UNIPROT:P04637 - FACTA Search

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)

To clarify the mechanism by which radon hot springs prevent cancer or not, in this study, blood was collected from residents in the Misasa hot spring district and in a control district. The level of a representative cancer-suppressive gene, p53, and the activity of a representative antioxidant enzyme, superoxide dismutase (SOD), were analyzed as indices. The level of serum p53 protein in the males in the Misasa hot spring district was found to be 2-fold higher than that in the control district, which is a significant difference. In the females in the Misasa hot spring district, SOD activity was approximately 15% higher than that in the control district, which is also statistically significant, and exceeded the reference range of SOD activity despite advanced age. These results suggested that routine exposure of the residents in the Misasa hot spring district to radon at a concentration about 3 times higher than the national mean induces trace active oxygen in vivo, potentiating products of cancer-suppressive gene and antioxidant function. As the p53 protein level was high in the residents in the Misasa hot spring district, apoptosis of cancer cells may readily occur.
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PMID:The elevation of p53 protein level and SOD activity in the resident blood of the Misasa radon hot spring district. 1580 55

The tumor suppressor gene p53 is activated by reactive oxygen species-generating agents. After activation, p53 migrates to mitochondria and nucleus, a response that eventually leads to apoptosis, but how the two events are related is unknown. Herein, we show that p53 translocation to mitochondria precedes its translocation to nucleus in JB6 skin epidermal cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Translocation of p53 to mitochondria occurs within 10 minutes after TPA application. In the mitochondria, p53 interacts with the primary antioxidant enzyme, manganese superoxide dismutase (MnSOD), consistent with the reduction of its superoxide scavenging activity, and a subsequent decrease of mitochondrial membrane potential. In contrast to the immediate action on mitochondria, p53 transcriptional activity in the nucleus increases at 1 hour following TPA application, accompanied by an increase in the levels of its target gene bax at 15 hours following TPA treatment. Activation of p53 transcriptional activity is preventable by application of a SOD mimetic (MnTE-2-PyP5+). Thus, p53 translocation to mitochondria and subsequent inactivation of MnSOD explains the observed mitochondrial dysfunction, which leads to transcription-dependent mechanisms of p53-induced apoptosis.
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PMID:p53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense protein-manganese superoxide dismutase. 1586 70

Peptidyl-proline isomerase (Pin1) is able to trigger some conformationally important change in the p53 protein: there is notable protection by p53 (tumour suppressor protein) of human cells that prevents their entry into the carcinogenesis-committed routeway. Pin1 controls the ready (low energy change) equilibrium between the cis and trans distinctive folding configurations differentially at a proline residue: this amino acid residue in proteins is unique in bending sharply its peptide chain (to 90 degrees change): in the cis rather than trans orientation with respect to the peptide bond to residue X "upstream" linked as XCONHR. Moreover p53 protein can arrest a cell cycle progression (or trigger apoptosis) by acting as a transcription factor to nuclear DNA acting at p53 nuclear responsive element controlling a larger number of genes that produce proteins that stop cell growth or stimulate apoptosis, in stressed cells. Oxidative stress by reactive oxygen species (ROS) is carcinogenic but also stops cell growth and triggers apoptosis, Cu-SOD removes ROS (see figure). Could superoxide dismutase (Cu-SOD), therefore, provide the DNA-damage direct second route (first route is binding of Pin1) in DNA-damaged cells to p53 activation? The p53 protein that prevents carcinogenesis is activated by Pin1. In addition, this p53 tumour suppressor protein is activated by Cu-SOD.
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PMID:p53 Protein is activated by Pin1: and also by Cu-SOD prion-like enzyme. 1589 13

Changes in intracellular redox status are crucial events that trigger downstream proliferation or death responses through activation of specific signaling pathways. Moreover, cell responses to oxidative challenge may depend on the pattern of redox-sensitive molecular factors. The stress-activated protein kinases c-Jun-N-terminal kinase (JNK) and p38 MAP kinase (p38MAPK) are implicated in different forms of apoptotic neuronal cell death. Here, we investigated the effects, on neuroblastoma cells, of the prooxidant molecule GSSG, which we previously demonstrated to be an efficient proapoptotic compound able to activate the p38MAPK death pathway in promonocytic cells. We found that neuroblastoma cells are not prone to GSSG-induced apoptosis, although the treatment slightly induced growth arrest through the accumulation of p53 and its downstream target gene, p21. However, GSSG treatment became cytotoxic when cells were previously depleted of intracellular GSH content. Under this condition, apoptosis was triggered by an increased production of superoxide that led to a specific activation of the JNK-dependent pathway. The involvement of superoxide and JNK was demonstrated by cell death inhibition in experiments carried out in the presence of Cu,Zn superoxide dismutase or with specific inhibitors of JNK activity. Our data give support to the studies that indicate preferential requirements for the involvement of stress-activated kinases in apoptotic neuronal cells.
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PMID:Activation of c-Jun-N-terminal kinase is required for apoptosis triggered by glutathione disulfide in neuroblastoma cells. 1599 33

The mechanisms of injury- and disease-related degeneration of motor neurons (MNs) need clarification. Unilateral avulsion of the sciatic nerve in the mouse induces apoptosis of spinal MNs that is p53 and Bax dependent. We tested the hypothesis that MN apoptosis is Fas death receptor dependent and triggered by nitric oxide (NO)- and superoxide-mediated damage to DNA. MNs in mice lacking functional Fas receptor and Fas ligand were protected from apoptosis. Fas protein levels and cleaved caspase-8 increased in MNs after injury. Fas upregulation was p53 dependent. MNs in mice deficient in neuronal NO synthase (nNOS) and inducible NOS (iNOS) resisted apoptosis. After injury, MNs increased nNOS protein but decreased iNOS protein; however, iNOS contributed more than nNOS to basal and injury-induced levels of NADPH diaphorase activity in MNs. NO and peroxynitrite (ONOO-) fluorescence increased in injured MNs, as did nitrotyrosine staining of MNs. DNA damage, assessed as 8-hydroxy-2-deoxyguanosine and single-stranded DNA, accumulated within injured MNs and was attenuated by nNOS and iNOS deficiency. nNOS deficiency increased DNA repair protein oxoguanine DNA-glycosylase, whereas iNOS deficiency blocked diaphorase activity. MN apoptosis was blocked by the antioxidant Trolox and by overexpression of wild-type human superoxide dismutase-1 (SOD1). In contrast, injured MNs in mice harboring mutant human SOD1 had upregulated Fas and iNOS, escalated DNA damage, and accelerated and increased MN degeneration and underwent necrosis instead of apoptosis. Thus, adult spinal MN apoptosis is mediated by upstream NO and ONOO- genotoxicity and downstream p53 and Fas activation and is shifted to necrosis by mutant SOD1.
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PMID:Adult motor neuron apoptosis is mediated by nitric oxide and Fas death receptor linked by DNA damage and p53 activation. 1600 Jun 35

Basic research and clinical chemoprevention trials support the protective role of selenium in cancer prevention but the mechanisms based on the molecular level remain to be fully defined. This mini-review focuses only on the elucidation of the molecular mechanisms of cancer prevention by selenium using the genomics approach; target organs discussed here are breast, prostate, colon and lung. The results described here support the utility of microarray technology in delineating the molecular mechanisms of cancer prevention by selenium. These results are based on studies employing human and rodent cell lines and tissues from animal models ranging from normal to frank cancer. The dose and the form of selenium are determining factors in cancer chemoprevention. The results of the microarray analysis reviewed here indicate that selenium, independent of its form and the target organ examined, alters several genes in a manner that can account for cancer prevention. Selenium can up regulate genes related to phase II detoxification enzymes, certain selenium-binding proteins and select apoptotic genes, while down regulating those related to phase I activating enzymes and cell proliferation. Independent of tissue type, selenium arrests cells in G1 phase of cell cycle, inhibits CYCLIN A, CYCLIN D1, CDC25A, CDK4, PCNA and E2F gene expressions while induces the expressions of P19, P21, P53, GST, SOD, NQO1, GADD153 and certain CASPASES. In addition to those described above, genes such as OPN, which is mainly involved in metastasis and recently reported to be down regulated by selenium, should be considered as potential molecular marker in clinical chemoprevention trials. Collectively, literature data indicate that some of these genes that were altered by selenium are also involved in the development of human cancers described in this review. It appears that androgen receptor status may influence the effect of selenium on gene expression profile in prostate cancer; whether estrogen receptor may influence the effect of selenium on gene expression in breast cancer requires further studies. Knowledge from gene array data in combination with proteomics approaches, using homogenous population of cell types with the aid of laser capture microdissection, may provide an individualized dimension of information on cancer risk and potential targets for its prevention. The molecular (genetic) biomarkers presented in this review will provide the foundation for future studies of the chemopreventive properties of structurally varied selenium compounds.
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PMID:Molecular chemoprevention by selenium: a genomic approach. 1609 79

Using 2-DE of total cell protein extracts, we compared soluble proteins from murine melanoma lines Tm1 and Tm5 with proteins from the nontumoral cell melan-a from which they were derived. Seventy-one of the 452 spots (average) detected with CBB were differentially accumulated, i.e., increased or decreased twofold. Forty-four spots were identified by PMF/MALDI-TOF, 15 with increased and 29 with decreased protein levels. SAGE showed that 17/34 (50%) of the differentially accumulated proteins, pI range 4-7, presented similar differences at the mRNA level. Major reductions in protein were observed in tumor cells of proteins that degrade reactive oxygen species (ROS). Decreases of > or = twofold in GST, superoxide dismutase, aldehyde dehydrogenase, thioredoxin, peroxiredoxin 2, and peroxiredoxin 6 protein were observed. SAGE indicated the reduction of other proteins involved in ROS degradation. As expected, the accumulation of exogenous peroxides was significantly higher in the tumor cells while the levels of glutathionylation were two times lower in the tumor cells compared to melan-a. The differential accumulation of proteins involved in oncogene/tumor suppressor pathways was observed. Melanoma cells can favor survival pathways activated by ROS by inhibiting p53 pathways and activation of Ras and c-myc pathways.
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PMID:Proteomic and SAGE profiling of murine melanoma progression indicates the reduction of proteins responsible for ROS degradation. 1642 58

Although the anticancer effects of selenium have been shown in clinical, preclinical, and laboratory studies, the underlying mechanism(s) remains unclear. Our previous study showed that sodium selenite induced LNCaP human prostate cancer cell apoptosis in association with production of reactive oxygen species, alteration of cell redox state, and mitochondrial damage. In the present study, we showed that selenite-induced apoptosis was superoxide mediated and p53 dependent via mitochondrial pathways. In addition, we also showed that superoxide production by selenite was p53 dependent. Our study showed that wild-type p53-expressing LNCaP cells were more sensitive to selenite-induced apoptosis than p53-null PC3 cells. Selenite treatment resulted in high levels of superoxide production in LNCaP cells but only low levels in PC3 cells. LNCaP cells also showed sequential increases in levels of phosphorylated p53 (serine 15), total p53, Bax, and p21(Waf1) proteins following selenite treatment. The effects of selenite were suppressed by pretreatment with a synthetic superoxide dismutase mimic or by knockdown of p53 via RNA interference. LNCaP cells treated with selenite also showed p53 translocation to mitochondria, cytochrome c release into the cytosol, and activation of caspase-9. On the other hand, restoration of wild-type p53 expression in PC3 cells increased cellular sensitivity to selenite and resulted in increased superoxide production, caspase-9 activation, and apoptosis following selenite treatment. These results suggest that selenite induces apoptosis by producing superoxide to activate p53 and to induce p53 mitochondrial translocation. Activation of p53 in turn synergistically enhances superoxide production and apoptosis induced by selenite.
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PMID:Expression of p53 enhances selenite-induced superoxide production and apoptosis in human prostate cancer cells. 1648 34

In this article, we studied the chemopreventive effects of sanguinarine on UVB-mediated responses in human HaCaT immortalized keratinocytes. For our studies, HaCaT cells were treated with a low dose (50 nmol/L) of sanguinarine for 24 hours followed by irradiation with UVB (15 or 30 mJ/cm2). Our data showed that UVB exposure, at both doses, resulted in decreased cell viability and increased apoptosis. Interestingly, pretreatment of the cells with sanguinarine caused a significant enhancement in the antiproliferative response of UVB. These responses on UVB and/or sanguinarine treatments were associated with (a) decrease in Bcl-2 and Bcl-X(L) and (b) increase in Bax, Bid, and Bak protein levels. Bax knockdown and Bcl-2 overexpression resulted in a rescue of HaCaT cells from sanguinarine-mediated apoptosis. DNA cell cycle analysis revealed that UVB treatment resulted in an accumulation of cells in the G2-M phase of the cell cycle, whereas pretreatment of sanguinarine resulted in a significant shift of cells in the S phase at a low UVB dose and a further accumulation of cells in the G2-M phase at a higher UVB dose. These effects on cell cycle were accompanied with modulations in the protein levels of cyclin (B1, E, and A) and cdc2 and cyclin-dependent kinase 1. Furthermore, sanguinarine treatment was found to result in significant modulations in p53, p66Shc, MsrA, and superoxide dismutase levels. Based on our data, we suggest the sanguinarine may protect skin cells from UVB-mediated damages via apoptotic elimination of damaged cells that escape programmed cell death and therefore possess a potential of clonal expansion.
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PMID:Enhancement of UVB radiation-mediated apoptosis by sanguinarine in HaCaT human immortalized keratinocytes. 1650 17

Esophageal carcinoma has a high incidence in India but its etiology remains unknown. In the present study the correlation between apoptosis regulatory proteins and anti-oxidant enzymes in 40 esophageal carcinoma patients was examined. Patients in one group were operated by transhiatal esophagectomy and in the second group were administered cisplatin (30 mg/m2/day) and 5-fluorouracil (5-FU) (750 mg/m2/day) daily for three days followed by surgery after four weeks of neo-adjuvant therapy (NAT). Complete pathological response was achieved in 15% of patients. Results obtained by Western blot analysis showed over-expressed p53 and COX-2 protein levels in the tumor tissues as compared to the adjoining tissue and its paired normal mucosa in both groups of patients. Immunohistochemical studies showed heterogenous p53 staining pattern with sections showing both nuclear and cytoplasmic staining with 36.8% mild, 10.5% moderate and 52.6% intense p53 immunoreactivity. Both COX-2 and iNOS immunostaining revealed 25% negative and 75% mild to strongly positive immunoreactivity. Correlation studies demonstrated a positive relationship between p53 and COX-2 (P=0.030; r = +0.70) in surgically treated patients. The association of COX-2 and p53 with various anti-oxidant enzymes showed a significantly positive correlation between COX-2 expression and catalase activity and an inverse correlation between p53 expression and superoxide dismutase and catalase activity in the tumor tissue of patients given NAT. In addition, we observed a negative trend between p53 expression levels and GPx enzyme levels in both the adjoining and tumor tissue of patients having undergone surgery as main mode of treatment.
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PMID:P53, COX-2, iNOS protein expression changes and their relationship with anti-oxidant enzymes in surgically and multi-modality treated esophageal carcinoma patients. 1657 97

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