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)

The pathophysiology of cerebral ischemia involves multiple mechanisms including neuroinflammation mediated by activated microglia and infiltrating macrophages/monocytes. The present study employed a rat permanent middle cerebral artery occlusion (pMCAO) model to study effects of histone deacetylase (HDAC) inhibition on ischemia-induced brain infarction, neuroinflammation, gene expression, and neurological deficits. We found that post-pMCAO injections with HDAC inhibitors, valproic acid (VPA), sodium butyrate (SB), or trichostatin A (TSA), decreased brain infarct volume. Postinsult treatment with VPA or SB also suppressed microglial activation, reduced the number of microglia, and inhibited other inflammatory markers in the ischemic brain. The reduction in levels of acetylated histone H3 in the ischemic brain was prevented by treatment with VPA, SB, or TSA. Moreover, injections with HDAC inhibitors superinduced heat-shock protein 70 and blocked pMCAO-induced down-regulation of phospho-Akt, as well as ischemia-elicited up-regulation of p53, inducible nitric oxide synthase, and cyclooxygenase-2. The motor, sensory, and reflex performance of pMCAO rats was improved by VPA, SB, or TSA treatment. The beneficial effects of SB and VPA in reducing brain infarct volume and neurological deficits occurred when either drug was administrated at least 3 h after ischemic onset, and the behavioral improvement was long-lasting. Together, our results demonstrate robust neuroprotective effects of HDAC inhibitors against cerebral ischemia-induced brain injury. The neuroprotection probably involves multiple mechanisms including suppression of ischemia-induced cerebral inflammation. Given that there is no effective treatment for stroke, HDAC inhibitors, such as VPA, SB, and TSA, should be evaluated for their potential use for clinical trials in stroke patients.
 ...
PMID:Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. 1737 5

p-Phenylenediamine (p-PD) is the main aromatic amine used in the formulation of hair dyes. Some epidemiologic studies have suggested that the use of p-PD-based hair dyes might be related to increased risk of human malignant tumors including bladder cancer and hematopoietic cancers. However, the toxicity and genotoxicity of p-PD on urothelial cells has not been reported yet. Therefore, we investigated the genotoxicity of p-PD on human urothelial cells and study its association with the expression of oncoproteins p53 and cyclooxygenase-2 (COX-2). Our results revealed that p-PD was able to induce DNA damage determined by Comet assay. In addition, our immunocytochemical and Western blotting results showed that p-PD induced overexpression of mutant p53 and COX-2 in a dose-dependent manner. The relationship between mutant p53 and COX-2 expression shows strong correlation. Furthermore, the accumulation of mutant p53 was linearly correlated with Comet scores. These results suggest that p-PD can induce DNA damage and accumulation of mutant p53 and COX-2 proteins; this may be one of the possible mechanisms that cause genotoxic carcinogenesis in the urothelial cells.
 ...
PMID:p-Phenylenediamine induced DNA damage in SV-40 immortalized human uroepithelial cells and expression of mutant p53 and COX-2 proteins. 1776 12

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, induces the apoptosis in various cancers in COX-2 dependent and/or independent manners. The p53 protein is mutated in 50% of all human tumors and plays a key role in apoptosis, cell cycle, and the expression of several proteins. In ovarian cancer, the rate of p53 mutation has been shown to be very high and associated with poor prognosis. To explore the importance of functional status of p53 in apoptosis by celecoxib in ovarian cancer cells, the cellular response to celecoxib was determined in SK-OV3 ovarian cancer cells with null type p53 and PA-1 with wild-type p53. Our results showed that celecoxib inhibited cell growth more in PA-1 than in SK-OV3. The underlying antiproliferative mechanism may differ between these two cell types dependent upon the functional status of p53, which plays integral roles in regulating cell cycle and survival. Higher sub-G1 was shown in PA-1 than in SK-OV3 in response to celecoxib (PA-1 versus SK-OV3; 60.28% versus 6.69%). Caspase -8, -9, and -3 were activated in PA-1 cells, but not in SK-OV3 cells. These results suggest that death receptor and mitochondria-mediated apoptotic pathways may be involved in celecoxib-induced apoptosis dependent upon the functional status of p53. Our article demonstrated that the celecoxib effectively inhibited cell growth and induced apoptosis in human ovarian cancer cells with wild-type p53. Thus, apoptotic effect by celecoxib seemed to be different dependent upon the functional status of p53.
 ...
PMID:Apoptotic effect of celecoxib dependent upon p53 status in human ovarian cancer cells. 1740 14

Extracts of Artemisia plants possess anti-inflammatory and antioxidative activities. Eupatilin (5,7-dihydroxy-3',4',6-tri-methoxy-flavone), a pharmacologically active flavone derived from Artemisia asiatica, was shown to inhibit phorbol ester-induced cyclooxygenase-2 expression and NF-kappaB activation in mouse skin, and also to induce cell cycle arrest in ras-transformed human mammary epithelial (MCF10A-ras) cells. In this article, we examined the ability of jaceosidin (4',5,7-trihydroxy-3',6-dimethoxyflavone) isolated from Artemisia argyi to inhibit the proliferation of MCF10A-ras cells. Jaceosidin reduced the viability of MCF10A-ras cells to a greater extent than eupatilin. Jaceosidin treatment resulted in increased intracellular accumulation of reactive oxygen species (ROS) in MCF10A-ras cells, which was blocked by the antioxidant N-acetylcysteine (NAC). NAC attenuated jaceosidin-induced cytotoxicity. To better assess the proapoptotic effects of jaceosidin, we analyzed the treated cells by the flow cytometry. MCF10A-ras cells treated with jaceosidin (100 microM) exhibited the increased proportion of hypodiploid or apoptotic cells (48.72% as composed to 7.78% in control cells). Jaceosidin treatment also increased the ratio of proapoptotic Bax to the antiapoptotic Bcl-2 and induced the cleavage of caspase-3 and poly(ADP-ribose)polymerase (PARP). Moreover, jaceosidin elevated the expression of p53 and p21, while the compound inhibited the activation of ERK1/2 that is an important component of cell survival signaling.
 ...
PMID:Jaceosidin induces apoptosis in ras-transformed human breast epithelial cells through generation of reactive oxygen species. 1740 61

Pathways of the molecular pathogenesis of colorectal carcinoma have been extensively studied and molecular lesions during the development of the disease have been revealed. High up in the list of colorectal cancer lesions are APC (adenomatous polyposis coli), K-ras, Smad4 (or DPC4-deleted in pancreatic cancer 4) and p53 genes. All these molecules are part of important pathways for the regulation of cell proliferation and apoptosis and as a result perturbation of these processes lead to carcinogenesis. The ubiquitin-proteasome system (UPS) is comprised of a multi-unit cellular protease system that regulates several dozens of cell proteins after their ligation with the protein ubiquitin. Given that among these proteins are regulators of the cell cycle, apoptosis, angiogenesis, adhesion and cell signalling, this system plays a significant role in cell fate and carcinogenesis. UPS inhibition has been found to be a pre-requisite for apoptosis and is already clinically exploited with the proteasome inhibitor bortezomib in multiple myeloma. Cyclooxygenase-2 (Cox-2) is the inducible form of the enzyme that metabolizes the lipid arachidonic acid to prostaglandin H2, the first step of prostaglandins production. This enzyme is up-regulated in colorectal cancer and in several other cancers. Inhibition of Cox-2 by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit proliferation of colorectal cancer cells and in epidemiologic studies has been shown to reduce colon polyp formation in genetically predisposed populations and in the general population. NSAIDs have also Cox-independent anti-proliferative effects. Targeted therapies, the result of increasingly understanding carcinogenesis in the molecular level, have entered the field of anti-neoplastic treatment and are used by themselves and in combination with chemotherapy drugs. Combinations of targeted drugs have started also to be investigated. This article reviews the molecular pathogenesis of colorectal cancer, the roles of UPS and Cox-2 in it and puts forward a rational for their combined inhibition in colorectal cancer treatment.
 ...
PMID:Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2. 1748 76

Curcumin was found to be cytotoxic in nature to a wide variety of tumor cell lines of different tissue origin. The action of curcumin is dependent on with the cell type, the concentration of curcumin (IC50: 2-40 microg/mL), and the time of the treatment. The major mechanism by which curcumin induces cytotoxicity is the induction of apoptosis. Curcumin decreased the expression of antiapoptotic members of the Bcl-2 family and elevated the expression of p53, Bax, procaspases 3, 8, and 9. Curcumin prevents the entry of nuclear factor KB (NF-KB) into the nucleus there by decreasing the expression of cell cycle regulatory proteins and survival factors such as Bcl-2 and survivin. Curcumin arrested the cell cycle by preventing the expression of cyclin D1, cdk-1 and cdc-25. Curcumin inhibited the growth of transplantable tumors in different animal models and increased the life span of tumor-harboring animals. Curcumin inhibits metastasis of tumor cells as shown in in vitro as well as in vivo models, and the possible mechanism is the inhibition of matrix metalloproteases. Curcumin was found to suppress the expression of cyclooxygenase-2, vascular endothelial growth factor, and intercellular adhesion molecule- and elevated the expression of antimetastatic proteins, the tissue inhibitor of metalloproteases-2, nonmetastatic gene 23, and Ecadherin. These results indicate that curcumin acts at various stages of tumor cell progression.
 ...
PMID:Antitumor, anti-invasion, and antimetastatic effects of curcumin. 1756 10

Resveratrol, a polyphenol found in numerous plant species, including mulberries, peanuts and grapes, has shown to possess chemopreventive properties against several cancers, and cardiovascular diseases. Recently, resveratrol has been shown to have positive effects on age longevity, lipid levels and a preventative quality against certain cancers and viral infections. Resveratrol induces apoptosis by up-regulating the expression of Bax, Bak, PUMA, Noxa, Bim, p53, TRAIL, TRAIL-R1/DR4 and TRAIL-R2/DR5 and simultaneously down-regulating the expression of Bcl-2, Bcl-XL, Mcl-1 and survivin. Resveratrol causes growth arrest at G1 and G1/S phases of cell cycle by inducing the expression of CDK inhibitors p21/WAF1/CIP1 and p27/KIP1. Resveratrol has also been shown to reduce inflammation via inhibition of prostaglandin production, cyclooxygenase-2 activity, and nuclear factor-kappaB activity. Modulation of cell signaling pathway by resveratrol explains its diverse bioactivities related with human health. Resveratrol also potentiates the apoptotic effects of cytokines, chemotherapeutic agents and gamma-radiation. Pharmacokinetic and pharmacodynamic studies demonstrated that the main target organs of resveratrol are liver and kidney, and it is metabolized by hydroxylation, glucuronidation, sulfation and hydrogenation. As a chemoprevention agent, resveratrol has been shown to inhibit tumor initiation, promotion, and progression. There is growing evidence that resveratrol can prevent or delay the onset of various cancers, heart diseases, ischemic and chemically induced injuries, pathological inflammation and viral infections. This review summarizes the molecular mechanisms of resveratrol and its clinical benefits for human diseases.
 ...
PMID:Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. 1756 14

Overexpression of Cyclooxygenase-2 (COX-2) is observed in most tumor types. Increased COX-2 activity and synthesis of prostaglandins stimulates proliferation, angiogenesis, invasiveness and inhibits apoptosis. Many stress and proinflammatory signals induce COX-2 expression, including oxyradicals or DNA-damaging agents. The latter also induces p53, a transcription factor often inactivated by mutation in cancer. Several studies have identified complex cross-talks between p53 and COX-2, whereby p53 can either up- or down-regulate COX-2, which in turn controls p53 transcriptional activity. However, the molecular basis of these effects are open to debate, in particular since no p53 binding sequences have been identified in COX-2 regulatory regions. In this review, we summarize the molecular mechanisms by which COX-2 contributes to carcinogenesis and discuss the experimental set-up, results and conclusions of studies analyzing cross-talks between p53 and COX-2. We propose 2 scenarios accounting for overexpression of COX-2 in precursor and cancer lesions. In the "inflammatory" scenario, p53, activated by DNA damage induced by oxygen and nitrogen species, recruits NF-kappaB to activate COX-2, resulting in antiapoptotic effects that contribute to cell expansion in inflammatory precursor lesions. In the "constitutive proliferation" scenario, oncogenic stress due to activation of growth signaling cascades may upregulate COX-2 promoter independently of NF-kappaB and p53, synergizing with TP53 mutation to promote cancer progression. These 2 scenarios, although not mutually exclusive, may account for the diversity of the correlations between COX-2 expression and TP53 mutation, which vary according to cancer types and biological contexts, and have implications for the use of COX-2 inhibitors in cancer prevention and therapy.
 ...
PMID:Cross-talks between cyclooxygenase-2 and tumor suppressor protein p53: Balancing life and death during inflammatory stress and carcinogenesis. 1758 97

Squamous-cell carcinoma (SCC) is the second most common tumor in horses, and 40%-50% may occur in ocular and adnexal structures. Cyclooxygenase (COX)-2 is an inducible enzyme responsible for the production of prostaglandins that control cell growth and the development and progression of cancer. Mechanisms responsible for the initial upregulation of COX-2 in neoplasia are unclear; prolonged sunlight exposure and mutations in the p53 gene may be possibilities. Because the etiopathogenesis of ocular SCC in horses may involve ultraviolet sunlight and p53 mutations, the purpose of this study was to characterize the immunoreactivity of COX-2 in these tumors. Cyclooxygenase-2 expression was found in 6 of 22 (27%) paraffin-embedded equine SCCs. Cyclooxygenase-2 immunoreactivity was associated with the mitotic index (P < 0.001). Strategies to inhibit COX-2 by the use of topical or systemic COX-2 inhibitors might prove to be a safe and economical treatment in some horses with SCC.
 ...
PMID:Cyclooxygenase-2 immunoreactivity in equine ocular squamous-cell carcinoma. 1760 59

p63 is a member of the p53 protein family that regulates differentiation and morphogenesis in epithelial tissues and is required for the formation of squamous epithelia. Barrett's mucosa is a glandular metaplasia of the squamous epithelium that develops in the lower esophagus in the context of chronic, gastroesophageal reflux and is considered as a precursor for adenocarcinoma. Normal or squamous cancer esophageal cells were exposed to deoxycholic acid (DCA, 50, 100, or 200 microM) and chenodeoxycholic and taurochenodeoxycholic acid at pH 5. p63 and cyclooxygenase-2 (COX-2) expressions were studied by Western blot and RT-PCR. DCA exposure at pH 5 led to a spectacular decrease in the levels of all isoforms of the p63 proteins. This decrease was observed within minutes of exposure, with a synergistic effect between DCA and acid. Within the same time frame, levels of p63 mRNA were relatively unaffected, whereas levels of COX-2, a marker of stress responses often induced in Barrett's mucosa, were increased. Similar results were obtained with chenodeoxycholic acid but not its taurine conjugate at pH 5. Proteasome inhibition by lactacystin or MG-132 partially blocked the decrease in p63, suggesting a posttranslational degradation mechanism. These results show that combined exposure to bile salt and acid downregulates a critical regulator of squamous differentiation, providing a mechanism to explain the replacement of squamous epithelium by a glandular metaplasia upon exposure of the lower esophagus to gastric reflux.
 ...
PMID:Downregulation of p63 upon exposure to bile salts and acid in normal and cancer esophageal cells in culture. 1761 80


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>