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)

Radiotherapy (RT) is a well established modality for treating many forms of cancer. However, despite many improvements in treatment planning and delivery, the total radiation dose is often too low for tumor cure, because of the risk of normal tissue damage. Gene therapy provides a new adjunctive strategy to enhance the effectiveness of RT, offering the potential for preferential killing of cancer cells and sparing of normal tissues. This specificity can be achieved at several levels including restricted vector delivery, transcriptional targeting and specificity of the transgene product. This review will focus on those gene therapy strategies that are currently being evaluated in combination with RT, including the use of radiation sensitive promoters to control the timing and location of gene expression specifically within tumors. Therapeutic transgenes chosen for their radiosensitizing properties will also be reviewed, these include: gene correction therapy, in which normal copies of genes responsible for radiation-induced apoptosis are transfected to compensate for the deletions or mutated variants in tumor cells (p53 is the most widely studied example). enzymes that synergize the radiation effect, by generation of a toxic species from endogenous precursors (e.g., inducible nitric oxide synthase) or by activation of non toxic prodrugs to toxic species (e.g., herpes simplex virus thymidine kinase/ganciclovir) within the target tissue. conditionally replicating oncolytic adenoviruses that synergize the radiation effect. membrane transport proteins (e.g., sodium iodide symporter) to facilitate uptake of cytotoxic radionuclides. The evidence indicates that many of these approaches are successful for augmenting radiation induced tumor cell killing with clinical trials currently underway.
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PMID:Radiogenic therapy: novel approaches for enhancing tumor radiosensitivity. 1602 55

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

Aged brain shows reduced biological plasticity to meet emergency conditions such as ischemia, a process in which nitric oxide (NO) and apoptosis have been shown to play important roles. Using a model of transient global ischemia, we have analyzed the NO system and the p53, bax and bcl-2 response in the cerebral cortex of aged rats. Although immediately after ischemia the NO level is maintained, the reperfusion period increases NO concentrations together with the following: (i) greater bulk-protein nitration mainly due to a 50-kDa immunoreactive band; (ii) an increase in p53 protein; and (iii) an up-regulation of Bax together with a down-regulation of Bcl-2. These results match up with induced endothelial nitric oxide synthase expression immediately after ischemia and in neuronal nitric oxide synthase with the reperfusion. However, inducible nitric oxide synthase was not altered with ischemia/reperfusion. Altogether, these data suggest that NO production in cerebral cortex of aged ischemic animals is due to the constitutive NO synthase isoforms. This response is accompanied by the increased expression of pro-apoptotic proteins.
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PMID:Constitutive nitric oxide synthases are responsible for the nitric oxide production in the ischemic aged cerebral cortex. 1605 96

Macrophage migration inhibitory factor (MIF), a member of the cytokine family, is beginning to be recognized as a pleiotropic proinflammatory molecule. MIF exerts function via antagonistic regulation of glucocorticoids, inhibition to apoptosis-mediated p53, influence on vasodilator gas NO and inducible nitric oxide synthase (iNOS), feedback counter-regulation of complement C5a controlling MIF release, and interaction with major cations as well. Interestingly, aforementioned glucocorticoids, apoptosis, NO, iNOS, C5a, Ca2+, Mg2+, Na+, K+, and H+ that are greatly associated with vascular tone or vasomotion. Nevertheless, the elevated serum and cytosolic concentrations of MIF exactly affect all above facets in septic shock models and patients, during which vasodilation of the peripheral resistance vessels occurs, and accompanied with decreased responsiveness to vascular pressors. Thus MIF may bring into play as one of point-controlling proteins in the onset of sustained vascular hypo-reactivity during the process of septic shock.
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PMID:Is macrophage migration inhibitory factor (MIF) the "control point" of vascular hypo-responsiveness in septic shock? 1612 29

Oral lichen planus (OLP) is a chronic inflammatory disease, which has been clinically associated with development to oral cancer. A double immunofluorescence labeling study found that 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) accumulated in oral epithelium in OLP and oral squamous cell carcinoma (OSCC) biopsy specimens, whereas little or no immunoreactivity was observed in normal oral mucosa. Colocalization of 8-nitroguanine and inducible nitric oxide synthase (iNOS) was found in oral epithelium of OLP and OSCC. Immunoreactivity of 3-nitrotyrosine, which is formed by protein tyrosine nitration and is considered to be a biochemical marker for inflammation, was also observed in oral epithelial cells and colocalized with 8-nitroguanine. Accumulation of p53 was more strongly observed in oral epithelium in OSCC than OLP, whereas there was no p53 accumulation in normal oral mucosa. Our findings demonstrate that iNOS-dependent DNA damage in OLP may lead to p53 accumulation in not only OLP but also OSCC. We conclude that the formation of potentially mutagenic DNA lesions including 8-nitroguanine and 8-oxodG may contribute to the development of oral cancer from OLP.
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PMID:Nitrative and oxidative DNA damage in oral lichen planus in relation to human oral carcinogenesis. 1612 40

Apoptosis has been shown to be an important regulator of endometrial function during the menstrual cycle and implantation. Recently, some possible implantation defects were identified in patients with unexplained infertility. In this study, we investigated the role of spontaneous apoptosis, which is regulated by death regulatory genes, such as Bcl-2, Bax, p53, and isoenzymes of nitric oxide synthases; eNOS and iNOS during the implantation window in women with unexplained infertility. Endometrial samples were evaluated from fertile (n=15) and unexplained-infertile women (n=15) during post-ovulatory 7th or 8th day of their menstrual cycles. Apoptotic cells were detected using the dUTP nick-end labelling assay and Bcl-2, Bax, p53, iNOS and eNOS were assessed immunohistochemically. Reduced apoptotic cells, weak immunoreactivity of p53 and strong immunoreactivity of Bcl-2 were observed in the unexplained-infertile group compared with the fertile group (p<0.001). Bax intensity was similar in both groups. While weak iNOS immunoreactivity was detected in both groups, moderately increased eNOS immunoreactivity was observed in infertile cases. Spontaneous apoptosis is reduced in the endometrium of unexplained-infertile women, and is associated with the changed Bcl-2:Bax ratio. This finding may be a contributing factor to defective implantation causing infertility in this group of patients.
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PMID:Changed Bcl:Bax ratio in endometrium of patients with unexplained infertility. 1613 38

Beta-catenin plays an important role in colonic tumorigenesis whereas inducible nitric oxide synthase and nitric oxide are elevated in colonic inflammation. Resistance of colonic epithelial cells to the induction of apoptosis may contribute to tumor development. Nitric oxide can stimulate apoptosis and, paradoxically, is implicated in the development of colon cancer. Our hypothesis was that beta-catenin could increase the resistance of colonic cancer cells to nitric oxide-induced apoptotic cell death. Here we show, using a beta-catenin overexpression system, that increased cytosolic beta-catenin renders colonic epithelial cells more resistant to nitric oxide-induced apoptotic cell death, independently of nitric oxide-induced accumulation of p53. Furthermore, we show that this occurs through inhibition of nitric oxide-induced release of cytochrome c from mitochondria and by blocking both the nitric oxide-induced suppression of the antiapoptotic protein, Bcl-xL, and the phosphorylation of Akt. We contend that increased nitric oxide production, such as that which occurs in chronic colonic inflammation, may select the cells with oncogenic mutant beta-catenin regulatory genes and contribute to human colonic carcinogenesis and tumor progression.
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PMID:Overexpressed beta-catenin blocks nitric oxide-induced apoptosis in colonic cancer cells. 1620 24

Heat stroke-induced death is a major killer worldwide. Mice were subjected to acute heat stress by exposing them to whole-body hyperthermia (WBH) treatment and were used as a model to study heat stroke. Administration of L-arginine (L-arg, 120 mg/kg, i.p) 2 h after the cessation of WBH rescued the mice from heat-induced death and reduced the hypothermia. Heat shock protein 70 levels in the liver were increased significantly in heat-stressed mice administered L-arg compared with the heat-stressed group. WBH induced apoptosis, as indicated by DNA fragmentation, and increased levels of p53 and caspase-3 activity, which were significantly reduced by the administration of L-arg. The levels of inducible nitric oxide synthase in the liver, nitrite, and inflammatory cytokines like interleukin 1beta and tumor necrosis factor-alpha in the serum increased in WBH-treated mice. The levels of the above markers of heat stress significantly decreased in L-arg-treated mice. Kinin-B1 receptor (kinin-B1R) in cardiac tissue that is upregulated in heat stressed mice was significantly lower in L-arg-administered mice. These data suggest the potential use of L-arg, a nonessential amino acid that is used as an enteral diet supplement, to treat heat stroke-related injury when administered at the appropriate dose and time.
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PMID:Therapeutic treatment with L-arginine rescues mice from heat stroke-induced death: physiological and molecular mechanisms. 1620 19

With ulcerative colitis (UC)-associated tumorigenesis, p53 gene alteration is considered to be a key event. To clarify whether the p53-checkpoint is operating in foci of inflammation and that its disruption is a feature of UC-associated neoplasms, the present immunohistochemical study was conducted. Since accumulation of butyric acid with active UC is associated with apoptosis, effects of in vitro exposure of newly established UC-cancer derived cell lines to organic acids were also assessed. The regulatory subunit of ribonucleotide reductase, p53R2, was found to be localized with p53 in situ, and levels of p53, phospho-p53, p53R2 and inducible nitric oxide synthase were significantly intercorrelated. However, p53R2 expression was clearly reduced with progression through UC-associated dysplasia to carcinoma, demonstrating an inverse relation with p53 overexpression. In vitro treatment with butyrate or propionic acid, but not succinic acid, elicited a positive response in the p53-p53R2 system. Moreover, p53-dependent DNA repair, investigated by radioactive nucleotide incorporation, was induced by butyric acid and inhibited by short-interfering p53 and p53R2 RNAs. Therefore, it was concluded that the p53-p53R2-dependent DNA repair system is constitutively stimulated by butyric acid, which accumulates in UC inflammatory lesions. Since failure of the p53-G(1) checkpoint may cause dysfunction of repair under the influence of butyrate, gene alterations may increase and spread through the genome, leading to tumorigenesis.
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PMID:Disruption of the p53-p53r2 DNA repair system in ulcerative colitis contributes to colon tumorigenesis. 1620 88

Oral leukoplakia is a premalignant lesion associated with development of oral cancer. To clarify the mechanism of development of oral carcinogenesis from leukoplakia, we examined DNA damage in oral epithelium of biopsy specimens of patients with leukoplakia by immunohistochemical methods. Histological changes, such as epithelial dysplasia and infiltration of inflammatory cells were observed in oral tissues of leukoplakia patients. A double immunofluorescence labeling study demonstrated that the accumulation of mutagenic 8-nitroguanine, an indicator of nitrative DNA damage, and 8-oxo-7,8-dihydro-2'-deoxyguanosine, an indicator of oxidative DNA damage, was apparently observed in the oral epithelium of patients with leukoplakia, whereas little or no immunoreactivity was observed in normal oral mucosa. Expression of inducible nitric oxide synthase (iNOS) was also observed in oral epithelium of leukoplakia patients. Immunoreactivity of 3-nitrotyrosine, an indicator of nitrative stress, was observed in oral epithelial cells and colocalized with 8-nitroguanine. Moreover, proliferating cell nuclear antigen and p53 were expressed in 8-nitroguanine-positive epithelial cells in the basal layer. These results suggest that iNOS-mediated nitrative stress contributes to development of oral carcinogenesis from leukoplakia through DNA damage as well as oxidative stress.
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PMID:8-Nitroguanine formation in oral leukoplakia, a premalignant lesion. 1629 60


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