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)

Epstein-Barr virus (EBV) as a member of the herpesvirus family persists lifelong in the human body and causes diseases associated with virus replication (infectious mononucleosis, oral hairy leukoplakia) as well as neoplastic conditions such as nasopharyngeal carcinoma, B-cell lymphoma, Hodgkin's disease associated with viral latency. This complex biology relates to a highly regulated control of the persisting virus. Still, EBV is lytically produced in certain compartments of the human body. Epithelial cells were found to be of key importance for this. Various routes (cell fusion, IgA receptor-mediated uptake) were described for EBV to enter epithelial cells in the absence of CR2 receptor. Viral entry into cells, however, via CR2 receptor fusion or IgA mediated was not found to be sufficient for viral production. The molecular mechanisms for the lack of viral production in most target cells are primarily the presence of silencer activities and the early elimination of cells entering the lytic cycle. Only terminally differentiated epithelial cells are capable of supporting an efficient lytic cycle of EBV replication. EBV-mediated suppression of apoptosis as well as down-regulation of cellular and viral gene products, such as HLA molecules, which mediate recognition by the immune system, are important contributing factors to the development of these neoplasias where viral genes, possibly via interaction with anti-oncogenes, such as p53, in context with genetic and environmental factors play a key role. Novel diagnostic tools and a vaccine have been developed which could help to control EBV-related diseases.
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PMID:Epstein-Barr virus and its interaction with the host. 840 48

The DNA binding activity of wild type p53 is central to its activity. The "central" part of the molecule, where most mutations appear in primary human tumors, is the actual DNA binding domain. The C-terminal part was shown to exert a negative effect on the DNA binding activity. In the present study we show that while anti-p53 antibodies recognizing the C terminus of the wild type p53 facilitate DNA binding activity, blocking of the wild type specific epitope by specific anti-p53 antibodies, inhibited the DNA binding activity of the wild type p53 protein. An alternatively spliced p53 protein exhibits an augmented DNA binding activity. The fact that most p53 mutants have lost the wild type p53 conformation specific epitope, coupled with the observation that blocking of this site by binding specific antibodies, prevents the interaction of wild type p53 with DNA, suggests that maintaining the correct structural conformation of this site is central for DNA binding activity. Still, the internal structure of the p53 target and particularly the length of the sequence between the two tandem inverted repeats, is critical for protein-DNA interaction behavior.
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PMID:DNA-binding activity of wild-type p53 protein is mediated by the central part of the molecule and controlled by its C terminus. 946 43

It has been reported that cases of ovarian endometriosis those with epithelial cytological atypia have potential for malignant transformation. This study was planned to determine the incidence of atypical endometriosis and its cytological criteria, to evaluate the malignant potential of atypical endometriosis via immunohistochemical methods (p53). In this study we evaluated 140 samples obtained from 120 cases of ovarian endometriosis and 10 ovarian endometrioid carcinomas that have been previously diagnosed histopathologically. We re-evaluated endometriosis cases with respect to their epithelial and stromal features, existence of acute or chronic inflammatory cells in endometriotic epithelium or stroma and other accompanying histological findings. We observed atypia in 7 (5.8%) cases; reactive atypia in 37 (30.8%) cases, no atypia in 76 (63.4%) cases. We evaluated immunohistochemical p53 expression in 7 atypical cases, 37 reactive atypical cases, and in 10 of those without atypia and in 10 endometrioid carcinoma cases. We noted no staining in cases with atypia, reactive atypia and without atypia while 3 cases of endometrioid carcinoma had positive staining for p53. We concluded that prominent nucleolus and angulation of nuclear contour could be added to criteria of atypia that were mentioned before in the literature. In our study, even though p53 expression could not be shown with immunohistochemical methods in atypical endometriotic cases; it can not be determined that atypical endometriosis lesions are not premalignant. Still, endometriosis cases should be evaluated carefully by the pathologist for foci of cytological atypia and it should be kept in mind that malignant transformation might occur in these atypical endometriosis cases.
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PMID:Atypical epithelial changes and mutant p53 gene expression in ovarian endometriosis. 1134 18

There are continuing concerns over the safety of the nation's and the world's blood supply. The allogeneic blood supply is tested for antibodies to HIV1/2, HTLVI/II, hepatitis B, hepatitis C (HCV) and syphilis. Testing is also performed for donor ALT (SGOT) levels, for the presence of hepatitis B surface antigen, human immunodeficiency virus (HIV) p24 antigen and, using nucleic acid amplification testing (NAT), for HIV and HCV nucleic acids. Still, there are concerns regarding other pathogenic agents. Dr. Roger Dodd addresses a series of pathogens that are already known to be transmissible by transfusion. These include malaria, Chagas' disease, babesiosis, bacteria and some viral agents. The need for new donor screening assays to protect the integrity and purity of the blood supply must be balanced against the loss of potential donors and the cost of developing and implementing these new screening assays. This issue will be highlighted. Dr. Edward Snyder reviews the status of research into development of systems for pathogen inactivation (PI) of blood and its components. A proactive technology wherein PI reagents such as psoralen, riboflavin, dimethylmethylene blue or inactine are added to blood collection bags could assure multiple log reduction of a variety of pathogens including viruses, bacteria, protozoa and fungi without the need to initially pre-screen the blood for a specific pathogen. Such a program could also cover new pathogens as they enter the blood supply. As a key issue relates to the toxicology of these agents, Dr. Snyder provides data on a novel carcinogenicity assay that uses a heterozygous p53 knock-out mouse model. The criteria likely to be needed for PI technology to be adopted by the transfusion community are summarized.
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PMID:Reducing the risk of blood transfusion. 1172 97

Serine/threonine phosphatase 5 (PP5) can act as a suppresser of p53-dependent growth suppression and has been reported to associate with several proteins, including the glucocorticoid receptor/heat-shock protein-90 complex. Still, the physiological/pathological roles of PP5 are unclear. To characterize the relationship of PP5, glucocorticoid receptor activation and p53, here we describe the development of chimeric antisense oligonucleotides that potently inhibit human p53 expression. This allowed us to regulate the expression of either p53 (e.g. with ISIS 110332) or PP5 (e.g. with ISIS 15534) in genetically identical cells. Studies with ISIS 110332 revealed that the suppression of p53 expression is associated with a decrease in the basal expression of the cyclin-dependent kinase inhibitor protein, p21(WAF1/Cip1), and a concomitant increase in the rate of cell proliferation. Suppression of p53 also blocks dexamethasone-induced p21(WAF1/Cip1) expression and G(1)-growth arrest. Furthermore, treatment with ISIS 110332, but not the mismatched controls, ablates the suppression of growth produced by prior treatment with dexamethasone. Additional studies revealed that dexamethasone-dependent p21(WAF1/Cip1) expression occurs without an apparent change in p53 protein levels or the phosphorylation status of p53 at Ser-6, -37, or -392. However, dexamethasone treatment is associated with an increase in p53 phosphorylation at Ser-15. Suppression of PP5 expression with ISIS 15534 also results in the hyperphosphorylation of p53 at Ser-15. Together, these findings indicate that the basal expression of p53 plays a functional role in a glucocorticoid receptor-mediated response regulating the expression of p21(Waf1/Cip1) via a mechanism that is suppressed by PP5 and associated with the phosphorylation of p53 at Ser-15.
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PMID:Identification of a functional link for the p53 tumor suppressor protein in dexamethasone-induced growth suppression. 1251 80

Checkpoints suppress improper cell cycle progression to ensure that cells maintain the integrity of their genome. During mitosis, a metaphase checkpoint requires the integration of all chromosomes into a metaphase array in the mitotic spindle prior to mitotic exit. Still, mitotic errors occur in mammalian cells with a relatively high frequency. Metaphase represents the last point of control in mitosis. Once the cell commits to anaphase there are no checkpoints to sense segregation defects. In this context, we will explore our recent finding that non-transformed mammalian cells have a checkpoint that acts subsequent to mitotic errors to block the proliferation of cells that have entered G1 with tetraploid status. This arrest is dependent upon both p53 and pRb, and may represent an important function of both p53 and pRb as tumor suppressors. Further, we discuss the possibility that this mechanism may similarly impose G1 arrest in cells that become aneuploid through errors in mitosis.
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PMID:G1 tetraploidy checkpoint and the suppression of tumorigenesis. 1257 1

Radical prostatectomy as a primary treatment for clinically localized prostate cancer has increased dramatically over the past decade due to prostate-specific antigen (PSA) screening and the awareness of the increased incidence of localized disease. Despite the stage migration to increase clinically localized disease, there are still vast numbers of men who harbor occult extraprostatic extension and develop recurrence after surgery. The study of molecular markers in the blood or tissue of surgical patients prior to treatment, called " molecular staging, " is the focus of this review. The reverse transcriptase- polymerase chain reaction (RT-PCR) test for PSA gene expression in peripheral blood or bone marrow has received considerable attention since its first report in 1992. The test detects messenger RNA species for prostate-specific/abundant genes such as PSA and prostate-specific membrane antigen. These messenger RNAs were not detected in normal blood or bone marrow, but were detected in some prostate cancer patients presumably due to circulating prostatic epithelial cells. These prostate epithelial cells are thought to be occult metastases cells, and early studies correlated a positive RT-PCR test with surgical pathology adverse features such as positive margins. Despite the many studies over the past few years, there have been inconsistent results, and the most recent studies have not been able to confirm clinical utility. Bone marrow RT-PCR has been more promising; however, it is still a research tool that needs further study. The study of molecular markers in tissue material, ie, prostate biopsy samples prior to radical prostatectomy, is problematic due to the sampling error inherent in a multifocal heterogeneous tumor such as prostate cancer. The tumor suppressor proteins p53 and p27, Bcl-2 oncoprotein, Ki-67 proliferation index protein, E-cadherin, and microvessel density have been assessed in preradical prostatectomy needle biopsy. Results have been conflicting, and none are yet accepted as a clinically useful marker. Current and future work is focusing on analysis of multiple gene expressions or proteins simultaneously via gene chip or proteomics technology. While these expression profiles might be of value in whole prostate surgical specimens where tissues are well characterized, it is unclear how this new technology will be applied to the needle biopsy samples. Although molecular staging of radical prostatectomy patients has been under study for a decade, all assays remain research tools. Still, this area holds great promise for improving the accuracy of staging and providing a more accurate prognosis of individual men with clinically localized prostate cancer.
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PMID:Molecular markers in prostate cancer: the role in preoperative staging. 1504 12

During the last ten years our knowledge of genetic alterations in prostate cancer has significantly increased. For example, several chromosomal loci possibly harboring predisposing or somatically mutated genes have been suggested. Still, we lack the comprehensive molecular model for the development and progression of prostate cancer. Only a few genes have been found to be aberrant in a significant proportion of prostate cancer. These include GSTP1, PTEN, TP53, and AR. Thus, they are natural targets for new treatment strategies.
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PMID:Molecular mechanisms of prostate cancer. 1514 39

Ovarian cancer represents the fifth leading cause of death from all cancers for women. During the last decades overall survival has improved due to the use of new chemotherapy schedules. Still, the majority of patients die of this disease. Research reveals that ovarian cancer patients exhibit significant immune responses against their tumor. In this review the knowledge obtained thus far on the interaction of ovarian cancer tumor cells and the immune system is discussed. Furthermore the role of p53 as tumor antigen and its potential role as target antigen in ovarian cancer is summarized. Based on the increased knowledge on the role of the immune system in ovarian cancer major improvements are to be expected of immunotherapy based treatment of this disease.
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PMID:Immunologic aspect of ovarian cancer and p53 as tumor antigen. 1616 49

Several studies have demonstrated that zinc is required for the optimal functioning of the skin. Changes in intracellular zinc concentrations have been associated with both improved protection of skin cells against various noxious factors as well as with increased susceptibility to external stress. Still, little is known about the role of intracellular zinc in hexavalent chromium (Cr(VI))-induced skin injury. To address this question, the effects of zinc deficiency or supplementation on Cr(VI)-induced cytotoxicity, oxidative stress, DNA injury and cell death were investigated in human diploid dermal fibroblasts during 48 h. Zinc levels in fibroblasts were manipulated by pretreatment of cells with 100 microM ZnSO4 and 4 or 25 microM zinc chelator TPEN. Cr(VI) (50, 10 and 1 microM) was found to produce time- and dose-dependent cytotoxicity resulting in oxidative stress, suppression of antioxidant systems and activation of p53-dependent apoptosis which is reported for the first time in this model in relation to environmental Cr(VI). Increased intracellular zinc partially attenuated Cr(VI)-induced cytotoxicity, oxidative stress and apoptosis by enhancing cellular antioxidant systems while inhibiting Cr(VI)-dependent apoptosis by preventing the activation of caspase-3. Decreased intracellular zinc enhanced cytotoxic effects of all the tested Cr(VI) concentrations, leading to rapid loss of cell membrane integrity and nuclear dispersion--hallmarks of necrosis. These new findings suggest that Cr(VI) as a model environmental toxin may damage in deeper regions residing skin fibroblasts whose susceptibility to such toxin depends among others on their intracellular Zn levels. Further investigation of the impact of Zn status on skin cells as well as any other cell populations exposed to Cr(VI) or other heavy metals is warranted.
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PMID:The role of intracellular zinc in chromium(VI)-induced oxidative stress, DNA damage and apoptosis. 1688 9


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