53 in vivo, which may account, at least in part, for the ability of each protein to regulate gene expression at both the transcriptional and the translational levels.
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PMID:The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro. 1034 43

Chronic hepatitis B progresses across a spectrum of asymptomatic carriers, active hepatitis, and liver cirrhosis. With more advanced disease stage, the risk for developing hepatocellular carcinoma (HCC) becomes higher. Recent studies suggest that this progressive risk may reflect an accumulation of multistage genetic mutations in the chromosomes of affected hepatocytes. Mutations of the known candidate genes such as p53 and beta-catenin have been found. Recent genome-wide analysis of HCC chromosomes by comparative genomic hybridization or loss of heterozygosity have identified more new loci implicated in hepatocarcinogenesis. Persistent hepatitis B is essential for inducing these mutations through immune-mediated injuries of the hepatocytes and the resulting hyperplasia. Prevention of hepatitis B by active immunization effectively interrupts persistent viral infections in children and subsequently reduces the risk of childhood HCC. Treatment for chronic hepatitis B by interferon or antiviral analogues can control hepatitis B activity, but its effect on controlling HCC remains to be seen. Insights for the hepatocarcinogenesis process should come from a multidisciplinary collaboration to explore important viral and host genes so that new approaches to diagnosis and treatment can be developed.
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PMID:Hepatitis B virus infection and hepatocellular carcinoma: molecular genetics and clinical perspectives. 1051 5

The effects of interferon-tau (IFN-tau) on tumor suppressor factors and virus oncoprotein expression were compared with two other type I IFN in human papillomavirus (HPV-16)-transformed cells. Nontumorigenic human keratinocytes, HuKc/HPV-16d-2C (d-2C), treated with recombinant human IFN-alpha2a (Roferon), a human recombinant alpha IFN hybrid, alpha B/D (IFN-alphaB/D), or ovine IFN-tau were evaluated for their effects on the levels of E6 and E7 expression. IFN-tau was comparable to IFN-alpha2a in decreasing intracellular levels of E6 and E7, and IFN-alphaB/D was more effective than IFN-a2a in suppressing E7 levels. All three IFN were capable of increasing the cellular concentration of wild-type p53 tumor suppressor with the magnitude IFN-tau > IFN-alpha2a > IFN-alphaB/D. Increases in p53 concentrations correlated with the observed decreases in E6 mRNA and protein levels. The antiviral effects observed in this study reveal that IFN-tau has potent antipapillomavirus activity. Sequences/structures unique to IFN-tau could allow for alternative IFN/receptor interactions and may explain the differences in biologic function.
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PMID:IFN-tau exhibits potent suppression of human papillomavirus E6/E7 oncoprotein expression. 1054 50

Recently, several advances have been made in understanding the pathogenesis of multiple myeloma. Increasing evidence favours a pre-switched, but somatically mutated B-cell as myeloma stem cell to give rise to the malignant clone. Deletions of the p53-gene, partial or total loss of chromosome 13 and rearrangements of band 14q32 and 11q13 are frequently found in multiple myeloma, and were shown to harbour prognostic significance. Presence or absence of distinct chromosomal aberrations may guide selection of treatment strategies in the future. Although melphalan/prednisolone remains the standard of myeloma treatment in elderly patients, significant improvement has been achieved in antimyeloma and in supportive therapy. High dose therapy with autologous stem cell transplantation enhances survival in younger patients and several trials are ongoing to substantiate these results. The effects of interferon maintenance treatment on overall survival is significant in metaanalysis, although the gain achieved is limited. Newer treatment strategies--targeting the molecular level--have just entered clinical trials, and may further improve outcome of myeloma patients.
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PMID:Multiple myeloma: an update on biology and treatment. 1067 51

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