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

Transpupillary thermotherapy (TTT) is a new treatment modality for uveal melanoma. We studied whether application of TTT influences the immunogenicity of the tumour cells in vivo or the expression of molecules related to apoptosis. Immunohistochemistry using monoclonal antibodies directed against HLA molecules, HMB45, P53, Fas ligand (FasL), Fas, Bcl-2 and tumour-infiltrating cells was applied to sections of an enucleated eye containing a uveal melanoma that received TTT 1 week before enucleation. The innermost part of the tumour which had been exposed directly to the laser treatment showed no staining for HLA antigens, nor for Fas or FasL epitopes. The intermediate part of the tumour showed a wet necrosis and HLA expression similar to the expression in the peripheral tumour. A large number of macrophages were observed in the necrotic as well as the intact tumour tissue, especially bordering the wet necrotic area. FasL and Bcl-2 were only expressed in the viable, outer part of the tumour. This immunological evaluation of one case of uveal melanoma treated with TTT revealed that TTT may not only have a direct destructive effect on the primary tumour, but may also influence the immunogenicity of uveal melanoma cells, induce infiltration of macrophages into the tumour, and induce apoptosis. The presence of many macrophages suggests that they play a role in the removal of the TTT-treated tumour tissue by phagocytosis.
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PMID:Effects of transpupillary thermotherapy on immunological parameters and apoptosis in a case of primary uveal melanoma. 1046 86

Melanoma of the uvea of the eye and melanoma of the skin share a common cell of origin, but differ substantially in their behaviour and response to chemotherapy. There is increasing evidence that this is related to differences in their molecular phenotype, particularly in relation to the expression of cell cycle-associated proteins. Since many cytotoxic agents act by damaging DNA, resistance is often associated with intact mechanisms which allow the neoplastic cells to arrest their growth while DNA is repaired, or to resist apoptosis in response to detection of DNA damage. p53 is important to these processes, but mutation appears to be a less common event in uveal melanoma than in skin melanoma, probably due to the lack of UV exposure in the uvea. There are also differences in proliferation-associated proteins such as c-myc and cyclin D1. Overexpression of the former molecule is associated with a poor prognosis in skin melanoma, but is associated with a good prognosis in uveal melanoma, although there is considerable genetic heterogeneity within each type. While prognostic studies may therefore be of little relevance to individual patients, they continue to inform our understanding of tumour biology.
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PMID:Cell cycle and melanoma--two different tumours from the same cell type. 1086 69

Malignant uveal melanoma is the commonest primary intraocular tumour in adults. It metastasizes frequently and 50% of patients die within 10 years of diagnosis. The expression of cyclin D1, p53, and MDM2 in uveal melanoma and their relationship to metastasis-free 5-year survival was determined, in order to investigate whether these proteins help to distinguish those patients with a favourable prognosis from those with a poorer one. Ninety-six eyes enucleated for uveal melanomas were immunohistochemically analysed for the protein expression of cyclin D1 and related cell-cycle markers, p53 and MDM2. The evaluation of the specimens was undertaken by two independent pathologists without knowledge of the outcome. Statistical analysis of clinical, morphological, and immunohistological features was performed. A 'favourable outcome' was defined as survival of at least 5 years after diagnosis, without metastases (n=57). An 'unfavourable outcome' was defined as death from metastases within the first 5 years after diagnosis of uveal melanoma (n=39). Cyclin D1 positivity (>15% positive tumour cells) as well as p53 positivity (>15% positive tumour cells) was associated with an unfavourable outcome (for cyclin D1: odds ratio=4. 2, 95% confidence interval 1.5-11.8, p=0.006; for p53: odds ratio=3. 2, 95% confidence interval 1.1-9.3, p=0.03). In addition, cyclin D1 positivity was associated with the presence of extraocular extension of the tumour (p=0.01), with the mixed or epithelioid cell type (p=0. 02), and with the tumour cell MIB-1 positivity (p=0.0001). MDM2 immunoreactivity of the tumour cells showed a potential correlation with clinical outcome (odds ratio=2.1, 95% confidence interval 0.8-5. 8, p=0.13). Multiple logistic regression models showed that cyclin D1 positivity is an independent prognostic factor after control for other prognostic markers. The expression of cyclin D1 in uveal melanoma is associated with a more aggressive course and histologically unfavourable disease. This could serve as a further independent prognostic factor in uveal melanoma.
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PMID:The prognostic value of cyclin D1, p53, and MDM2 protein expression in uveal melanoma. 1086 67

beta-Catenin promotes epithelial architecture by forming cell surface complexes with E-cadherin and also interacts with TCF/LEF-1 in the nucleus to control gene expression. By DNA transfection, we overexpressed beta-catenin and/or LEF-1 in NIH 3T3 fibroblasts, corneal fibroblasts, corneal epithelia, uveal melanoma cells, and several carcinoma cell lines. In all cases (with or without LEF-1), the abundant exogenous beta-catenin localizes to the nucleus and forms distinct nuclear aggregates that are not associated with DNA. Surprisingly, we found that with time (5-8 d after transfection) cells overexpressing beta-catenin all undergo apoptosis. LEF-1 does not need to be present. Moreover, LEF-1 overexpression in the absence of exogenous beta-catenin does not induce apoptosis, even though some endogenous beta-catenin moves with the exogenous LEF-1 into the nucleus. TOPFLASH/FOPFLASH reporter assays showed that full-length beta-catenin is able to induce LEF-1-dependent transactivation, whereas Arm beta-catenin totally abolishes the transactivating function. However, Arm beta-catenin, containing deletions of known LEF-1-transactivating domains, has the same apoptotic effects as full-length beta-catenin. Overexpressed beta-catenin also induces apoptosis in cells transfected with nuclear localization signal-deleted LEF-1 that localizes only in the cytoplasm. Thus, the apoptotic effects of overexpressed exogenous beta-catenin do not rely on its transactivating function with nuclear LEF-1. Overexpressed delta-catenin, containing 10 Arm repeats, induces only minor apoptosis, suggesting that the major apoptotic effect may be due to domains specific to beta-catenin as well as to Arm repeats. The absence of p53, Rb, cyclin D1, or E2F1 does not affect the apoptotic effect of overexpressed beta-catenin, but Bcl-x(L) reduces it. We hypothesize that in vivo apoptosis of cells overexpressing beta-catenin might be a physiological mechanism to eliminate them from the population.
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PMID:Overexpression of beta-catenin induces apoptosis independent of its transactivation function with LEF-1 or the involvement of major G1 cell cycle regulators. 1102 52

Uveal melanoma is the most common primary eye cancer, yet its molecular pathogenesis is poorly understood. In this study, we investigated the immunohistochemical expression of proteins in the Rb and p53 tumor suppressor pathways in 33 uveal melanomas from enucleated eyes. Strong nuclear staining for Rb was present in most tumors. However, a few cases displayed weak nuclear staining and strong cytoplasmic staining (possibly indicating Rb mutation), and this aberrant staining correlated strongly with failed radiotherapy or thermotherapy before enucleation. Staining for cyclin D1 was positive in most tumors and was associated with advanced age and larger tumor size, which are both poor prognostic factors. Generally, immunostaining for p53 was weak (suggesting a lack of p53 mutations), although p53 positivity correlated strongly with staining for phosphorylated Rb, supporting the notion that inappropriate phosphorylation of Rb can induce p53. Strong immunostaining for MDM2, which can functionally block p53 activity, was observed in most tumors and correlated significantly with female sex. Strong cytoplasmic staining was observed for Bcl2, which can inhibit both p53-dependent and -independent apoptosis. We conclude that Rb and p53 are mutated infrequently in uveal melanoma, but their respective pathways may be functionally inactivated.
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PMID:Deregulation of the Rb and p53 pathways in uveal melanoma. 1110 51

Immunohistochemical studies of regulator proteins p53, Bcl-2, Bax, Ki-67, and CD-95L showed that apoptosis suppression, allowing unlimited proliferation of tumor cells, plays an important role in the carcinogenesis of uveal melanoma. This fact dictates the need of including drugs arresting suppression or inducing apoptosis in therapeutic protocols for uveal melanoma. Prognostic significance of p53, Bcl-2, Bax, and CD-95L was demonstrated. Each of the peptides can be used as a prognostic marker.
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PMID:[Prospects for developing treatment of uveal melanoma from the position of modern carcinogenesis concepts]. 1189 58

The current therapy of uveal melanoma (UM) metastases remains inefficient, which warrants the development of new treatment modalities. For the first time we investigated the effects of retinoic acid (RA) on a panel of UM cell lines and found that RA induces morphological changes compatible with differentiation, suppresses proliferation and causes apoptosis in these cells. RA treatment resulted in an increase of p21, p27 and p53 protein levels and G1 arrest in UM cells, which correlated with significant down-modulation of surface Her2/neu proto-oncogene expression. In addition, RA-treated UM cells exhibited increased sensitivity to both MHC class I-restricted killing by cytotoxic T lymphocytes and NK cell-mediated lysis that were accompanied by more efficient conjugate formation between UM cells and killer lymphocytes. Taken together, our results implicate UM as a new target for treatment with retinoids and suggest that retinoids and T- or NK-cell based immunotherapy can have mutually enhancing effects in UM patients.
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PMID:Retinoic acid elicits cytostatic, cytotoxic and immunomodulatory effects on uveal melanoma cells. 1675 55

Expression of PERP (p53 apoptosis effector related to PMP-22) was investigated in primary uveal melanomas and its variation was analyzed in relation to clinico-pathological and cytogenetical characteristics of these tumors. The transcriptional level of PERP gene was measured by quantitative real-time RT-PCR in 26 uveal melanomas with known chromosomes 3 and 8 status. PERP protein levels were assessed by Western blot analysis of 22 fresh-frozen tumors and by immunohistochemical analysis of 16 paraffin-embedded tumor specimens. Differential expression of PERP was identified in primary choroidal melanoma specimens, both at transcriptional and protein level. Reduced PERP mRNA level was significantly associated with monosomy 3 (two-way ANOVA and t-test, p=0.004) but not with gains in chromosome 8. Transcriptional downregulation of PERP did not present a statistically significant association with ciliary body involvement, size, PAS-positive loops or cell type. Immunoblotting and immunohistochemistry further demonstrated significantly reduced PERP protein level in monosomy 3 melanomas, as compared with disomy 3 tumors. The altered expression of PERP highlighted this apoptosis-specific target of p53 as a possible contributor to apoptosis in uveal melanoma with PERP downregulation being particularly relevant to the aggressive (monosomy 3) type of uveal melanoma. As PERP is a novel type of p53 effector that is likely to stimulate apoptosis through a mechanism distinct from that of Bcl-2-related mitochondrial effectors, further elucidation of its role in uveal melanoma pathogenesis will assist in the design of novel therapeutic approaches aimed at increasing the rate of apoptosis in this tumor.
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PMID:Expression of p53-induced apoptosis effector PERP in primary uveal melanomas: downregulation is associated with aggressive type. 1678 42

Secondary metabolites from plants serve as defense against herbivores, microbes, viruses, or competing plants. Many medicinal plants have pharmacological activities and may, thus, be a source for novel treatment strategies. During the past 10 years, we have systematically analyzed medicinal plants used in traditional Chinese medicine and focused our interest on Artemisia annua L. (qinhao, sweet wormwood). We found that the active principle of Artemisia annua L., artemisinin, exerts not only antimalarial activity but also profound cytotoxicity against tumor cells. The inhibitory activity of artemisinin and its derivatives towards cancer cells is in the nano- to micromolar range. Candidate genes that may contribute to the sensitivity and resistance of tumor cells to artemisinins were identified by pharmacogenomic and molecular pharmacological approaches. Target validation was performed using cell lines transfected with candidate genes or corresponding knockout cells. The identified genes are from classes with diverse biological functions; for example, regulation of proliferation (BUB3, cyclins, CDC25A), angiogenesis (vascular endothelial growth factor and its receptor, matrix metalloproteinase-9, angiostatin, thrombospondin-1) or apoptosis (BCL-2, BAX, NF-kappaB). Artesunate triggers apoptosis both by p53-dependent and -independent pathways. Antioxidant stress genes (thioredoxin, catalase, gamma-glutamylcysteine synthetase, glutathione S-transferases) as well as the epidermal growth factor receptor confer resistance to artesunate. Cell lines overexpressing genes that confer resistance to established antitumor drugs (MDR1, MRP1, BCRP, dihydrofolate reductase, ribonucleotide reductase) were not cross-resistant to artesunate, indicating that artesunate is not involved in multidrug resistance. The anticancer activity of artesunate has also been shown in human xenograft tumors in mice. First encouraging experience in the clinical treatment of patients suffering from uveal melanoma calls for comprehensive clinical trials with artesunate for cancer treatment in the near future.
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PMID:Willmar Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin--from bench to bedside. 1735 63

The loss of chromosome 1p and chromosome 3 is associated with metastatic disease and decreased survival of uveal melanoma (UM) patients. The p53 homologues, p73 and p63, are located on chromosomes 1p and 3q, respectively. Both are able to activate p53 target genes, resulting in growth arrest, apoptosis and differentiation. N-terminally truncated isoforms of these genes may act as dominant negative inhibitors of wild-type p53 and transactivating activity. Although, p53 is frequently involved in several malignancies it does not play a major role in UM. Altered expression has been reported for both p63 and p73 in various malignancies. In this study, fluorescent in-situ hybridization was performed to identify gains or losses of p63 and p73 loci in UM. The expression of the different p63 and p73 isoforms was evaluated by reverse transcriptase PCR followed by Southern blot analysis. Furthermore, the expression pattern of the various DeltaTAp73 transcripts was analysed in seven primary UMs and 11 UM-derived cell lines using isoform-specific real-time PCR. Our results indicated that the isoform p73Deltaex2/3 was abundantly expressed and a relative loss of the p73 locus was associated with the upregulation of p73Deltaex2 and TAp73 transcripts. N-terminal transactivation forms of both p73 and p63 were observed in primary and metastasis-derived cell lines, as well as in primary melanomas, but in only one of the cell lines a DeltaNp63 mRNA transcript was observed. Our data suggest a potential function of p73 deletion transcripts in UM progression.
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PMID:Increased expression of p73Deltaex2 transcript in uveal melanoma with loss of chromosome 1p. 1847 95


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