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)

TP53 mutations are common in lung cancers of smokers, with high prevalence of G:C-to-T:A transversions generally interpreted as mutagen fingerprints of tobacco smoke. In this study, TP53 (exons 5-9) and KRAS (codon 12) were analyzed in primary lung tumors of never (n = 40), former (n = 27), and current smokers (n = 64; mainly heavy smokers). Expression of p53, cyclooxygenase-2 (Cox-2), and nitrotyrosine (N-Tyr), a marker of protein damage by nitric oxide, were analyzed by immunohistochemistry. TP53 mutations were detected in 47.5% never, 55.6% former, and 77.4% current smokers. The relative risk for mutation increased with tobacco consumption (P(linear trend) < 0.0001). G:C-to-T:A transversions (P = 0.06, current versus never smokers) and A:T-to-G:C transitions (P = 0.03, former versus never smokers) were consistently associated with smoking. In contrast, G:C-to-A:T transitions were associated with never smoking (P = 0.02). About half of mutations in current smokers fell within a particular domain of p53 protein, suggesting a common structural effect. KRAS mutations, detected in 20 of 131 (15.3%) cases, were rare in squamous cell carcinoma compared with adenocarcinoma [relative risk (RR), 0.2; 95% confidence interval (95% CI), 0.07-1] and were more frequent in former smokers than in other categories. No significant differences in Cox-2 expression were found between ever and never smokers. However, high levels of N-Tyr were more common in never than ever smokers (RR, 10; 95% CI, 1.6-50). These results support the notion that lung tumorigenesis proceeds through different molecular mechanisms according to smoking status. In never smokers, accumulation of N-Tyr suggests an etiology involving severe inflammation.
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PMID:TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. 1595 51

The mouse model for familial adenomatous polyposis, Apc(Min/+) mouse, contains a truncating mutation in the Apc gene and spontaneously develops numerous adenomas in the small intestine but few in the large bowel. Our study investigated whether dextran sodium sulfate (DSS) treatment promotes the development of colonic neoplasms in Apc(Min/+) mice. Apc(Min/+) and Apc+/+ mice of both sexes were exposed to 2% dextran sodium sulfate in drinking water for 7 days, followed by no further treatment for 4 weeks. Immunohistochemistry for cyclooxygenase-2, inducible nitric oxide synthase, beta-catenin, p53, and nitrotyrosine, and mutations of beta-catenin and K-ras and loss of wild-type allele of the Apc gene in the colonic lesions were examined. Sequential observation of female Apc(Min/+) mice that received DSS was also performed up to week 5. At week 5, numerous colonic neoplasms developed in male and female Apc(Min/+) mice but did not develop in Apc+/+ mice. Adenocarcinomas developed in Apc(Min/+) mice that received DSS showed loss of heterozygosity of Apc and no mutations in the beta-catenin and K-ras genes. The treatment also significantly increased the number of small intestinal polyps. Sequential observation revealed increase in the incidences of colonic neoplasms and dysplastic crypts in female Apc(Min/+) mice given DSS. DSS treatment increased inflammation scores, associated with high intensity staining of beta-catenin, cyclooxygenase-2, inducible nitric oxide synthase and nitrotyrosine. Interestingly, strong nuclear staining of p53 was specifically observed in colonic lesions of Apc(Min/+) mice treated with DSS. Our results suggest a strong promotion effect of DSS in the intestinal carcinogenesis of Apc(Min/+) mice. The findings also suggest that strong oxidative/nitrosative stress caused by DSS-induced inflammation may contribute to the colonic neoplasms development.
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PMID:Dextran sodium sulfate strongly promotes colorectal carcinogenesis in Apc(Min/+) mice: inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms. 1604 79

Our study investigates the effect of a highly selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the cytotoxicity of docetaxel in nude mice bearing A549 tumor xenografts and elucidates the molecular mechanisms of the antitumor effect of this combination. Female nu/nu mice, xenografted with s.c. A549 tumors were treated with either celecoxib (150 mg/kg/day), docetaxel (10 mg/kg) or a combination of both. The tumor tissues were quantified for the induction of apoptosis, intratumor levels/expressions of prostaglandin E2 (PGE2), 15 deoxy prostaglandin J2 (15-d PGJ2), microsomal prostaglandin E synthase (mPGES) and cytoplasmic phospholipase A2 (cPLA2). The combination of celecoxib with docetaxel significantly inhibited the tumor growth (p < 0.03) as compared to celecoxib or docetaxel alone, decreased the levels of PGE2 by 10-fold and increased the 15-d PGJ2 levels by 4-fold as compared to control. The combination also enhanced the peroxisome proliferator-activated receptor (PPAR)-gamma expression, decreased the expression of cPLA2, mPGES and vascular endothelial growth factor (VEGF), but had no effect on the expression of COX-1 or COX-2 in tumor tissues. TUNEL staining of the tumor tissues showed a marked increase in the apoptosis in the combination group as compared to the celecoxib- or docetaxel-treated groups and this was associated with an increase in the intratumor p53 expression. In conclusion, the combination of celecoxib with docetaxel produces a greater antitumor effect in s.c. A549 tumors as compared to celecoxib or docetaxel alone and this effect is associated with concomitant alterations in the intratumor levels of PGE2 and 15-d PGJ2.
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PMID:Enhancement of antitumor activity of docetaxel by celecoxib in lung tumors. 1605 15

Signet ring cell carcinoma and mucinous carcinoma are distinct subtypes of colorectal adenocarcinoma. The morphologic and molecular spectra of colorectal carcinomas with various signet ring cell components and colorectal carcinomas with various mucinous components, compared to non-mucinous adenocarcinomas, have not been examined. The study groups consisted of 39 carcinomas with various signet ring cell components ('the signet group'), 167 carcinomas with various mucinous components ('the mucinous group'), and 457 nonmucinous adenocarcinoma. We visually estimated the amounts of signet ring cell and mucinous components in tumors, and subclassified the signet and mucinous groups according to the amount of each component (< or = 19, 20-49, and > or = 50%). We sequenced BRAF and KRAS, analyzed for microsatellite instability (MSI) and 18q loss of heterozygosity (LOH), and performed immunohistochemistry for TP53, cyclooxygenase-2 (COX2), MLH1, O-6-methylguanine DNA methyltransferase (MGMT), p16 (CDKN2A), and fatty acid synthase (FASN). Signet ring cell carcinoma (> or = 50% signet ring cell tumors) and < or = 49% signet ring cell tumors showed similar molecular features. Except for MSI and MGMT, > or = 50% mucinous tumors and < or = 49% mucinous tumors also showed similar molecular features. BRAF mutations, MSI, and MLH1 loss were more frequent in both the signet and mucinous groups than nonmucinous carcinoma. More frequent KRAS mutations and less frequent p16 loss and TP53 positivity were observed in the mucinous group than nonmucinous carcinoma. 18q LOH and COX2 overexpression were less common in the signet group than nonmucinous carcinoma. FASN levels were highest in the mucinous group, followed by nonmucinous carcinoma, and lowest in the signet group. In conclusion, a minor (< or = 49%) signet ring cell or mucinous component in colorectal carcinoma suggests molecular features similar to > or = 50% signet ring cell or mucinous carcinoma, respectively. Signet ring cell carcinoma and mucinous carcinoma are related subtypes of colorectal adenocarcinoma, but have molecular features distinct from each other.
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PMID:Distinct molecular features of colorectal carcinoma with signet ring cell component and colorectal carcinoma with mucinous component. 1611 24

Apoptotic and inflammatory processes occur in human arteriosclerotic lesions. We examined the hypothesis whether both processes are possibly associated by studying the colocalization of corresponding markers. In 11 human arteriosclerotic carotid arteries, proapoptotic markers (CPP32 (caspase-3), poly(ADP-ribose) polymerase, apoptosis-inducing factor, c-Jun/AP-1, and p53) and proinflammatory markers (macrophage migration inhibitory factor (MIF) and cyclooxygenase-2) were found in macrophages (MPhi) evaluated by computer-assisted immunohistomorphometry. Double-labeling studies demonstrated a colocalization of, both, proapoptotic and proinflammatory markers in these MPhi. Moreover, these MPhi also contained oxidized low-density lipoproteins (oxLDL). Exposure of cultured human MPhi to oxLDL, C6-ceramide, and tumor necrosis factor-alpha or H2O2 resulted in a significant increase of the apoptosis rate as well as of the MIF protein expression. Our study of MPhi in arteriosclerotic carotid arteries and in vitro experiments provide evidence that markers of apoptosis and inflammation are not only significantly increased but are also coexpressed. We conclude there are reciprocal modulatory interactions between apoptotic and inflammatory pathways in human plaque MPhi, which might importantly modify plaque progression or stability.
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PMID:Colocalization of oxidized low-density lipoprotein, caspase-3, cyclooxygenase-2, and macrophage migration inhibitory factor in arteriosclerotic human carotid arteries. 1613 50

Cyclooxygenase-2 (COX-2) is one of the important targets for the chemoprevention of colorectal cancer by non-steroidal anti-inflammatory drugs (NSAIDs). To evaluate the role of COX-2 in early stages of colorectal tumorigenesis, we immunohistochemically investigated the frequency and localization of COX-2 in sporadic colorectal polyps that showed various histology using a commercially available monoclonal antibody. A total of 105 colorectal polyps were examined. These included 33 low-grade adenomas (LGAs), 28 high-grade adenomas (HGAs), 32 HGAs with p53 overexpression (HGAs-p53), and 12 cases of carcinoma in adenoma (CIA). Regarding the immunohistochemical expression of p53, MIB-1, and CD63, histological classification was made for each case. COX-2 was expressed in neoplastic epithelial cells and interstitial macrophages that were distributed mainly in the superficial areas of polyps. COX-2 labeling indices (LIs) were 8.2% in LGAs, 6.3% in HGAs, 0.9% in HGAs-p53, and 0.6% in the carcinomatous components of CIAs. COX-2 LIs were significantly higher in adenomas, including LGAs and HGAs, than in HGAs-p53 and CIAs (p < 0.001). Within CIAs, significantly higher COX-2 LIs were obtained in the adenomatous components than in the carcinomatous components (p < 0.05). The size of polyps was not correlated with COX-2 expression irrespective of their histology. The results show that COX-2 might be involved in early stages of colorectal tumorigenesis. Colorectal adenomas could be a target for the chemopreventive strategy irrespective of their sizes.
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PMID:Cyclooxygenase-2 in sporadic colorectal polyps: immunohistochemical study and its importance in the early stages of colorectal tumorigenesis. 1613 48

Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin synthesis, is induced in many cells by numerous inflammatory mediators, including nitric oxide (NO). Upregulation of COX-2 expression has been implicated in the pathophysiology of neuronal cell death. In the present study, we have found that the NO-induced upregulation of COX-2 via activation of activator protein-1 (AP-1) signaling leads to apoptotic cell death. Cultured rat pheochromocytoma (PC12) cells treated with sodium nitroprusside (SNP), a NO-releasing compound, exhibited marked induction of COX-2 expression, which was associated with apoptotic cell death as evidenced by internucleosomal DNA fragmentation, cleavage of poly(ADP-ribose) polymerase, activation of caspase-3, accumulation of p53, increased Bax/Bcl-XL ratio, and dissipation of mitochondrial membrane potential. In addition to the upregulation of COX-2 expression, SNP treatment led to activation of AP-1. Pretreatment of PC12 cells with c-fos antisense oligonucleotide abolished the NO-induced increase in DNA binding of AP-1 and upregulation of COX-2 expression. Furthermore, pretreatment with a selective COX-2 inhibitor (SC58635) rescued the PC12 cells from the apoptotic cell death induced by NO. Similar results were obtained when the NO-induced upregulation of COX-2 expression was blocked by the siRNA interference. These results suggest that excessive NO production during inflammation induces apoptosis in PC12 cells through AP-1-mediated upregulation of COX-2 expression.
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PMID:Nitric oxide induces apoptosis via AP-1-driven upregulation of COX-2 in rat pheochromocytoma cells. 1614 Feb 9

The purpose of this study was to evaluate cyclooxygenase-2 (COX-2) expression in the successive steps of breast carcinogenesis and to determine its correlation with HER-2/neu and p53 expression in invasive ductal carcinomas of the breast. Immunohistochemical staining with anti-COX-2 antibody was performed in normal breast tissue, usual hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Expression of COX-2 in invasive ductal carcinoma was correlated with immunohistochemical expression of HER-2/neu and p53 protein. COX-2 expression was found to be progressively elevated along the continuum from normal breast tissue to invasive ductal carcinoma (P<0.001). COX-2 expression significantly correlated with p53 and HER-2/neu protein expression (P<0.05 and P<0.001). On multivariate analysis, only TNM stage and elevated COX-2 expression correlated with survival. Our results suggest that COX-2 may be involved in the carcinogenesis of the breast and may be an independent prognostic indicator in patients with invasive ductal carcinoma. HER-2/neu and p53 are likely to be involved in the regulation of COX-2 expression in invasive ductal carcinomas of the breast.
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PMID:Expression of cyclooxygenase-2 in breast carcinogenesis and its relation to HER-2/neu and p53 protein expression in invasive ductal carcinoma. 1616 26

Nitric oxide (NO), synthesized from L-arginine by NO synthases, is a small, lipophilic, diffusible, highly reactive molecule with dichotomous regulatory roles in many biological events under physiological and pathological conditions. NO can promote apoptosis (pro-apoptosis) in some cells, whereas it inhibits apoptosis (anti-apoptosis) in other cells. This complexity is a consequence of the rate of NO production and the interaction with biological molecules such as metal ion, thiol, protein tyrosine, and reactive oxygen species. Long-lasting overproduction of NO acts as a pro-apoptotic modulator, activating caspase family proteases through the release of mitochondrial cytochrome c into cytosol, up-regulation of the p53 expression, and alterations in the expression of apoptosis-associated proteins, including the Bcl-2 family. However, low or physiological concentrations of NO prevent cells from apoptosis that is induced by the trophic factor withdrawal, Fas, TNFalpha/ActD, and LPS. The anti-apoptotic mechanism is understood on the basis of gene transcription of protective proteins. These include: heat shock protein, hemeoxygenase, or cyclooxygenase-2 and direct inhibition of the apoptotic executive effectors caspase family protease by S-nitrosylation of the cysteine thiol group in their catalytic site in a cell specific way. Our current understanding of the mechanisms by which NO exerts both pro- and anti-apototic action is discussed in this review article.
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PMID:Nitric oxide as a pro-apoptotic as well as anti-apoptotic modulator. 1624 76

The purpose of this study was to evaluate cyclooxygenase-2 (COX-2) expression in epithelial ovarian tumors and its correlation with vascular endothelial growth factor (VEGF) and p53 expression. Immunohistochemical studies with anti-COX-2, anti-VEGF, and anti-p53 antibodies were carried out in 54 malignant and 23 borderline epithelial ovarian tumors. Elevated COX-2 expression was detected in 77.8% of ovarian carcinomas, which was significantly higher than that of borderline tumors (26.1%) (P < 0.001). In ovarian carcinomas, there was no significant correlation between COX-2 expression and other clinicopathologic features. Elevated VEGF expression was detected in 74.1% of ovarian carcinomas, and p53 expression was found in 64.8% of ovarian carcinomas. COX-2 expression was statistically correlated with elevated VEGF expression (P < 0.001) and p53 positivity (P < 0.05). On a univariate analysis, FIGO stage (P < 0.0001), histologic type (P= 0.0104), and COX-2 expression (P= 0.0135) were significant prognostic factors for overall survival. In a multivariate analysis, FIGO stage (P < 0.0001) was the only independent prognostic factor for poor survival. These findings suggest that COX-2 may play a role in the progression of epithelial ovarian tumors and that COX-2 expression may contribute to ovarian tumor angiogenesis by stimulating VEGF expression. p53 may be responsible for the regulation of COX-2 expression.
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PMID:Expression of cyclooxygenase-2 in epithelial ovarian tumors and its relation to vascular endothelial growth factor and p53 expression. 1651 99


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