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)

Distinction of urothelial carcinoma in situ (CIS) from reactive atypia on the basis of morphology alone may be difficult in some cases. Because this distinction is therapeutically and prognostically critical, we attempted to determine if an immunohistochemical panel would help in this differential diagnosis. The immunoprofile of 21 cases of CIS and 25 non-neoplastic urothelia (15 urothelial biopsies with reactive atypia from patients without a history of bladder cancer and 10 normal ureter sections from nephrectomies performed for renal cell carcinoma) was determined using antibodies against cytokeratin 20 (CK20), p53, and CD44 (standard isoform). In the normal urothelium CK20 showed patchy cytoplasmic immunoreactivity in only the superficial umbrella cell layer and CD44 stained only the basal cells. Nuclear immunoreactivity to p53 varied from negative to weak and patchy. Reactive urothelium also showed CK20 immunoreactivity in only the umbrella cell layer in all 15 cases, and p53 nuclear staining was predominantly negative with occasional weak positivity in the basal and parabasal intermediate cells. CD44 was overexpressed in the entire reactive urothelium in 9 cases (60%) or focally positive in intermediate cells in 6 cases (40%). In contrast, CIS showed intense CK20 and p53 positivity (81% and 57%, respectively) in the majority (>50%) of malignant cells. CD44 staining revealed residual basal cells with membranous reactivity in 44% of the cases of CIS; however, the neoplastic cells were immunonegative in all cases. At least one positive immunomarker (CK20 or p53) was abnormally expressed in all cases of CIS. Abnormal expression of CK20 (increased), p53 (increased), and CD44 (decreased) in urothelial CIS, and increased expression of CD44 in reactive atypia allows more confident distinction of urothelial CIS from non-neoplastic urothelial atypias. From a differential diagnosis perspective, use of a panel of all three antibodies with morphologic correlation would be essential.
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PMID:Discriminatory immunohistochemical staining of urothelial carcinoma in situ and non-neoplastic urothelium: an analysis of cytokeratin 20, p53, and CD44 antigens. 1147 93

Inactivation of wild-type p53 tumor suppressor function is the primary mechanism of tumor initiation in Li-Fraumeni syndrome (LFS) individuals with germline p53 mutations. Tumors derived from LFS patients frequently retain the normal p53 allele, suggesting that alternative mechanisms in addition to gene deletion must be involved in inactivating wild-type p53 protein. DNA tumor viruses, such as SV40, target p53 for inactivation through the action of viral oncoproteins. We studied the probands from two unrelated LFS families, each of whom presented with multiple malignant neoplasms. Patient 1 developed an embryonal rhabdomyosarcoma (RMS) and a choroid plexus carcinoma (CPC), while patient 2 developed a CPC and subsequently presented with both an osteosarcoma (OS) and renal cell carcinoma (RCC). We utilized DNA sequence analysis and immunohistochemistry to determine p53 gene status in the germline and tumors, as well as evidence for SV40 T-antigen oncoprotein expression. Each patient harbored a heterozygous germline p53 mutation at codons 175 and 273, respectively. In patient 1, the normal p53 gene was lost while the mutant p53 allele was reduced to homozygosity in the RMS. Both normal and mutant genes were maintained in the CPC. In patient 2, normal and mutant p53 alleles were retained in both the CPC and RCC. Both specific PCR and immunostaining detected SV40 T-antigen in both CPCs and the RCC. In addition to chromosomal alterations, epigenetic mechanisms may disrupt p53 function during tumorigenesis. In two LFS patients, we found SV40 DNA sequences and viral T-antigen expression that could account for inactivation of the normal p53 protein. Inactivation of p53 or other tumor suppressors by viral proteins may contribute to tumor formation in specific tissues of genetically susceptible individuals.
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PMID:Tissue-specific expression of SV40 in tumors associated with the Li-Fraumeni syndrome. 1149 39

Cytotoxic chemotherapy has shown little antitumour activity against renal cell carcinoma (RCC). Although immunotherapy is relatively effective against RCC, the response rate is approximately 20%. Therefore, there is an urgent need to increase this response rate. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L) is one member of the tumour necrosis factor ligand family that selectively induces apoptosis of cancer cells. Since several cytotoxic anticancer drugs including 5-fluorouracil (5-FU) also mediate apoptosis, we reasoned that combined treatment of cancer cells with TRAIL and drugs might result in synergy and overcome the resistance of the cancer cell. This study has examined whether TRAIL can synergise with 5-FU in both cytotoxic and apoptotic assays against drug-resistant RCC cells. Cytotoxicity was determined by an 1-day microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. Treatment of Caki-1 cells with TRAIL in combination with 5-FU resulted in a synergistic cytotoxic effect. Synergy was also achieved in freshly derived RCC cells from 3 patients. The enhanced cytotoxicity was obtained irrespective of the sequence of the treatment, but the highest cytotoxicity was observed when Caki-1 cells were treated with TRAIL and 5-FU simultaneously. The synergy achieved in cytotoxicity with TRAIL and 5-FU was shown to be due to apoptosis. The mechanisms responsible for the synergistic cytotoxicity and apoptosis were examined. Treatment of Caki-1 cells with 5-FU enhanced the expression of p53 and bax, but had no effect on the expression of bcl-2. Incubation of Caki-1 cells with TRAIL enhanced the intracellular accumulation of 5-FU and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). Treatment of Caki-1 cells with TRAIL downregulated the expression of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) modestly, and upregulated the expression of orotate phosphoribosyltransferase (OPRT). However, the expression level of thymidine phosphorylase (TP) was not affected by TRAIL. This study demonstrates that combined treatment of RCC cells with TRAIL and 5-FU overcomes their resistance. The sensitisation obtained with freshly isolated RCC cells required low subtoxic concentrations of 5-FU. These findings support the potential application in vivo of a combination of TRAIL and 5-FU in the treatment of TRAIL/5-FU-resistant RCC.
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PMID:Potentiation of the sensitivity of renal cell carcinoma cells to TRAIL-mediated apoptosis by subtoxic concentrations of 5-fluorouracil. 1182 14

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

We report a case of renal angiomyolipoma (AML) with malignant transformation. A 28-year-old woman developed large bilateral renal masses 5 months before admission to our hospital. She was diagnosed with tuberous sclerosis when she was 4 years old. Total nephrectomy of the left kidney was performed, but she died during the operation. Although the focal region of the resected tumor had the appearance of a classic AML, most of the lesion showed a diffuse proliferation of atypical epithelioid cells resembling that in renal cell carcinoma. The epithelioid cells had extremely pleomorphic and hyperchromatic nuclei with frequent mitotic figures, including atypical forms. Immunohistochemical analysis revealed that the atypical epithelioid cells and the typical AML lesions were both positive for HMB-45 but that the former were negative for epithelial and myogenic markers. The smooth muscle cells and thick-walled vessels were focally positive for muscle-specific actins. Furthermore, the atypical epithelioid cells were immunoreactive for p53, whereas the foci of the typical AML were negative. Examination of the microdissected paraffin-embedded tissues revealed p53 mutations in the malignant epithelioid areas in AML but not in the renal parenchyma or typical AML areas. In this case it is proposed that p53 mutation may play an important role in malignant transformation of renal AML.
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PMID:Malignant transformation of renal angiomyolipoma: a case report. 1191 33

Both chromophobe carcinoma and sarcomatoid carcinoma of the kidney are rare. The former is characterized by a relatively good prognosis, while the latter is a highly aggressive tumor. Coexistence of the two components in one renal tumor, which has been reported only rarely, is therefore paradoxical. Both sarcomatoid and chromophobe renal carcinoma were diagnosed in a 52-year-old woman following nephrectomy and resection of metastases in the right lobe of the liver. She died of the disease two months after the first operation; only the sarcomatoid component of her tumor was seen in the liver metastasis and the recurrent carcinoma. Differences in phenotype, immunophenotype and DNA-ploidy patterns of the two components are reported. The intensive p53 staining observed only in the sarcomatoid area supports the role of the TP53 gene in the transformation of chromophobe renal carcinoma to sarcomatoid carcinoma.
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PMID:Sarcomatoid renal cell carcinoma with foci of chromophobe carcinoma. 1217 80

beta-Catenin and its close homologue plakoglobin (gamma-catenin) are major constituents of submembranal cell-cell adhesion sites. In addition, beta-catenin is a key component in the canonical Wnt pathway. Aberrantly activated beta-catenin signaling contributes to cancer progression by inducing [in complex with lymphocyte enhancer factor (LEF)/T-cell factor (TCF)] the transcription of proliferation-related genes such as cyclin D1 and c-myc. Plakoglobin can also activate LEF/TCF-mediated transcription. Excessive beta-catenin signaling in MEF triggers a p53-mediated antiproliferative response by inducing the expression of ARF. We have demonstrated previously that plakoglobin also exerts a tumor-suppressive effect in certain cancer cell lines. To identify genes induced by beta-catenin and plakoglobin, DNA microarray analysis was carried out, and PML was among those genes of which the expression was significantly elevated by both plakoglobin and beta-catenin. Activation of the PML promoter by beta-catenin and plakoglobin was LEF/TCF-independent. We found that PML forms a complex with beta-catenin in cells, and the two proteins colocalize in the nucleus. In addition, PML, p300, and beta-catenin cooperated in transactivation of a subset of beta-catenin-responsive genes including ARF and Siamois but not cyclin D1. Retroviral expression of beta-catenin, plakoglobin, or PML suppressed the tumorigenicity of p53-negative human renal carcinoma cells, thus pointing to a novel antioncogenic response triggered by catenins that is mediated by the induction of PML.
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PMID:PML is a target gene of beta-catenin and plakoglobin, and coactivates beta-catenin-mediated transcription. 1238 61

CD44 is an adhesion molecule involved in cell-to-cell and cell-to-matrix interactions. Recent evidence indicates a role of CD44 in tumor growth and metastatic potential of tumor cells. Moreover, it is widely known that the p53 tumor suppressor gene controls cell proliferation and loss of its normal function may lead to carcinogenesis. To investigate the role of these biomarkers in renal cancer, we analyzed the immunohistochemical distribution of CD44's expression on formalin fixed paraffin embedded tissue from 67 renal cell carcinomas and correlated with clinicopathologic parameters as well as with p53 suppressor gene expression. The monoclonal antibodies CD44 and p53 were applied to the tissues using the streptavidin biotin peroxidase method after microwave antigen retrieval. For CD44 and p53 more than 10% membranous and 5% nuclear staining, respectively, were estimated as positive. CD44's membranous immunoreactivity was detected in 24/67 tumors (35%) and mostly in carcinomas of clear/granular cell type. Nine tumors expressed nuclear immunoexpression of p53 protein (13.4%). Statistically significant correlation was noted between CD44 expression and nuclear grade (P < 0.001), tumor stage (P < 0.001), vascular invasion (P < 0.05) and p53 expression (P < 0.01). These results suggest that CD44s and p53 are markers of tumor progression in renal cell cancer.
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PMID:Expression of CD44 protein in renal cell carcinomas: association with p53 expression. 1247 36

Proline oxidase is a p53-induced gene that can mediate apoptosis in lung carcinoma cells. Here, we provide evidence implicating a role for proline oxidase in renal carcinoma. We observed absent or reduced expression of proline oxidase in 8 of 12 primary renal cell carcinomas, with respect to their normal tissue counterparts. Two renal cell carcinomas, which displayed little or no expression of proline oxidase, expressed p53s that were less capable of inducing proline oxidase than p53 isolated from normal renal tissue. One of those tumor-derived p53s contained a double transition mutation at amino acid residues 125 (Ala to Thr) and 193 (Arg to His), and the other exhibited a single transition mutation at amino acid 149 (Ser to Phe). Forced up-regulation of proline oxidase induced the formation of reactive oxygen species and mediated apoptosis in the 786-0 renal cell carcinoma cell line. A proline oxidase antisense vector repressed p53-induced up-regulation of proline oxidase, release of cytochrome c from mitochondria, and apoptosis in 786-0 renal carcinoma cells. Taken together, these findings support a role for proline oxidase as a downstream effector in p53-mediated apoptosis. We hypothesize that its altered expression can contribute to the development of renal carcinomas. The presence of proline oxidase in mitochondria, a primary organelle that regulates apoptosis, places this molecule in a subcellular localization that can directly influence the apoptotic pathway and thus tumorigenesis.
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PMID:Proline oxidase induces apoptosis in tumor cells, and its expression is frequently absent or reduced in renal carcinomas. 1251 85

At the present time, there is no reliable laboratory marker for the diagnosis and prognosis of clear cell renal cell carcinoma (RCC), while about 20% of small tumours detected by modern imaging techniques are benign and the clinical course is difficult to predict with considerable differences for the same stage and same grade. The molecular identification of clear cell RCC cells could satisfy these new requirements in the context of diagnosis of atypical or small renal tumours, allowing a more refined prognostic assessment, which is currently uncertain. Some of the antigens used for molecular diagnosis of clear cell RCC, such as cadherin-6, are present in the normal kidney, while others are newly formed antigens (TuM2PK, MN/CA9, CA12, calpain) or ectopic (PSMA, PSA, KLKI, cytokeratin 7 vimentin) or induce abnormal glycosylation (sialyl Lewis'X, galectins) indicating the malignant nature of the cells. The tumour's capacity for progression is related to dysregulations of the cycle (ras, Pax2, Tiam 1, waf/p21), division (tetracyclines, MIB1, PCNA, Nor Ag), apoptosis (bcl2, p53, CD95/Apo1), and the capacities for tissue invasion (proteases), disorganization (cadherin, catenins) or nidation (ICAM-1, CD44). Finally, chromosomal anomalies (mutations, translocations) also occur. MN/CA9, cadherin-6, vimentin, mucin 1 and DNA content are particularly useful for the diagnosis and/or prognosis of clear cell RCC. These markers can be analysed by extremely sensitive cytometric (flow cytometry, plate cytometry) or molecular methods (RT-PCR, in situ hybridization). These techniques lower the limit of detection of tumour cells in biological products (aspiration cytology, microbiopsy) and eventually in circulating blood. Proteomic and genomic methods (biochips) should considerably accelerate research in this field leading to the development of routine clinical applications.
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PMID:[Molecular and cytometric analysis of renal cell carcinoma cells. Concepts, techniques and prospects]. 1270 48


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