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)

The developing cerebral cortex undergoes overlapping periods of neurogenesis, suicide, and differentiation to generate the mature cortical plate. The following experiments examined the role of the gonadal hormone estrogen in comparison to the neurotrophins, in the regulation of p53-dependent cortical cell fate. To synchronize choices between neurogenesis, apoptosis, and neural differentiation, embryonic rat cerebral cortical neuroblasts were conditionally immortalized with the SV40 large T antigen containing the tsA58/U19 temperature-sensitive mutations. At the nonpermissive temperature, cessation of large T antigen expression was accompanied by induction of p53, as well as the p53-dependent proteins, wild-type p53-activated fragment-1/Cdk (cyclin-dependent kinase)-interacting protein-1 (p21/Waf1), Bcl (B-cell lymphoma)-associated protein (Bax), and murine double minute 2 (MDM2), that lead to cell cycle-arrest, suicide, and p53 inhibition, respectively. Simultaneously, neuroblasts exit cell cycle and die apoptotically or differentiate primarily into astrocytes and immature postmitotic neuroblasts. At the nonpermissive temperature, estrogen specifically induced an antagonist-independent increase in phosphorylated p53 expression, while increasing p21/Waf1 and decreasing Bax. Coincidentally, estrogen rapidly increased and then decreased MDM2 relative to controls, suggesting temporal modulation of p53 function. Both estrogen and neurotrophins prevented DNA fragmentation, a marker for apoptosis. However, estrogen also induced a transient increase in released lactate dehydrogenase, suggesting that estrogen simultaneously induced rapid cell death in a subpopulation of cells. In contrast to the neurotrophins, estrogen also increased cell proliferation. Both estrogen and the neurotrophins supported neuronal differentiation. However, in contrast to the neurotrophins, estrogen only supported the expression of a subset of oligodendrocytic markers. These results suggest that estrogen and the neurotrophins support overlapping and distinct aspects of differentiation in the developing cerebral cortex.
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PMID:Overlapping and divergent actions of estrogen and the neurotrophins on cell fate and p53-dependent signal transduction in conditionally immortalized cerebral cortical neuroblasts. 1043 55

Hyperoxia increases free radical production, leading to DNA damage. Recent studies indicate that oxygen augments the expression of p53 and p21(WAF1/CIP1), and increases apoptotic labeling of airway epithelial cells. Similar changes in regulatory gene products have not been reported in other pulmonary cells, nor have these changes been investigated in conjunction with alterations in cell-cycle distribution. The present study was conducted to determine whether oxygen alters the expression of p53 and p21(WAF1/CIP1) in human bronchial smooth-muscle cells (BSMC). BSMC placed in room air (RA), 40% O(2), or 95% O(2) were examined for 3 d to determine cell number, thymidine incorporation, cell-cycle distribution, and lactate dehydrogenase release. Apoptosis was assessed through the terminal deoxynucleotidyl transferase-deoxyuridine triphosphate end-nick labeling (TUNEL) technique, and p53 and p21(WAF1/CIP1) protein levels were determined through enzyme-linked immunosorbent assay. Exposure of BSMC to 95% O(2) decreased proliferation and DNA synthesis within 24 h, and was accompanied by an increase in S-phase cells (72 h; RA: 12.9 +/- 4.6%, versus 95% O(2): 34.6 +/- 7.0%; P < 0.01). By comparison, exposure to 40% O(2) resulted in decreased proliferation at 48 h without significant alterations in cell-cycle distribution. Both p53 and p21(WAF1/CIP1) levels were increased by 95% O(2), with maximal differences noted at 24 and 48 h, respectively. All atmospheres showed < 8% cell death and few TUNEL-positive cells. Our results indicate that oxygen-mediated alterations in BSMC proliferation are time- and concentration-dependent. Furthermore, high oxygen levels induce S-phase arrest and increased expression of p53 and p21(WAF1/CIP1). Activation of these genes may prevent replication without inducing apoptosis to allow for the repair of oxidative damage.
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PMID:Oxygen induces S-phase growth arrest and increases p53 and p21(WAF1/CIP1) expression in human bronchial smooth-muscle cells. 1046 Jul 57

Expression of the lung resistance protein (LRP) is associated with resistance to various anticancer drugs including melphalan and, therefore, may affect the clinical outcome in multiple myeloma (MM). To determine the clinical significance of LRP, we have compared LRP expression in bone marrow plasma cells with clinical parameters including response to chemotherapy and survival of previously untreated patients with MM (n = 72). LRP expression immunocytochemically assessed by means of the LRP-56 monoclonal antibody was positive (> or =10% staining plasma cells) in 44 (61%) samples. There was no correlation between LRP expression and age, sex, type of the paraprotein, serum creatinine, stage, beta2-microglobulin, serum lactate dehydrogenase, or C-reactive protein. However, LRP expression was more frequently observed in patients with a p53 deletion than in those without such a deletion (P = 0.01). The overall response rate for all of the patients evaluable for response to induction chemotherapy (n = 58) was 67%. The response rate was 87% for patients without LRP expression but only 54% for patients with LRP expression (P = 0.01). Kaplan-Meier analysis revealed that patients with LRP expression had a shorter overall survival (median, 33 months) than those without LRP expression (median not reached; P = 0.04). These data show that LRP expression is an important marker for clinical drug resistance and predicts a poor outcome in MM.
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PMID:Expression of the lung resistance protein predicts poor outcome in patients with multiple myeloma. 1049 14

The inhibitory effects of Chinonin, a natural antioxidant extracted from a Chinese medicine, on apoptotic and necrotic cell death of cardiomyocytes in hypoxia-reoxygenation process were observed in this study. The possible mechanisms of Chinonin on scavenging reactive oxygen species and regulating apoptotic related genes bcl-2 and p53 were also investigated. Neonatal rat cardiomyocytes were subjected to 24-h hypoxia and 4-h reoxygenation. Cell death was evaluated by DNA electrophoresis on agarose gel, cell death ELISA and annexin-V-FLUOS/propidium iodide (PI) double staining cytometry. Hypoxia caused the increase of apoptotic rates and the release of lactate dehydrogenase (LDH), while reoxygenation not only further increased the apoptotic rates and leakage of LDH, but also induced necrosis of cardiomyocytes. In addition, hypoxia increased the levels of NO(2)(-)/NO(3)(-) and thiobarbituric acid reacted substances (TBARS), while reoxygenation decreased NO(2)(-)/NO(3)(-), but further increased TBARS in the cultured media. Moreover, hypoxia up-regulated the expression levels of bcl-2 and p53 proteins, while reoxygenation down-regulated bcl-2 and further up-regulated p53. Chinonin significantly decreased the rates of apoptotic and necrotic cardiomyocytes, and inhibited the leakage of LDH. It also diminished NO(2)(-)/NO(3)(-) and TBARS, down-regulated the expression level of p53 protein, and up-regulated bcl-2 protein, respectively. The results suggest that Chinonin has preventive effects against apoptotic and necrotic cell death and its protective mechanisms are related to the antioxidant properties of scavenging nitric oxide and oxygen free radicals, and the modulating effects on the expression levels of bcl-2 and p53 proteins.
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PMID:Chinonin, a novel drug against cardiomyocyte apoptosis induced by hypoxia and reoxygenation. 1065 91

On the basis of a retrospective study of 327 patients with Hodgkin's disease (HD), the prognostic significance of several factors, accepted previously and recently proposed, has been analyzed with regard to response to treatment and the survival time. Multivariate regression analysis strongly decreased the number of potentially prognostic parameters. The only independent, pretreatment factors negatively influenced by either time of survival or response to treatment were the following: age at diagnosis of more than 45 years, advanced (IIIB/IV) clinical stage, poor clinical status according to Karnofsky's scale (score less than 70), presence of systemic symptoms, mixed cellularity/lymphocyte depletion histological type, multisite peripheral nodal localization of the disease, abdominal lymphadenopathy, and large primary tumor mass (bulky disease). Short time to achieve complete remission (during the first four courses of chemotherapy) has proven to be significantly positive predictive factor. Cumulative dose of cytostatics lower than programmed was a significantly negative prognostic factor that correlated with a shorter time of survival. Lack of or a too-low dose of radiotherapy had the same predictive value. High activity of serum lactate dehydrogenase correlated moderately with poor response to the first-line treatment but did not influence the survival time. Other clinical, morphological, and biochemical parameters influenced neither the prognosis nor the response to treatment. Additionally, immunohistochemical examinations for proliferating cell nuclear antigen and the protein products of the p53 and bcl-2 genes were performed on the lymph nodes obtained from the patients with HD. High expression of proliferating cell nuclear antigen, p53, and BCL-2 correlated with poor response to the treatment and/or short time of survival. Statistical analysis has led us to the conclusion that the pretreatment expression of these oncoproteins can be taken into consideration as a new prognostic factor in HD.
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PMID:Prognostic factors in Hodgkin's disease: multivariate analysis of 327 patients from a single institution. 1074 46

Abnormalities of the TP53 tumor suppressor gene at 17p13.1 are prognostically adverse in a variety of hematolymphoid malignancies. The present study utilized interphase fluorescence in situ hybridization (I-FISH) to detect TP53 deletions and trisomy 12 in 101 clinical specimens from 98 patients with B-cell lymphoproliferative disorders (B-LPDs). Twelve patients had TP53 deletions (group A), 23 had trisomy 12 (group B), and 63 had neither (group C). The groups did not significantly differ in age, duration of disease, absolute lymphocyte count, or percentage with an immunophenotype or cytology atypical for chronic lymphocytic leukemia (CLL). The clinical stage of disease and lactate dehydrogenase (LDH) level were higher in group A, with less response to therapy. After a median follow-up of 19 months, seven of the patients in group A had died of disease (another patient subsequently has had large cell transformation) compared with none in group B and nine in group C. Multivariate analysis found the stage of disease and TP53 deletions as the only parameters independently associated with shortened survival (P < 0.001). Thirty-nine patients had conventional cytogenetic analysis (CCA) which was complexly abnormal in 11 patients; 6 of whom died of disease. There was a trend for complex cytogenetics to be seen more frequently in group A, often with 17p involvement. For most laboratories, CCA may be the preferable initial study to identify prognostically different subgroups of B-LPDs. However, as more probes and clinical outcome data become available, I-FISH will likely play an increasingly important ancillary role.
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PMID:TP53 deletions but not trisomy 12 are adverse in B-cell lymphoproliferative disorders. 1086 51

Radiation-induced alterations in the levels of p53 and lactate dehydrogenase activities were studied in fibrosarcoma, following exposure to different doses of gamma-irradiation (2-10 Gy). The levels of p53 were elevated in the cytoplasm, while the lactate dehydrogenase activity in tumor tissue was considerably decreased.
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PMID:Expression of p53 and lactate dehydrogenase in murine fibrosarcoma following exposure to gamma-radiation. 1121 4

Although mesangial cell death has been shown to be correlated with mesangial cell mitosis in vivo, little is known about how these two apparently opposite events are regulated. We show that the addition of platelet-derived growth factor (PDGF; 10-50 ng/ml) to primary cultured rat mesangial cells for 24 h caused continuous proliferation along with simultaneous cell death. This process was accompanied by the fragmentation of DNA into nucleosomal oligomers, the development of apoptotic morphological changes in the nucleus, and increased expression of p53. Accumulation of lactate dehydrogenase (LDH) was also observed in the culture medium, suggesting that both apoptosis and necrosis are involved in the cell death mechanisms observed. We also observed that addition of 30 microM lysophosphatidic acid (LPA) to the culture medium greatly suppressed PDGF-induced cell death, leading to synergistically enhanced mesangial cell proliferation. DNA fragmentation, p53 expression and LDH release were all suppressed by LPA. We suggest that PDGF is a bifunctional molecule in mesangial cells that evokes both cell proliferation and cell death simultaneously, whereas LPA is a survival factor. We speculate that PDGF and LPA may play important roles in the progression or exacerbation of proliferative glomerulonephritis.
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PMID:Bimodal effects of platelet-derived growth factor on rat mesangial cell proliferation and death, and the role of lysophosphatidic acid in cell survival. 1141 Jan 9

The endothelium is the first physiological barrier between blood and tissues and can be injured by physical or chemical stress, particularly by the drugs used in cancer therapy. We found that four anticancer agents: etoposide, doxorubicin, bleomycin and paclitaxel induced apoptosis in human umbilical vein endothelial cells (HUVECs) (as judged by DNA fragmentation) with a time- and concentration-dependent decrease in bcl-2 protein but without the involvement of p53. As revealed by immunoblotting, bax protein was expressed in HUVECs treated with 1 mg/ml etoposide whereas bcl-2 protein disappeared. Oncosis occurred parallel to apoptosis with the release of lactate dehydrogenase into the supernatant, and, for doxorubicin and etoposide with the inversion of the distribution of angiotensin I-converting enzyme between supernatant and cells. Among the four tested anticancer drugs, only doxorubicin induced an oxidative stress, with significative malondialdehyde production. Thus, human endothelial cells in confluent cultures seem to be in an equilibrium of resistance to apoptosis related to bcl-2 expression; this equilibrium can be disrupted by a chemical stress, such as the antiproliferative drugs known as pro-apoptotic for tumour cells. For doxorubicin and bleomycin, this cellular toxicity can be related to their unwanted effects in human cancer therapy. Low doses of doxorubicin, paclitaxel or etoposide, however, could induce apoptosis of endothelial cells of new vessels surrounding the tumour, thus leading to specific vessel regression with minimal toxic effects for the endothelium of the other vessels. These findings provide evidence of relationships between endothelial toxicity of anticancer drugs and the key role of bcl-2 for resistance of endothelium cells toward apoptosis; moreover lack of p53 and bax in quiescent cells contributes to resistance of endothelial cells to DNA-damaging agents.
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PMID:Anticancer drugs induce necrosis of human endothelial cells involving both oncosis and apoptosis. 1148 35

This is, to our knowledge, the first report of papillary adenocarcinoma originating in the subvesical bile duct. A 77-year-old man was referred to our hospital for further evaluation of liver dysfunction. Serum liver function test results on admission included: aspartate aminotransferase, 99 IU/l; alanine aminotransferase, 149 IU/l; lactate dehydrogenase, 438 IU/l; alkaline phosphatase, 992 IU/l; leucine aminopeptidase, 320 IU/l; and gamma-glutamyl transpeptidase, 593 IU/l. Serum carbohydrate antigen (CA) 19-9 value was high (80 U/ml). Abdominal ultrasonogram, computed tomographic scan, and percutaneous transhepatic cholangiogram demonstrated a mass in the common hepatic duct, and dilatation of the intrahepatic bile ducts. A laparotomy was performed on May 14, 1997. The tumor originated in the dilated subvesical duct that joined the common hepatic duct, and projected into the common hepatic duct. The patient underwent cholecystectomy, resection of the subvesical duct and the common hepatic duct, dissection of regional pericholedochal lymph nodes, and Roux-en-Y hepaticojejunostomy. The resected tumor presented macroscopically as a papillary mass measuring 4.0 x 2.0 cm. The pathological diagnosis was papillary adenocarcinoma. The immunostaining positivity rates for MIB-1 and p53 protein were 49.6% and 33.8%, respectively.
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PMID:Papillary adenocarcinoma of the subvesical duct. 1170 63


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