UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiology and pathogenesis of Hodgkin lymphoma (HL) are not yet known. There are implications of genes involved in programmed cell death (apoptosis), and there have been repeated suggestions of an association with Epstein-Barr virus (EBV). The aim of this study was to investigate the protein expression patterns of key cell cycle-related genes, together with evidence of apoptosis and EBV status, in relation to clinical stage in HLs. A double immunohistochemical and in situ hybridization technique was used to detect the expression of bcl-2, p53, retinoblastoma (Rb), p21, Ki67 (MIB 1), and topoisomerase IIalpha (TopoIIalpha), together with latent membrane protein-1 and EBER for EBV status and TdT-mediated dUTP-FITC nick end-labeling (TUNEL) as a measure of apoptosis, on tissue microarray sections of 62 cases of classic HL (35 NS, 17 MC, 8 LR, and 2 LD). A panel of phenotypic markers was used to facilitate recognition of Hodgkin and Reed-Sternberg (H-RS) cells: CD3, CD20, CD30, CD15, and EMA. The H-RS cells of 62 classic Hodgkin lymphomas were bcl-2-positive in 35 cases (56.45%), p53-positive in 14 (22.58%), and positive for both EBV latent membrane protein-1 and EBER in 37 (59.68%); there was complete concordance of results for EBV by both procedures. No correlation was found between expression of bcl-2, p53, or EBV markers in H-RS cells and clinical stage (P > 0.05). Expression of Rb, Ki67, p21, and TopoIIalpha did, however, show significant differences with clinical stage. Expression of Rb and p21 in CD30-positive H-RS cells decreased with more advanced stage (P < 0.001). In contrast, Ki67 and ToPoIIalpha expression increased with later stage (P < 0.01). No correlation was found between expression of any of these markers in H-RS cells and the subtypes of nodular sclerosis HL, mixed cellularity HL, and LRHL (P > 0.05). TUNEL was found in the nonneoplastic cellular background in all cases and in H-RS cells in only 10 of 62 cases (16.12%) (8 nodular sclerosis HL, 1 mixed cellularity HL, and 1 LRHL). There was a significant correlation between high expression of bcl-2 and a low score by TUNEL (P < 0.05). These data are consistent with the notion that overexpression of bcl-2 may be linked to blockage of apoptosis-mediated death of H-RS cells in classic HL. Abnormal expression of p53-related protein may not play a major role in HL, because it is present in H-RS cells in only a minority of cases. Increased expression of Ki67 and TopoIIalpha by H-RS cells is significantly associated with advanced stage and may indicate aggressive disease. Adverse clinical outcome in HL also is associated with loss of Rb and p21 protein expression, consistent with the possible roles of Rb and p21 in inhibition of the growth of H-RS cells. Within the limitations of the methods used, almost two thirds of cases of HL provide evidence of an association with EBV. The tissue microarray technique is valuable not only for examination of large numbers of cases of a disease by a complex panel of markers but also potentially as a control for staining quality in immunohistochemistry and in situ hybridization.
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PMID:Apoptosis and cell cycle-related genes and proteins in classical Hodgkin lymphoma: application of tissue microarray technique. 1296 46

We assessed the contribution of the cellular prion protein (PrPc) in the control of neuronal apoptosis by examining cell death in both human cells and murine primary cultured neurons. We first confirmed our previous finding that staurosporine-induced caspase activation is increased by PrPc overexpression in HEK293 cells. We show here that this phenotype is fully dependent on p53 and that the control of p53 activity by PrPc occurs at both transcriptional and post-transcriptional levels in human cells. Of most interest, we demonstrate that neuronal endogenous PrPc also controls a p53-dependent pro-apoptotic phenotype. Thus, DNA fragmentation and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling)-positive cells were lower in primary cultured neurons derived from Zrch-1 mice embryos in which PrPc has been abrogated than in wild-type neurons. PrPc knock-out neurons also displayed drastically diminished caspase-3-like activity and immunoreactivity together with reduced p53 expression and transcriptional activity, a phenotype complemented in part by PrPc transfection. Interestingly, p53 expression was also reduced in the brain of adult Prnp-/- mice. Neuronal PrPc likely controls p53 at a post-transcriptional level because the deletion of cellular prion protein is accompanied by a higher Mdm2-like immunoreactivity and reduced phosphorylated p38 MAPK expression. We therefore propose that the physiological function of endogenous cellular prion could be to regulate p53-dependent caspase-3-mediated neuronal cell death. This phenotype likely occurs through up-regulation of p53 promoter transactivation as well as downstream by controlling p53 stability via Mdm2 expression.
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PMID:Primary cultured neurons devoid of cellular prion display lower responsiveness to staurosporine through the control of p53 at both transcriptional and post-transcriptional levels. 1457 Aug 92

The accumulation of p53 protein, which is considered to be caused by a p53 gene mutation, is closely associated with poor prognosis in patients with certain types of carcinomas. The progression of esophageal squamous cell carcinoma (ESCC) is also suspected to depend on p53 gene status. We analyzed the relationship between p53 and p21 protein accumulation in ESCC, and simultaneously analyzed the frequency of apoptosis. Formalin-fixed paraffin-embedded sections were taken from 46 patients who underwent esophagectomy for ESCC. These sections were examined by immunostaining with monoclonal antibodies PAb1801 and EA10 to determine p53 and p21 protein accumulation, respectively. We also analyzed the frequency of apoptosis by TdT-mediated dUTP-biotin nick end-labeling (TUNEL). For estimation of the proportion of stained cells, we used computer analysis with NIH image analysis software. p21 protein accumulation showed an almost inverse distribution to that of p53 protein. In areas where both p53 and p21 proteins were accumulated, few apoptotic cells were observed. Particularly in cases of mucosal tumors, p53 protein was prominently accumulated in the lower layer of the tumor, whereas p21 protein accumulation was confined to the upper layer. Our results suggest that progression of esophageal squamous cell carcinoma is controlled by a p53-dependent pathway.
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PMID:p53 expression and p21 expression are mutually exclusive in esophageal squamous cell carcinoma. 1465 3

1-beta-D-Arabinofuranosylcytosine (Ara-C), a DNA-damaging agent, severely inhibits fetal growth and has teratogenicity. Recently, we reported that Ara-C also causes placental growth retardation and increases placental apoptosis. The aim of the present study is to elucidate the mechanisms of placental injury induced by genotoxic stress and involvement of p53, which mediates apoptosis and cell-cycle arrest after DNA damage. We injected Ara-C into pregnant rats on Day 13 of gestation and examined the placentas from 1 to 48 h after the administration. Terminal deoxynucleotidyltransferase-mediated dUTP end-labeling (TUNEL) revealed that the apoptosis of trophoblastic cells in the placental labyrinth zone increased from 3 h after the treatment and peaked at 6 h before returning to control levels at 48 h. An increase in cleaved caspase-3 immunoreactivity was also detected at 6 h. Proliferative activity as measured by immunohistochemistry for topoisomerase II alpha and by mitotic index significantly decreased after the treatment in the labyrinth zone. Immunoreactivity for p53 protein in the placental labyrinth zone was remarkably enhanced and peaked at 3 h after treatment, although no increase in p53 mRNA expression was detected with a reverse transcription- polymerase chain reaction. Regarding p53 target genes, p21, cyclinG1, and fas mRNA levels increased significantly and peaked at around 9 h after the treatment. These results indicate that Ara-C would induce apoptosis and impair cell proliferation in the placental labyrinth zone, and p53 and its transcriptional target genes may play an important role in the pathogenesis of the Ara-C-induced placental toxicity.
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PMID:Involvement of p53 in 1-beta-D-arabinofuranosylcytosine-induced trophoblastic cell apoptosis and impaired proliferation in rat placenta. 1476 21

The fragile histidine triad (FHIT) gene, located at chromosome 3p14.2, is deleted in many solid tumors, including lung cancer. Its protein product is presumed to have tumor suppressor function. We investigated the incidence of loss of heterozygosity and loss of FHIT expression in a series of non-small-cell lung carcinomas and its correlation to apoptosis, proliferation index and prognosis. FHIT expression was determined by immunohistochemistry in formalin-fixed paraffin-embedded tissues from 54 squamous cell carcinomas (SCC) and 44 adenocarcinomas (AC) of the lung. DNA from frozen tumor and corresponding normal tissues were analyzed for allelic losses at two loci located internal (D3S1300, D3S1234) and three loci in flanking regions centromeric and telomeric (D3S1210, D3S1312, D3S1313) to the FHIT gene. Apoptosis was detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL). Proliferation index was determined with ki-67 and flow cytometric analysis. We correlated the results with tumor histology, prognosis and some immunohistochemical markers (p53, bcl-2, bax, c-myc, p21(waf1), cyclin-D1). FHIT expression was related to tumor histology: 52 of 54 (96.3%) SCC and 20 of 44 (45.5%) AC were negative for FHIT (P<0.0001). We found LOH at 3p14.2 in 67.8% of the 98 cases: 72.3% of SCC and 61.4% of AC. Loss of FHIT expression was associated with a higher proliferation index (ki-67, P=0.007; flow cytometry, P<0.004) and lower apoptotic index (P=0.018). LOH at FHIT gene were associated to a high proliferation (flow cytometry, P<0.001) and lower apoptotic level (P=0.043). The log-rank test demonstrated a significant inverse correlation (P=0.039) between loss of FHIT expression and patient survival. FHIT plays an important role in the development of non-small-cell lung cancer, particularly in SCC. Loss of FHIT protein is correlated with a high proliferation and low apoptotic index in tumor cells, and is an independent prognostic indicator for the clinical outcome in patients with these tumors.
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PMID:Loss of FHIT protein expression is related to high proliferation, low apoptosis and worse prognosis in non-small-cell lung cancer. 1497 24

The present study focused on the effects of simulated microgravity on the human follicular thyroid carcinoma cell line ML-1. Cultured on a three-dimensional clinostat ML- 1 cells formed three-dimensional multicellular tumor spheroids (MCTS: 0.3 +/= 0.01mm in diameter). Furthermore, ML-1 cells grown on the clinostat showed elevated amounts of the apoptosis-associated Fas protein, of p53 and of bax, but reduced quantities of bcl-2. In addition, signs of apoptosis as assessed by TdT-mediated DUTP digoxigenin nick end labeling, DAPI staining, DNA laddering and 85-kDa apoptosis-related DNA fragments became detectable. The latter ones resulted from enhanced 116-kDa poly(ADP-ribose)polymerase activity. Electron microscopy revealed all morphological signs of apoptosis. Caspase 3 was clearly upregulated. In conclusion, our experiments show that conditions of simulated microgravity induce early programmed cell death and use different pathways of apoptosis.
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PMID:Simulated microgravity induces programmed cell death in human thyroid carcinoma cells. 1500 88

The peritoneal mesothelial cell is a critical component of the peritoneal membrane. The intraperitoneal use of several antibiotics to treat bacterial peritonitis is current clinical practice. Our previous study showed that cephalothin (CPL) and cefotaxime (CFT) have cytotoxic effects on human peritoneal mesothelial cells (HPMC), however, the exact mechanism of cytotoxicity has not been elucidated. In the present study, flow cytometry, TdT-mediated dUTP nick-end labelling (TUNEL) staining and electron microscopy were used to detect the apoptosis of HPMCs. Immunofluorescent staining was used to evaluate the cytochrome c distribution pattern. Western blotting was used to assess apoptotic signalling proteins. We found that CPL (0.5 mg/mL) and CFT (1 mg/mL) induced apoptosis of HPMCs, whereas cefazolin (0.5 mg/mL) and ceftriaxone (0.5 mg/mL) failed to induce apoptosis of HPMCs. While the DNA content of CFT- or CPL-treated cells was reduced, as determined by flow cytometry, cefazolin and ceftriaxone had no such effect. The CFT- or CPL-treated cells displayed the features of apoptosis both under the electron microscope and by using TUNEL staining. However, cefazolin and ceftriaxone produced the same result as the medium controls. Furthermore, CFT and CPL increased the expression of Bax and p53, and caused the translocation of cytochrome c from the mitochondria to the cytoplasm. The HPMC treated by CFT but not by CPL induced the cleavage of procaspase-3 to form active caspase-3. In conclusion, cefotaxime and cephalothin induce apoptosis of HPMCs in vitro. Signal transduction may be through the mitochondrial pathway.
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PMID:Antibiotics induce apoptosis of human peritoneal mesothelial cells. 1501 31

A preliminary clinical experience suggested tazarotene, a new acetylenic retinoid, as an effective alternative topical treatment of basal cell carcinomas (BCC). The mechanisms of action of this synthetic retinoid, however, have not been yet clarified. In this work we assessed the in vivo effects of daily application of tazarotene for 24 wk, on 30 small superficial and nodular BCC, and the in vitro effects of tazarotene on immortalized basal and squamous tumor epidermal cells. Cellular proliferation, apoptosis and changes in expression of retinol and retinoic acid receptors (RAR), p53, bcl-2, and bax were studied by immunohistochemistry, western blotting and PCR. Overall, 76.7% of treated tumors showed >50% regression. Complete healing was observed in 46.7% of all treated BCC, without recurrences at 2-y observation. Regression was associated with reduced proliferation and increased apoptosis, demonstrated by Ki-67- and TdT-mediated dUTP-biotin nick-end labelling-positive nuclear staining, and with enhanced RAR-beta and bax expression, with RAR-alpha and -gamma expression unchanged. In vitro, tazarotene induced a concentration-dependent increase of RAR-beta and bax associated with a greater rate of apoptosis and growth inhibition in basaloid tumor cells compared with squamous tumor cells. Our studies provide convincing evidence that tazarotene induces BCC regression possibly by synergistic RAR-beta-dependent anti-proliferative and pro-apoptotic pathways.
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PMID:Evidence of increased apoptosis and reduced proliferation in basal cell carcinomas treated with tazarotene. 1510 95

Tetracyclines exhibit significant anti-inflammatory properties in a variety of rheumatologic and dermatologic conditions. They have also been shown to inhibit apoptosis in certain neurodegenerative disorders. Because ischemic renal injury is characterized by both apoptosis and inflammation, we investigated the therapeutic potential of tetracyclines in a rat model of renal ischemia-reperfusion. Male Sprague-Dawley rats underwent bilateral renal artery clamp for 30 min followed by reperfusion and received either minocycline or saline for 36 h before ischemia. Minocycline reduced tubular cell apoptosis 24 h after ischemia as determined by terminal transferase-mediated dUTP nick end-labeling staining and nuclear morphology. It also decreased cytochrome c release into the cytoplasm and reduced upregulation of p53 and Bax after ischemia. The minocycline-treated group showed a significant reduction in tubular injury and cast formation. In addition, minocycline reduced the number of infiltrating leukocytes, decreased leukocyte chemotaxis both in vitro and ex vivo, and downregulated the expression of ICAM-1. Serum creatinine 24-h postischemia was significantly reduced in the minocycline-treated group. We conclude that minocycline has potent antiapoptotic and anti-inflammatory properties and protects renal function in this model of ischemia-reperfusion. Tetracyclines are among the safest and best-studied antibiotics. They are thus attractive candidates for the therapy of human ischemic acute renal failure.
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PMID:Minocycline inhibits apoptosis and inflammation in a rat model of ischemic renal injury. 1517 83

Eicosapentaenoic acid (EPA) has been demonstrated to induce apoptosis and cell cycle arrest in various cancer cell lines in vitro. In this study, we investigated the anti-tumor effects of EPA on hepatoma cell lines and the mechanisms responsible for induced cell death. Three hepatoma cell lines tested had different p53 status: HepG2 with a wild-type p53; Hep3B, of which the endogenous p53 was deleted; and Huh7 with its p53 mutated. MTT assay showed reduced viability of HepG2 cells after exposure to EPA, and the cytotoxicity of EPA was time and dose dependent. However, EPA had no effect on the viability and cell death in the two other hepatoma cell lines containing dysfunctional p53. DNA fragmentation analysis and TUNEL (terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridine diphosphate [dUTP] nick end labeling) staining showed a typical pattern of DNA laddering and DNA breaks staining, respectively, in wild-type p53-containing HepG2 cells after EPA treatment. We also observed that EPA induced transient nuclear accumulation of P53 protein that subsequently up-regulated the expression of Fas messenger RNA and protein in HepG2 cells. In contrast, these findings were not observed in Hep3B and Huh7 cells exposed to EPA. Most notably, EPA-induced apoptosis in HepG2 cells could be reduced almost completely by treatment with FasL antisense oligonucleotides. We conclude that EPA inhibits the growth of HepG2 cells and mediates its effect, at least in part, via the Fas-mediated apoptosis. It appears that the effects of EPA on hepatoma cells are determined by the status of p53 and that wild-type p53 is a prerequisite for the anticancer effect of EPA.
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PMID:Eicosapentaenoic acid induces Fas-mediated apoptosis through a p53-dependent pathway in hepatoma cells. 1528 29

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