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)

Expression and pharmacological studies support a contribution of cyclooxygenase (COX)-2 to mammary gland tumorigenesis. In a recent transgenic study, mouse mammary tumor virus promoter-driven COX-2 expression in mouse mammary glands was shown to result in alveolar hyperplasia, dysplasia, and carcinomas after multiple rounds of pregnancy and lactation. In the study presented here, the effects of constitutive COX-2 overexpression in keratin 5-positive myoepithelial and luminal cells, driven by the keratin 5 promoter in a hormone-independent manner, was investigated. In nulliparous female mice, aberrant COX-2 overexpression correlated with increased prostaglandin (PG) E(2) levels and caused cystic duct dilatations, adenosis, and fibrosis whereas carcinomas developed rarely. This phenotype depended on COX-2-mediated PGE(2) synthesis and correlated with increased expression of proliferation-associated Ki67 in epithelial cells. No changes in the expression of apoptosis-related Bcl-2, caspase 3, or p53 were observed. Hyperproliferation of the mammary gland epithelial cells was associated with increased aromatase mRNA levels in this tissue. The spontaneous pathologies bear analogies to the human breast with fibrocystic changes. Intriguingly, strong COX-2 expression was observed in fibrocystic changes, as compared to low expression in normal breast epithelium. These results show for the first time that aberrant COX-2 expression contributes to the development of fibrocystic changes (FC), indicating that COX-2 and COX-2-mediated PG synthesis represent potential targets for the therapy of this most frequent benign disorder of the human breast.
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PMID:Cystic duct dilatations and proliferative epithelial lesions in mouse mammary glands upon keratin 5 promoter-driven overexpression of cyclooxygenase-2. 1568 40

Recent studies have suggested that pancreatobiliary reflux occurs not only in patients with pancreaticobiliary maljunction (PBM), but also in patients without PBM and thereby possibly causes biliary tract disease. In this study, we examined prospectively histological findings and genetic analysis in the non-cancerous epithelium of the gallbladder in patients with high biliary amylase levels and a normal pancreaticobiliary junction. Ki-67 L.I of non-cancerous epithelium was 14.4 and 3.5% in the high biliary amylase levels (HBA) group and the low biliary amylase levels (LBA) group, respectively (p<0.01). There was no case showing p53 overexpression regardless of amylase levels of bile. COX-2 expression was detected in the cytoplasm of non-cancerous epithelium in 9 cases in the HBA group and 5 cases in the LBA group. The positive rate of COX-2 overexpression was significantly higher in the HBA group than in the LBA group (p<0.05). COX-2 overexpression cases showed higher Ki-67 L.I than COX-2 non-overexpression cases (21.2 vs. 7.9%, p<0.05). Mutations of the K-ras gene were detected in non-cancerous gallbladder epithelium in 3 cases, only in the HBA group. Patterns of K-ras mutation at codon 12 were GAT in two cases and GTT in one case. Three cases showing COX-2 overexpression also showed K-ras mutation. These three cases showing K-ras mutation had comparatively high cellular proliferative activity (28, 26 and 14%). In conclusion, our data suggest that occult pancreaticobiliary reflux, especially with high biliary amylase levels, represents an important risk factor for the development of gallbladder carcinoma as well as PBM, and it may be possible to detect patients with such high biliary amylase levels by ERCP.
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PMID:Histologic and genetic analysis of the gallbladder in patients with occult pancreatobiliary reflux. 1570 32

Gastric adenomatous polyps are rare findings in upper gastrointestinal endoscopy; however, they are associated strongly with malignant transformation. Few series describe the oncogenic characteristics of gastric adenomas. In the present study, we immunohisto-chemically assessed the expression of cyclooxygenase (COX)-2, beta-catenin, p53, and adenomatous polyposis coli (APC) in paraffin-embedded specimens of 14 gastric adenomas. Control samples of normal gastric tissue and gastric adenocarcinoma also were analyzed. Of the adenomas, 7 demonstrated overexpression of COX-2, and all demonstrated nuclear p53 accumulation. Accumulation of beta-catenin in the nucleus and cytoplasm was detected in 38% (3/8) of specimens. Loss of APC staining was observed in 50% (4/8). Similar alterations in oncoprotein expression were seen in gastric cancers but not in normal control sections. Gastric adenomas display alterations in the expression of COX-2, beta-catenin, and APC similar to those seen in adenocarcinomas; however, accumulation of p53 was significantly more common in adenomas than in cancers.
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PMID:Cyclooxygenase 2, p53, beta-catenin, and APC protein expression in gastric adenomatous polyps. 1571 38

Cyclo-oxygenase (COX) is a key enzyme in the conversion of arachidonic acid to prostanoids. The expression of its isoforms, COX-1 and -2 is found in many human malignancies. This study analyzed the correlation between COX expression and the pathobiological nature of human oral mucosa, dysplasias and squamous cell carcinomas (SCCs). We examined 9 specimens of normal oral epithelia, 65 lesions with dysplasias and 50 SCCs. Labeling indices (LIs) for COX-1, COX-2, Ki-67 and P53, microvessel density (MVD) and apoptotic index (AI) were evaluated using immunohistochemistry and TUNEL methods. Western blot analysis of COX-1 and -2 was performed on four human oral SCC cell lines, all of which showed expression. The LIs for COX-1 and -2 were higher for the dysplasias than the SCCs. LIs of COX-2 but not COX-1 correlated with the histological grade of dysplasia, being highest for the severe dysplasias (p < 0.05). In contrast, the COX-2 LIs as well as COX-1 were significantly (p < 0.05) inversely correlated with the histological differentiation of the SCCs. COX-2 expression was significantly correlated with LIs of COX-1 for dysplasia (p < 0.05), but not for the SCCs. In addition no significant relationship was noted between COX-2 expression and the Lis of Ki-67, P53, AI as well as MVD for the dysplasias and SCCs. The expression of COX-1 and -2 is correlated with early stage tumorigenesis and cellular differentiation of SCCs in the oral dysplasia-carcinoma sequence.
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PMID:Cyclo-oxygenase-1 and -2 expression in human oral mucosa, dysplasias and squamous cell carcinomas and their pathological significance. 1574 93

The aim of this study was to investigate the relationship of cyclooxygenase (COX)-2 and p53 expression with prognosis in patients with conventional renal cell carcinoma (RCC). Formalin-fixed, paraffin-embedded tissue sections of conventional RCC from 92 patients, who had undergone radical nephrectomy, were examined for COX-2 and p53 expression by immunohistochemistry and compared with clinicopathological variables. The COX-2 expression significantly correlated only with tumor size (p=0.049), whereas the p53 expression profoundly correlated with the TNM stage (p=0.024), M stage (p=0.001), and metastasis (synchronous or metachronous; p=0.004). The COX-2 overexpression did not significantly associate with p53 positivity (p=0.821). The survival rate of patients correlated with the p53 expression (p<0.0001) but not with the COX-2 expression (p=0.7506). Multivariate analyses indicated that tumor size, M stage, and p53 expression were independent prognostic factors for cancer-specific survival. The COX-2 expression was not an independent factor. These results show that the increased expression of p53 was associated with metastasis and a worse prognosis in conventional RCC, which suggests that p53 might have played an important role in the progression of conventional RCC. The increased expression of COX-2 was associated only with tumor size, but may not be an important prognostic factor in conventional RCC. No association was observed between COX-2 overexpression and p53 positivity in conventional RCC.
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PMID:Cyclooxygenase-2 and p53 expression as prognostic indicators in conventional renal cell carcinoma. 1574 16

Chronically irradiated murine skin and UV light-induced squamous cell carcinomas overexpress the inducible isoform of cyclooxygenase (COX-2), and COX-2 inhibition reduces photocarcinogenesis in mice. We have reported previously that DNA oligonucleotides substantially homologous to the telomere 3'-overhang (T-oligos) induce DNA repair capacity and multiple other cancer prevention responses, in part through up-regulation and activation of p53. To determine whether T-oligos affect COX-2 expression, human newborn keratinocytes and fibroblasts were pretreated with T-oligos or diluent alone for 24 h, UV-irradiated, and processed for Western blotting. In both cell types, T-oligos transcriptionally down-regulated base-line and UV light-induced COX-2 expression, coincident with p53 activation. In fibroblasts with wild type versus dominant negative p53 (p53(WT) versus p53(DN)), T-oligos decreased constitutive expression of a COX-2 reporter plasmid by >50%. We then examined NFkappaB, a known positive regulator of COX-2 transcription. In p53(WT) but not in p53(DN) fibroblasts and in human keratinocytes, T-oligos decreased readout of an NFkappaB promoter-driven reporter plasmid and decreased NFkappaB binding to DNA. After T-oligo treatment and subsequent UV irradiation, binding of the transcriptional co-activator protein p300 to NFkappaB was decreased, whereas binding of p300 to p53 was increased. Human skin explants provided with T-oligos had markedly decreased COX-2 immunostaining both at base-line and post-UV light, coincident with increased p53 immunostaining. We conclude that T-oligos transcriptionally down-regulate COX-2 expression in human skin via activation and up-regulation of p53, at least in part by inhibiting NFkappaB transcriptional activation. Decreased COX-2 expression may contribute to the observed ability of T-oligos to reduce photocarcinogenesis.
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PMID:T-oligo treatment decreases constitutive and UVB-induced COX-2 levels through p53- and NFkappaB-dependent repression of the COX-2 promoter. 1604 1

The nuclear factor kappaB signaling pathway has gained attention for its role in the carcinogenic process. We have measured the protein levels of the p65 subunit during a growth of adenomas in the Min mouse model for colon cancer. To study how an accelerated growth of adenomas affect cell signalling, adenoma growth was increased by an inulin diet (10%) that we have shown previously to be a promotor of adenoma formation. In our study, the association between NF-kappaB, p53, beta-catenin, Fas and COX-2 were evaluated by measuring their protein levels in 9- and 15-week old Min mouse adenomas and surrounding mucosa. The amount of p65 rouse between 9- and 15-weeks in the mucosa of the control-fed mice (p = 0.032). The inulin-fed mice had less p65 in the nucleus of the mucosa at 15 weeks of age compared to the control (p = 0.064), although the adenomas were significantly larger (1.46 mm +/- 0.12 for inulin, 0.97 mm +/- 0.12 for control, p < 0.001). Nuclear p65 correlated positively with nuclear p53 in the mucosa (p < 0.001) and adenoma (p < 0.001) tissues. Also, p65 correlated positively with nuclear beta-catenin in the mucosa (p = 0.012) and the adenoma (p = 0.001). Fas expression increased in the inulin group between 9-15 weeks (p = 0.034) and correlated negatively with p65 (p = 0.03). The amount of COX-2 in the adenoma tissue increased between 9-15 weeks and did not correlate with p65. The results suggest that p65 is involved in a p53-dependent apoptotic response in the Min mouse.
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PMID:Nuclear factor kappaB is downregulated and correlates with p53 in the Min mouse mucosa during an accelerated tumor growth. 1604 62

In a previous study, we demonstrated that elevation of COX-2 is significantly associated with lymph node metastasis in squamous cell carcinoma (SCC) of cervix. The main objective of this study is to characterize the relationship between elevation of COX-2 and its possible clinical role in adenocarcinoma (AC) of cervix. Using immunohistochemistry, we examined COX-2 expression levels in 84 patients with AC of uterine cervix [71 ACs, 13 adenosquamous carcinomas (ASCs)]. Elevation of COX-2 was correlated with clinicopathological variables and p53 expression, as detected by immunohistochemistry. Elevation of COX-2 was detected in 13.0% (11 of 84) of the tumors. Elevation of COX-2 was significantly correlated with histologic type (AC 8.5% vs. ASC 38.5%, P=0.011). Both tumor stage and lymph node metastasis were correlated with elevation of COX-2 with a borderline significance (P=0.062 and 0.068, respectively). Elevation of p53 was not associated with elevation of COX-2. The association between lymph node metastasis and elevation of COX-2 was stronger in cases of AC than in cases of ASC (28.4 vs. 4.3%, P=0.023). According to the results of univariate analysis, elevation of COX-2 was significantly associated with decreased overall survival (P=0.003, log-rank test). However, multivariate analyses revealed that only tumor stage was independently associated with overall survival, suggesting that elevation of COX-2 itself may not be an independent prognostic factor. The present study shows that elevation of COX-2 may contribute to lymph node metastasis in AC of uterine cervix. This suggests that the potential therapeutic role of COX-2 inhibitors should be validated, not only in SCC, but also in AC of uterine cervix.
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PMID:Elevation of cyclooxygenase-2 is related to lymph node metastasis in adenocarcinoma of uterine cervix. 1611 7

The aim of the current study was to evaluate the protein expression involved in the progression from dysplasia to invasive esophageal squamous cell carcinomas and to analyze the prognostic value of markers. Immunohistochemistry was performed for cell cycle regulators [p53, p21, p27, p16, cyclin D1, Rb], apoptosis-related proteins [Fas, Fas-L, FADD, TRAIL, DR4, DR5, caspase-8, caspase-3, bcl-2, Bax], tumor suppressor proteins [beta-catenin, E-cadherin, FHIT, Smad 4, VHL, PTEN, KAI-1], and oncoproteins [c-myc, COX-2, EGFR]. Caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR revealed significant differences between dysplasia and their corresponding invasive cancer portion in 25 cases. In a total of 118 cases of invasive cancer, proteins with frequent (> or = 60% of the cases) alterations were p53 (overexpression in 64% of SCCs), p27 (loss in 91%), p16 (loss in 81%), and FHIT (loss in 75%). Early clinical stage and bcl-2 immunopositivity were related to the survival rate of patients. In conclusion, caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR may be involved in the progression from dysplasia to invasive esophageal SCCs. Clinical stage and bcl-2 are independent prognostic factors throughout the multivariate analysis.
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PMID:Differential protein expression between esophageal squamous cell carcinoma and dysplasia, and prognostic significance of protein markers. 1613 47

Alterations to the Wnt signalling pathway occur in the majority of colorectal cancers and result in abnormal accumulation of beta-catenin. The secreted frizzled related proteins (sFRPs) are antagonists that bind Wnt and inhibit signalling along this pathway. We investigated expression of the sFRP family member, sFRP-4, and beta-catenin in 1,044 human colorectal carcinomas using tissue microarrays and immunohistochemistry. Both proteins showed markedly increased expression levels in tumors compared to normal mucosa, but no significant associations with pathological features or with patient outcome. sFRP-4 was co-expressed with beta-catenin, p53, and COX-2, while the absence of beta-catenin expression was strongly associated with loss of expression of the MLH1 mismatch repair gene. In contrast to other sFRP family members, sFRP-4 expression appears to be upregulated in colorectal carcinoma.
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PMID:Expression of sFRP-4 and beta-catenin in human colorectal carcinoma. 1635 38

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