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)

CUG triplet repeat-binding protein 2 (CUGBP2) is a RNA-binding protein that regulates mRNA translation and modulates apoptosis. Here, we report the identification of two splice variants (termed variants 2 and 3) in cultured human intestinal epithelial cells and in mouse gastrointestinal tract. The variants are generated from alternative upstream promoters resulting in the inclusion of additional NH(2)-terminal residues. Although variant 2 is the predominant isoform in normal intestine, its expression is reduced, whereas variant 1 is overexpressed following gamma-irradiation. All three variants bind cyclooxygenase-2 (COX-2) mRNA. However, only variant 1 inhibits the translation of the endogenous COX-2 mRNA and a chimeric luciferase mRNA containing the COX-2 3'untranslated region. Furthermore, whereas variant 1 is predominantly nuclear, variants 2 and 3 are predominantly cytoplasmic. These data imply that the additional amino acids affect CUGBP2 function. Previous studies have demonstrated that variant 1 induces intestinal epithelial cells to undergo apoptosis. However, in contrast to variant 1, the two novel variants do not affect proliferation or apoptosis of HCT116 cells. In addition, only variant 1 induced G(2)/M cell cycle arrest, which was overcome by prostaglandin E(2). Moreover, variant 1 increased cellular levels of phosphorylated p53 and Bax and decreased Bcl2. Caspase-3 and -9 were also activated, suggesting the initiation of the intrinsic apoptotic pathway. Furthermore, increased phosphorylation of checkpoint kinase (Chk)1 and Chk2 kinases and increased nuclear localization of Cdc2 and cyclin B1 suggested that cells were in mitotic transition. Taken together, these data demonstrate that cells expressing CUGBP2 variant 1 undergo apoptosis during mitosis, suggesting mitotic catastrophe.
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PMID:Novel intestinal splice variants of RNA-binding protein CUGBP2: isoform-specific effects on mitotic catastrophe. 1825 90

Controversies are still seen in the histological differential diagnosis of hyperplasia and well-differentiated endometrial carcinoma. Prediction of endometrial cancer in patients with hyperplasia with atypia, with the available markers has not been reliable yet. Hence these patients require more attention in the clinical management. Endometrial hyperplasia is proliferation of endometrial glands resulting in a higher gland : stroma ratio. Cytological atypia, which may progress to or co-exist with endometrial cancer and other pathological changes, result from estrogen stimulation unopposed by progesterone. Biomarkers whose expression is altered in cases of endometrial hyperplasia or cancer such as progesterone receptor, insulin-like growth factor I, retinaldehyde dehydrogenase type II, and secreted frizzled-related protein 4, seem to be promising to use as early-stage tumor markers. Mutation of PTEN is present in 83% of endometrial adenocarcinoma cases, making it the most frequent early molecular genetic alteration in type 1 endometrial tumors, which are generally associated with hyperplasia. p53 gene mutation is not found in endometrial hyperplasia, but researchers have detected this mutation in 20% of cases of endometrial carcinoma and 90% of cases of serous endometrial tumors. Cyclooxygenase-2 is important in tumorogenic transformation of hyperplasia. Expression of cyclooxygenase-2 decreases apoptosis, increases angiogenesis, and is related to invasiveness. Cyclooxygenase-2 expression increases significantly in cases of well-differentiated endometrial adenocarcinoma. Prostaglandin E2 is known to regulate aromatase gene expression and is the product of cyclooxygenase-2. The data about aromatase inhibitors are promising; in breast cancer patients, treatment with tamoxifen induces uterine abnormalities as early as 3 months after the initiation of therapy. In contrast, these abnormalities are not seen in patients who receive aromatase inhibitors and switched therapy after tamoxifen withdrawal may reverse tamoxifen-associated endometrial thickening.
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PMID:From endometrial hyperplasia to endometrial cancer: insight into the biology and possible medical preventive measures. 1828 70

The molecular mechanisms whereby hyperbaric oxygen (HBO) improves ischemic wound healing remain elusive. In this study, a rat model of wound ischemia was used to test the hypothesis that HBO enhances wound healing by modulating hypoxia-inducible factor-1alpha (HIF-1alpha) signaling. Male Sprague-Dawley rats underwent creation of a previously validated ischemic flap. Three groups underwent daily treatment: HBO (90 minutes, 2.4 atm); systemic administration of the free radical scavenger, N-acetylcysteine (NAC 150 mg kg(-1) intraperitoneal); control (neither HBO nor NAC). HBO treatment improved healing of the ischemic wounds. Analysis of ischemic wound tissue extracts demonstrated significantly reduced expression of HIF-1alpha, p53, and BNip3. Additionally, HBO increased expression of Bcl-2 while decreasing cleaved caspase-3. DNA fragmentation was abolished and the number of TUNEL-positive cells was reduced compared to the other groups. Vascular endothelial growth factor, cyclooxygenase-2, and neutrophil infiltration were reduced in ischemic wounds treated with HBO. These results indicate that HBO improves ischemic wound healing by downregulation of HIF-1alpha and subsequent target gene expression with attenuation of cell apoptosis and reduction of inflammation.
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PMID:Hyperbaric oxygen attenuates apoptosis and decreases inflammation in an ischemic wound model. 1833 31

Although traditional medicines have been used for thousands of years, for most such medicines neither the active component nor their molecular targets have been very well identified. Curcumin, a yellow component of turmeric or curry powder, however, is an exception. Although inhibitors of cyclooxygenase-2, HER2, tumor necrosis factor, EGFR, Bcr-abl, proteosome, and vascular endothelial cell growth factor have been approved for human use by the United States Food and Drug Administration (FDA), curcumin as a single agent can down-regulate all these targets. Curcumin can also activate apoptosis, down-regulate cell survival gene products, and up-regulate p53, p21, and p27. Although curcumin is poorly absorbed after ingestion, multiple studies have suggested that even low levels of physiologically achievable concentrations of curcumin may be sufficient for its chemopreventive and chemotherapeutic activity. Thus, curcumin regulates multiple targets (multitargeted therapy), which is needed for treatment of most diseases, and it is inexpensive and has been found to be safe in human clinical trials. The present article reviews the key molecular mechanisms of curcumin action and compares this to some of the single-targeted therapies currently available for human cancer.
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PMID:Multi-targeted therapy by curcumin: how spicy is it? 1919 14

Cyclooxygenase-2 (COX-2) content is increased in many types of tumor cells. We have investigated the mechanism by which resveratrol, a stilbene that is pro-apoptotic in many tumor cell lines, causes apoptosis in human head and neck squamous cell carcinoma UMSCC-22B cells by a mechanism involving cellular COX-2. UMSCC-22B cells treated with resveratrol for 24 h, with or without selected inhibitors, were examined: (1) for the presence of nuclear activated ERK1/2, p53 and COX-2, (2) for evidence of apoptosis, and (3) by chromatin immunoprecipitation to demonstrate p53 binding to the p21 promoter. Stilbene-induced apoptosis was concentration-dependent, and associated with ERK1/2 activation, serine-15 p53 phosphorylation and nuclear accumulation of these proteins. These effects were blocked by inhibition of either ERK1/2 or p53 activation. Resveratrol also caused p53 binding to the p21 promoter and increased abundance of COX-2 protein in UMSCC-22B cell nuclei. Resveratrol-induced nuclear COX-2 accumulation was dependent upon ERK1/2 activation, but not p53 activation. Activation of p53 and p53-dependent apoptosis were blocked by the COX-2 inhibitor, NS398, and by transfection of cells with COX-2-siRNA. In UMSCC-22B cells, resveratrol-induced apoptosis and induction of nuclear COX-2 accumulation share dependence on the ERK1/2 signal transduction pathway. Resveratrol-inducible nuclear accumulation of COX-2 is essential for p53 activation and p53-dependent apoptosis in these cancer cells.
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PMID:Resveratrol causes COX-2- and p53-dependent apoptosis in head and neck squamous cell cancer cells. 1844 86

Hepatitis B virus (HBV) X protein (HBx) and cyclooxygenase-2 (COX-2) are all playing roles in hepatocellular carcinoma (HCC), but the reversing effects of COX-2 inhibitors on the neoplastic features caused by HBx protein is still unclear. To further evaluate the therapeutic potential of celecoxib on HBx mediated transformation, HCC cells transfected with HBx gene were treated with COX-2 selective inhibitor, celecoxib. The amount the main metabolite of COX-2, prostaglandin E2 (PGE2), was determined by using high sensitivity ELISA. Electron microscope and flow cytometry was used to analyze cell apoptosis and cell cycle distribution. RT-PCR and Western blot were used to identify the molecules involved in celecoxib induced cell apoptosis. The results showed that celecoxib inhibited cell growth more significantly and also induced more cell apoptosis in HBx over-expression cells than in control cells. Celecoxib could selectively inhibited COX-2 expression and PGE2 production. Celecoxib also inhibited p(473Ser)Akt, raf and p53 expression, and induced apoptosis by release of cytochrome c and activation of caspase 9, 3, and 6, which were more remarkably in HBx positive cells than in control cells. These results suggest that celecoxib had potent cell growth inhibitory effects on HBx positive HCC cells mainly through inducing more cell apoptosis, and these findings provide a new insight into the anticancer effects of celecoxib against HBx related HCC.
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PMID:Potent cell growth inhibitory effects in hepatitis B virus X protein positive hepatocellular carcinoma cells by the selective cyclooxygenase-2 inhibitor celecoxib. 1850 60

Over 90% of digestive tract malignancies are adenocarcinomas (ADC) and almost 95% of them have gastric (G), colorectal (CR) or pancreatic (P) localizations. The objectives of this work are to review the genetic abnormalities of ADC in these locations and their potential coincidences, along with the histogenetic correlation of their emergence. Genetic abnormalities affecting over 50% of cases include: in G-ADC, inactivation of suppressor genes of p53, APC and DCC tumor in its intestinal variant, hypoexpression of of caderine E in the diffuse variant and hyperexpression of cyclooxygenase-2 and cyclyn D in the intestinal form; in in CR-ADC, inactivation of of genes p53, APC and DCC together with mutational activation of k-ras oncogen, and in P-ADC, the inactivation of suppressor genes p53, p16 and DPC4 along with mutational activation of k-ras oncogen. P-ADC is the one showing a more characteristic and exclusive genetic mark, followed by CR-ADC. Finally, the histogenetic correlation in the tumorigenic sequence is more evident in CR-ADC, followed by P-ADC. The complex biologic reality of G-ADC makes it more difficult to draw its genetic profile and its histogenetic correlation. In order to understand better the arguments of this work, the authors comment on the genetic-molecular basis governing the life and death of normal somatic cells and the biologic profile of the groups of genes mainly involved in tumorigenesis.
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PMID:[Genetic abnormalities of digestive tract adenocarcinomas and correlation with the histologic sequence of their development]. 1867 2

Proline oxidase (POX), a flavoenzyme localized at the inner mitochondrial membrane, catalyzes the first step of proline degradation by converting proline to pyrroline-5-carboxylate (P5C). POX is markedly elevated during p53-induced apoptosis and generates proline-dependent reactive oxygen species (ROS), specifically superoxide radicals, to induce apoptosis through both mitochondrial and death receptor pathways. These previous studies also showed suppression of the mitogen-activated protein kinase pathway leading us to broaden our exploration of proliferative signaling. In our current report, we used DLD-1 colorectal cancer cells stably transfected with the POX gene under the control of a tetracycline-inducible promoter and found that three pathways which cross talk with each other were downregulated by POX: the cyclooxygenase-2 (COX-2) pathway, the epidermal growth factor receptor (EGFR) pathway and the Wnt/beta-catenin pathway. First, POX markedly reduced COX-2 expression, suppressed the production of prostaglandin E2 (PGE(2)) and importantly, the growth inhibition by POX was partially reversed by treatment with PGE(2.) Phosphorylation of EGFR was decreased with POX expression and the addition of EGF partially reversed the POX-dependent downregulation of COX-2. Wnt/beta-catenin signaling was decreased by POX in that phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) was decreased on the one hand and phosphorylation of beta-catenin was increased on the other. There changes led to decreased accumulation of beta-catenin and decreased beta-catenin/TCF/LEF-mediated transcription. Our newly described POX-mediated suppression of proliferative signaling together with the previously reported induction of apoptosis suggested that POX could function as a tumor suppressor. Indeed, in human colorectal tissue samples, immunohistochemically-monitored POX was dramatically decreased in tumors compared with normal counterparts. Thus, POX metabolism of substrate proline affects multiple signaling pathways, modulating both apoptosis and tumor growth, and could be an attractive target to metabolically control the cancer phenotypes.
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PMID:Proline oxidase, a p53-induced gene, targets COX-2/PGE2 signaling to induce apoptosis and inhibit tumor growth in colorectal cancers. 1879 9

Ulcerative colitis (UC) is a dynamic, idiopathic, chronic inflammatory condition associated with a high colon cancer risk. American ginseng has antioxidant properties and targets many of the players in inflammation. The aim of this study was to test whether American ginseng extract prevents and treats colitis. Colitis in mice was induced by the presence of 1% dextran sulfate sodium (DSS) in the drinking water or by 1% oxazolone rectally. American ginseng extract was mixed in the chow at levels consistent with that currently consumed by humans as a supplement (75 p.p.m., equivalent to 58 mg daily). To test prevention of colitis, American ginseng extract was given prior to colitis induction. To test treatment of colitis, American ginseng extract was given after the onset of colitis. In vitro studies were performed to examine mechanisms. Results indicate that American ginseng extract not only prevents but it also treats colitis. Inducible nitric oxide synthase and cyclooxygenase-2 (markers of inflammation) and p53 (induced by inflammatory stress) are also downregulated by American ginseng. Mucosal and DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes. We therefore tested the hypothesis that American ginseng extract can inhibit leukocyte activation and subsequent epithelial cell DNA damage in vitro and in vivo. Results are consistent with this hypothesis. The use of American ginseng extract represents a novel therapeutic approach for the prevention and treatment of UC.
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PMID:American ginseng suppresses inflammation and DNA damage associated with mouse colitis. 1880 31

It has been recently proposed that pro-inflammatory genes such as cyclooxygenase-2 (COX-2) play a key role in the aging process. However, it remains unclear whether the pro-inflammatory activity of COX-2 is involved in the aging process and whether COX-2 inhibitors prevent aging. We therefore examined the effect of COX-2 inhibitors on aging in the cellular senescence model of human dermal fibroblasts (HDFs). While the catalytic activity of COX-2 was observed to increase in the senescence process, we found that among three selective COX-2 inhibitors studied, only NS-398 inhibited the senescence whereas celecoxib and nimesulide accelerated the senescence. Non-selective COX inhibitors including aspirin, ibuprofen and flurbiprofen accelerated the senescence. The senescence-regulating effect of selective COX-2 inhibitors had no correlation with cellular reactive oxygen species levels, NF-kappaB activities or protein levels of p53 and p21. We instead found that selective COX-2 inhibitors regulate caveolin-1 expression at transcriptional levels, which was closely associated with the inhibitors' effect on the senescence. Collectively, these results suggest that COX-2 catalytic activity does not mediate HDF senescence and that selective COX-2 inhibitors modulate HDF senescence by a catalytic activity-independent mechanism.
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PMID:Selective COX-2 inhibitors modulate cellular senescence in human dermal fibroblasts in a catalytic activity-independent manner. 1884 76


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