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 purpose of this study was to investigate the prognostic implications of BCL6 rearrangement in a uniformly treated population of patients with diffuse large B-cell lymphoma (DLBCL) and to characterise the relationship between BCL6 rearrangement and prognostic factors. A total of 269 patients with DLBCL entered a randomised trial comparing the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) to the MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) regimen. In 44 cases, frozen tissue was available for assessment of BCL6 status by Southern blot analysis. BCL6 was rearranged in six of 43 evaluable cases (14%), and was associated with elevated lactate dehydrogenase (LDH), and a higher patient age. No association between BCL6 status and expression of BCL2, Ki-67 or TP53 was found. Patients presenting with BCL6 rearrangement displayed a weak trend towards better overall and failure-free survival (67 and 67% at 5 years), compared to patients with germline BCL6 (63 and 52%), but the difference was not statistically significant. In accordance with previously published series, the presence of BCL6 rearrangement does not define a prognostically distinct subgroup of DLBCL. Assessment of BCL6 status may, however, be of clinical interest when related to other prognostic variables.
 ...
PMID:Prognostic implications of BCL6 rearrangement in uniformly treated patients with diffuse large B-cell lymphoma--a Nordic Lymphoma Group study. 1174 58

We have reported previously that sigma-2 receptors are expressed in high densities in a variety of tumor cell types (B. J. Vilner et al., Cancer Res., 55: 408-413, 1995) and that various sigma ligands have cytotoxic effects (B. J. Vilner et al., J. Neurosci., 15: 117-134, 1995). Other investigators have demonstrated increased expression of sigma-2 receptors in rapidly proliferating tumors (R. H. Mach et al., Cancer Res., 57: 156-161, 1997) and the ability of some sigma ligands to inhibit proliferation (P. J. Brent and G. T. Pang, Eur. J. Pharmacol., 278: 151-160, 1995). We demonstrate here the ability of sigma-2 receptor agonists to induce cell death by a mechanism consistent with apoptosis. In breast tumor cell lines that are sensitive (MCF-7) and resistant (MCF-7/Adr-, T47D, and SKBr3) to antineoplastic agents, incubation with the sigma-2 subtype-selective agonists CB-64D and CB-184 produced dose-dependent cytotoxicity (measured by lactate dehydrogenase release into medium). The EC(50) for this response was similar across cell lines, irrespective of p53 genotype and drug-resistance phenotype. CB-64D and the subtype nonselective sigma-2 agonists haloperidol and reduced haloperidol induced terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining in MCF-7 and T47D cells, indicating that cell death occurs via apoptosis. Apoptosis was also indicated by increases in Annexin V binding caused by CB-64D. In MCF-7 cells, cytotoxicity and Annexin V binding induced by the antineoplastics doxorubicin and actinomycin D was partially or completely abrogated by certain specific and general inhibitors of caspases. In contrast, caspase inhibitors had no effect on sigma-2 receptor-mediated (CB-64D and CB-184) cytotoxicity or Annexin V binding. Marked potentiation of cytotoxicity was observed when a subtoxic dose of CB-184 was combined with doxorubicin or actinomycin D, both in drug-sensitive (MCF-7) and drug-resistant (MCF-7/Adr-) cell lines. Haloperidol potentiated doxorubicin only in drug-resistant cells. These findings suggest the involvement of a novel p53- and caspase-independent apoptotic pathway used by sigma-2 receptors, which is distinct from mechanisms used by some DNA-damaging, antineoplastic agents and other apoptotic stimuli. These observations further suggest that sigma-2 receptors may be targets that can be therapeutically exploited in the treatment of both drug-sensitive and drug-resistant metastatic tumors.
 ...
PMID:Sigma-2 receptor agonists activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. 1178 94

Redband trout (Oncorhynchus mykiss ssp.) in southeastern Oregon inhabit high-elevation streams that exhibit extreme variability in seasonal flow and diel water temperature. Given the strong influence and potential limitations exerted by temperature on fish physiology, we were interested in how acute temperature change and thermal history influenced the physiological capabilities and biochemical characteristics of these trout. To this end, we studied wild redband trout inhabiting two streams with different thermal profiles by measuring (1) critical swimming speed (U(crit)) and oxygen consumption in the field at 12 degrees and 24 degrees C; (2) biochemical indices of energy metabolism in the heart, axial white skeletal muscle, and blood; and (3) temperature preference in a laboratory thermal gradient. Further, we also examined genetic and morphological characteristics of fish from these two streams. At 12 degrees C, maximum metabolic rate (Mo2max) and metabolic power were greater in Little Blitzen redband trout as compared with those from Bridge Creek (by 37% and 32%, respectively). Conversely, Bridge Creek and Little Blitzen trout had similar values for Mo2max and metabolic power at 24 degrees C. The U(crit) of Little Blitzen trout was similar at the two temperatures (61+/-3 vs. 57+/-4 cm s(-1)). However, the U(crit) for Bridge Creek trout increased from 62+/-3 cm s(-1) to 75+/-3 cm s(-1) when water temperature was raised from 12 degrees to 24 degrees C, and the U(crit) value at 24 degrees C was significantly greater than for Little Blitzen fish. Cost of transport was lower for Bridge Creek trout at both 12 degrees and 24 degrees C, indicating that these trout swim more efficiently than those from the Little Blitzen. Possible explanations for the greater metabolic power of Little Blitzen redband trout at 12 degrees C include increased relative ventricular mass (27%) and an elevation in epaxial white muscle citrate synthase activity (by 72%). Bridge Creek trout had 50% higher lactate dehydrogenase activity in white muscle and presumably a greater potential for anaerobic metabolism. Both populations exhibited a preferred temperature of approximately 13 degrees C and identical mitochondrial haplotypes and p53 gene allele frequencies. However, Bridge Creek trout had a more robust body form, with a relatively larger head and a deeper body and caudal peduncle. In summary, despite the short distance ( approximately 10 km) and genotypic similarity between study streams, our results indicate that phenotypic reorganization of anatomical characteristics, swimming ability at environmentally pertinent temperatures and white axial muscle ATP-producing pathways occurs in redband trout.
 ...
PMID:Metabolism, swimming performance, and tissue biochemistry of high desert redband trout (Oncorhynchus mykiss ssp.): evidence for phenotypic differences in physiological function. 1252 43

ASPP2 interacts with the tumor suppressor protein p53, promotes damage-induced apoptosis, and can specifically stimulate p53 apoptotic function. Thus, ASPP2 may function as a tumor suppressor and/or play a role in the cellular response to cytotoxic injury. To explore the role of ASPP2 in human cancer, we determined ASPP2 expression in two lymphoma subtypes with differing clinical outcomes: diffuse large B-cell lymphoma (DLBCL) and follicular center lymphoma (FCL). A real-time reverse transcription-polymerase chain reaction (RT-PCR) assay was developed to detect ASPP2 mRNA. Sixty-one DLBCL and twenty-three FCL cases were analyzed and normalized ASPP2 levels were expressed relative to an mRNA standard. We found that ASPP2 mean expression strongly correlated with lymphoma subtype: DLBCL = 11.74 and FCL = 4.99 (p = 0.029, unpaired 2-tailed t-test). Importantly, ASPP2 expression was variable in DLBCL but not FCL (DLBCL-range, 0.04-94.6; FCL-range, 1.2-15.0). In these DLBCL cases, serum lactate dehydrogenase (LDH) was an independent predictor of survival with median survival in the high LDH group of 24 months and median survival not achieved in the normal-low LDH group (p = 0.014, Log-Rank Test). Mean ASPP2 levels trended toward an inverse correlation with LDH levels: High LDH, ASPP2 = 6.2; Normal-low LDH, ASPP2 = 18.2 (p = 0.074, unpaired 2-tailed t-test). In the DLBCL cases with ASPP2 levels > 7.8, only 10% (1/10) had a high LDH, in contrast to cases with ASPP2 levels < 7.8 in which 59% (26/44) had a high LDH (p = 0.011, Fisher Exact Test). Thus, low ASPP2 mRNA levels may correlate with poor clinical outcome in lymphoma which is consistent with the hypothesis that ASPP2 may play a role in tumor formation and/or sensitivity to cytotoxic agents. Larger studies as well as analysis of different tumor types are warranted.
 ...
PMID:Apoptosis stimulating protein of p53 (ASPP2) expression differs in diffuse large B-cell and follicular center lymphoma: correlation with clinical outcome. 1261 17

Mechanical load as stimulus for apoptosis and necrosis could be responsible for the loss of cardiomyocytes. Ventricular myocytes from young (3 mo) and old (14-24 mo) rats underwent cyclical mechanical stretch (CMS; 5% elongation, 1 Hz) for 24 h. Spontaneous apoptosis was in myocytes from young rats 0.33 +/- 0.12% and from old rats 1.05 +/- 0.35% [Tdt-mediated dUTP nick-end labeling (TUNEL) assay]; associated with a decrease of Bcl-2. CMS increased the apoptosis to 0.58 +/- 0.18% in myocytes from young rats. Western blot analysis showed that CMS reduced Bcl-2 and increased p53 (young rats). Bax was not changed by CMS. These were confirmed by cytochrome c release (31 +/- 13%) and by the enrichment of cytosolic nucleosomes (11 +/- 8%). CMS did not influence the apoptosis in myocytes from old rats (TUNEL assay, Bcl-2, Bax, or p53). CMS did not cause necrosis in myocytes from young rats. CMS increased the number of necrotic cells by showing the cell membrane rupture in myocytes from old rats (50 +/- 13% 5-hexadecanoylaminofluorescein-positive and 38 +/- 6% propidium iodide-positive cells) as well as by measuring the lactate dehydrogenase release. The results suggest that CMS-induced apoptosis in myocytes of young rats but necrosis in myocytes from old rats, which could be attributed to more stress sensitivity of cells from old rats.
 ...
PMID:Cyclical mechanical stretch-induced apoptosis in myocytes from young rats but necrosis in myocytes from old rats. 1280 17

We have shown previously that nasal natural killer (NK)/T-cell lymphoma was associated with Epstein-Barr virus (EBV) and had peculiar clinical features. However, little is known about its biological and genetic changes. The aim of this study is to determine the p53, N- and K-ras, and beta-catenin status in this lymphoma in relation to EBV status and clinical features. The study group consisted of 32 Japanese patients with nasal NK/T-cell lymphoma. The p53 and beta-catenin expression, phenotype, and EBV-oncogenic protein latent membrane protein type 1 (LMP-1) were determined by immunoperoxidase staining. The presence of EBV-encoded small nuclear early region (EBER) RNA was determined by in situ hybridization. The p53 mutations (exons 5 to 9), N- and K-ras mutations (exons 1 and 2), and beta-catenin mutations (exon 3) were analyzed by direct sequencing of the PCR-amplified products that were obtained from laser-microdissected tissues. CD56, CD43, and CD3 were expressed in 32 (100%), in 31 (96%), and in 18 (56%) tumors, respectively. EBER RNA was detected in 31 (96%) tumors. LMP-1 was expressed in 15 (48%) tumors, and p53 and beta-catenin protein were overexpressed in 18 (56%) and 4 (13%) tumors, respectively. Six mutations of the p53 gene, 1 mutation of each N- and K-ras gene, and 8 mutations of beta-catenin gene were detected in 6 (19%), 1 (3%), and 5 (16%) tumors, respectively. The p53 missense mutation was associated with LMP-1 expression (P = 0.038), but not with p53 overexpression. Kaplan-Meier analysis as well as univariate analysis using Cox proportional hazards model showed that high lactate dehydrogenase (LDH) level (P = 0.009, P = 0.0100, respectively), large cell, immunoblastoid polymorphous histology (P = 0.005, P = 0.0162, respectively), and p53 missense mutations (P = 0.021, P = 0.0342, respectively) were significantly related to worse cause-specific survival. Multivariate analysis showed that p53 missense mutation was the most independent among these 3 factors. Although the incidence of thep53, N- and K-ras, and beta-catenin gene mutations is not high, p53 missense mutation has a prognostic value for aggressive course in nasal NK/T-cell lymphoma.
 ...
PMID:P53, N- and K-Ras, and beta-catenin gene mutations and prognostic factors in nasal NK/T-cell lymphoma from Hokkaido, Japan. 1474 29

Amyloid beta-peptide (Abeta) contributes to the pathogenesis of Alzheimer's disease (AD), causing neuronal death through apoptosis. In this study, the neuroprotective role of small peptides, Gly-Pro-Glu (GPE), Gly-Glu (GE), Gly-Pro-Asp (GPD), and Gly-Pro-Arg (GPR) were examined against Abeta-induced toxicity in cultured rat hippocampal neurons. We report here that GPR (10-100 microM) prevented Abeta-mediated increase in lactate dehydrogenase (LDH) release and Abeta inhibition of MTT reduction, even in neurons that were pre-exposed to Abeta for 24 or 48 h. Since GPR prevented Abeta inhibition of MTT reduction, the anti-apoptotic effect of GPR was studied by examining activation of caspase-3 and expression of p53 protein. Caspase-3 was significantly activated by 20 microM Abeta25-35 and 5 microM Abeta1-40, but GPR effectively prevented the Abeta-mediated activation of caspase-3. Similarly, Abeta increased numbers of p53-positive cells, but GPR prevented this Abeta effect. Our findings suggest that GPR can rescue cultured rat hippocampal neurons from Abeta-induced neuronal death by inhibiting caspase-3/p53-dependent apoptosis.
 ...
PMID:A three amino acid peptide, Gly-Pro-Arg, protects and rescues cell death induced by amyloid beta-peptide. 1476 84

We have investigated the dose (in the range of microM) and time-dependent effects of four different retinoids (retinol, retinal, retinoic acid and retinol palmitate) on human dermal fibroblasts cultivated in vitro. Retinol and retinal, at a concentration of 20 microM, caused cell damage as evaluated by lactate dehydrogenase activity released into the culture medium. The oxidised glutathione (GSSG)/reduced glutathione (GSH) ratio and malondialdehyde production indicated that 20 microM of retinol provoked oxidative stress in the cultivated human fibroblasts. In the first 8 h after retinol treatment the levels of p53 and Bax proteins as well as caspase 3 activity increased, suggesting apoptotic cell death during the first hours of treatment. If the retinol treatment exceeded 18-24 h we observed necrotic cell death. Vitamin E and coenzyme Q(10) had a protective effect against oxidative stress generated by retinol. Both antioxidant molecules reduced retinol uptake, and in the case of vitamin E the expression of CRABP-II mRNA was induced, providing a plausible explanation for its protective effect.
 ...
PMID:Retinol, at concentrations greater than the physiological limit, induces oxidative stress and apoptosis in human dermal fibroblasts. 1500 15

Rituximab is widely used for the treatment of B-cell non-Hodgkin's lymphoma (NHL), and encouraging results have been obtained. However, some CD20-positive NHL show minimal response to rituximab, indicating that the treatment effect depends on the presence or absence of an unidentified factor. We analyzed the relationship between the effect of rituximab plus chemotherapy and expression of Ki-67, p53 and bcl-2 and several clinical variables in cases of B-NHL, particularly follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Forty-four patients were included in the present study, and the overall treatment response rate was 68%. Twelve of 30 patients (40%) achieved a complete response, five (16%) reached an unconfirmed complete response and 13 (43%) achieved a partial response. A high serum lactate dehydrogenase level and International Prognostic Index of high or high intermediate risk were associated with a decreased response in the case of FL. Immunohistochemical assays were performed in 18 FL patients (55%) and 15 DLBCL patients (45%). Significant correlation was found between an inferior response to treatment and high Ki-67 expression in the cases of FL (P = 0.006). p53 and bcl-2 expression did not correlate significantly with the response rate. The cell cycle appears to be an important factor in the efficacy of rituximab treatment. Ki-67 expression might be a predictor of efficacy of rituximab plus chemotherapy.
 ...
PMID:Efficacy of rituximab plus chemotherapy in follicular lymphoma depends on Ki-67 expression. 1536 34

Polybrominated diphenyl ethers (PBDEs) are an important class of flame retardants. Because of their presence in maternal milk and their structural similarity to polychlorinated biphenyls (PCBs), concern has been raised on their possible developmental neurotoxicity. Aim of the present study was to investigate the in vitro effects of PBDE-99 (2,2', 4,4', 5-pentabromodiphenyl ether) on astroglial cells (human 132-1N1 astrocytoma cells) and comparing it with those of the PCB mixture Aroclor 1254. Both PBDE-99 and Aroclor 1254 caused a concentration-dependent inhibition of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) reduction, however, only the latter increased lactate dehydrogenase (LDH) release or cell death, assessed by the trypan blue assay. PBDE-99 caused translocation of the three protein kinase C (PKC) isozymes (alpha, epsilon, zeta) present in 132-1N1 astrocytoma cells, while Aroclor 1254 affected only PKCalpha and epsilon translocation. However, pre-incubation with the PKC inhibitor GF109203X or PKC down-regulation by the phorbol ester PMA, had minimal or no effect on PBDE-99 or Aroclor 1254-induced cytotoxicity. Similarly, the calcium chelator BAPTA-AM, the tyrosine kinase inhibitor genistein, and the MEK (mitogen activated protein kinase kinase) inhibitor PD98059 had no effect on PBDE-99 and Aroclor 1254 cytoxicity. On the other hand, the phosphatidylinositol 3 kinase (PI-3K) inhibitor LY290042 enhanced PBDE-99 toxicity, but did not affect Aroclor 1254. Because of the involvement of PI-3K in apoptotic cell death, the ability of PBDE-99 and Aroclor 1254 to induce apoptosis in astrocytoma cells was investigated. PBDE-99, but not Aroclor 1254, caused apoptotic cell death in astrocytoma cells, assessed by the TUNEL method and by Hoechst 33258 staining, via a p53 dependent mechanism. These results suggest that PBDE-99 and Aroclor 1254 exert differential cytotoxic effects on human astroglial cells.
 ...
PMID:Differential in vitro neurotoxicity of the flame retardant PBDE-99 and of the PCB Aroclor 1254 in human astrocytoma cells. 1547 74


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