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)

Recent advance in cell-molecular biological studies have revealed various prognostic factors in lung cancer. The aim of this paper is to critically review the current status of molecular biological prognostic markers in non-small cell lung cancer. DNA ploidy, AgNORs and PCNA as marker of tumor cellular proliferative activity are reported to be a prognostic marker but still remain controversial. The proteases such as uPA, MMPs and CB catalyze degradation of the extracellular matrix and basement membranes. Although the prognostic implications of the uPA and MMPs still remain unclear, cathepsin B appears to be one of the most useful prognostic markers so far reported for non-small cell lung cancer. In a number of studies, genetic abnormalitis has been reported to be a prognostic marker in cancer patients. In non-small cell lung cancer, the prognostic implication of the altered p53 expression or ras p21 expression still remain unclear, especially p53 is conflicting. The most useful clinical prognostic marker may be obtained by the combined analysis of some prognostic information.
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PMID:[Molecular biological prognostic markers in lung cancer]. 904 11

The aim of this study was to assess the relation between silver-strained nucleolar organizer regions (AgNOR), tumor stage, tumor grade and p53 expression with cathepsin B staining in transitional cell carcinoma of bladder. Tissue sections from 64 transitional cell carcinomas of the bladder were evaluated for the relation between AgNOR, tumor stage, tumor grade and p53 expression with cathepsin B staining in the neoplastic and stromal cells. Mean AgNOR values were significantly higher and the presence of p53 expression were different in cathepsin B positive and negative tumor and stromal cells. Although the number of cases is limited, this pilot study shows that cathepsin B staining may have a prognostic value in transitional cell carcinoma, but more studies are needed for a definite conclusion.
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PMID:Cathepsin B, p53 expression and AgNORs in transitional cell carcinoma. 1021 Jan 9

The deoxyadenosine-resistant mouse leukemia L1210 cell line (Y8) has previously been shown to have phenotypic differences that appear to be unrelated to the altered properties observed at the level of ribonucleotide reductase (RR). One of these changes is that the Y8 cells do not express p53. In response to DNA damaging agents, x-irradiation and doxorubicin, both the parental wild-type L1210 (WT) and Y8 cells undergo G2/M arrest, which is consistent with cells lacking wild-type p53 function. However, Y8 cells are much more sensitive to apoptosis induced by these agents than WT cells. Previous studies have also shown that expression of certain genes involved in cell cycle regulation is different between WT and Y8 cells. Recent evidence suggests that a serine/threonine kinase is involved in the divergent cellular responses of these cells. In the present study, the effects of roscovitine, a cyclin-dependent kinase inhibitor, were examined on the WT and Y8 cells. The WT cells blocked in G2/M, whereas Y8 cells became apoptotic. Apoptosis induced by roscovitine in the Y8 cells was mediated by a caspase-3-like activity. NF kappa B was activated to a much greater extent by roscovitine in the WT cells than in Y8 cells. The data also indicate that cyclin B1/cdc2 plays a role in the divergent p53-independent G2/M block and apoptotic responses of the WT and Y8 cells, respectively. Several key factors such as cathepsin B, caspase-1, release of cytochrome c into the cytosol, TNF-alpha signaling, FasL/Fas signaling, c-myc overexpression, and E2F-1 overexpression and induction were shown not to be involved in the apoptotic pathway(s) in the Y8 cells.
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PMID:Enhanced roscovitine-induced apoptosis is mediated by a caspase-3-like activity in deoxyadenosine-resistant mouse leukemia L1210 cells. 1113 34

One of the major challenges of early-stage breast cancer is to select the adjuvant therapy that ensures the most benefits and the least harm for the patient. The definition of accurate predictive factors is therefore of paramount importance. So far the choice of adjuvant therapy has been based on the number of affected lymph nodes and the hormone receptor status of the patient. This paper evaluates the use of other tumor-related markers as predictive factors for adjuvant therapy. These include HER2, p53 and Bcl-2, cathepsin B, p27, proliferating cell nuclear antigen (PCNA), cyclin D, Ki-67, and vascular endothelial growth factor (VEGF).
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PMID:Predictive factor for the response to adjuvant therapy with emphasis in breast cancer. 1173 86

Sphingosine kinase 1 (SK1), a key enzyme in sphingosine 1-phosphate (S1P) synthesis, regulates various aspects of cell behavior, including cell survival and proliferation. DNA damaging anti-neoplastic agents have been shown to induce p53, ceramide levels, and apoptosis; however, the effects of anti-neoplastic agents on SK have not been assessed. In this study, we investigated the effects of a DNA damaging agent, actinomycin D (Act D), on the function of sphingosine kinase (SK1). Act D caused a reduction in the protein levels of SK1, as indicated by Western blot analysis, with a concomitant decrease in SK activity. The down-regulation was post-transcriptional, because the mRNA levels of SK1 remained unchanged. Similar decreases in SK1 protein were observed with other DNA damaging agents such as doxorubicin, etoposide, and gamma-irradiation. ZVAD, the pancaspase inhibitor, and Bcl-2 annulled the effect of Act D on SK1, demonstrating a role for cysteine proteases downstream of Bcl-2 in the down-regulation of SK1. Inhibition of caspases 3, 6, 7, and 9 only partially reversed Act D-induced SK1 loss. Inhibition of cathepsin B, a lysosomal protease, produced a significant reversal of SK1 decline by Act D, suggesting that a multitude of ZVAD-sensitive cysteine proteases downstream of Bcl-2 mediated the SK1 decrease. When p53 up-regulation after Act D treatment was inhibited, SK1 down-regulation was rescued, demonstrating p53 dependence of SK1 modulation. Treatment of cells with S1P, the product of SK1, partially inhibited Act D-induced cell death, raising the possibility that a decrease in SK1 may be in part necessary for cell death to occur. Furthermore, the knockdown of SK1 by small interfering RNA in MCF-7 cells resulted in a significant reduction in cell viability. These studies demonstrate that SK1 is down-regulated by genotoxic stress, and that basal SK1 function may be necessary for the maintenance of tumor cell growth.
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PMID:Down-regulation of sphingosine kinase-1 by DNA damage: dependence on proteases and p53. 1498 93

The p53 tumor-suppressor protein is a critical mediator of cellular growth arrest and the induction of apoptosis. To identify proteins involved in the modulation of p53 transcriptional activity, a gain-of-function cellular screen was carried out with an arrayed matrix of approximately 20,000 cDNAs. Nine genes previously unknown to be involved in regulating p53 activity were identified. Overexpression of seven of these genes (Hey1, Hes1, TFAP4, Osr1, NR2F2, SFRS10, and FLJ11339) resulted in up-regulation of p53 activity; overexpression of two genes (M17S2 and cathepsin B) resulted in down-regulation of p53 activity in mammalian cells. HES1, HEY1, and TFAP4, which are members of the basic helix-loop-helix transcription family, and OSR1 were shown to activate p53 through repression of HDM2 transcription. Ectopic expression of these basic helix-loop-helix transcription factors in both zebrafish and avian developmental systems activated p53 and induced apoptosis in vivo, resulting in a phenotype similar to that of p53 overexpression. Furthermore, ras- and myc-mediated transformation of mouse embryonic fibroblasts was abrogated by expression of HEY1 in a p53-dependent manner. These results suggest that these transcription factors are members of an evolutionarily conserved network that governs p53 function.
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PMID:Identification of p53 regulators by genome-wide functional analysis. 1499 Jul 90

The p53 protein activates cellular death programs through multiple pathways. Because the high frequency of p53 mutations in human tumors is believed to contribute to resistance to commonly used chemotherapeutic agents, it is important to identify drugs that induce p53-independent cell death and to define the mechanisms of action of such drugs. Here we screened a drug library (the National Cancer Institute mechanistic set; 879 compounds with diverse mechanisms of actions) and identified 175 compounds that induced caspase cleavage of cytokeratin-18 in cultured HCT116 colon cancer cells at <5 microM. Interestingly, whereas most compounds elicited a stronger apoptotic response in cells with functional p53, significant apoptosis was observed also in p53-null cells. A subset of 15 compounds showing weak or no dependence on p53 for induction of apoptosis was examined in detail. Of these compounds, 11 were capable of activating caspase-3 in enucleated cells. Seven such compounds with nonnuclear targets were found to induce lysosomal membrane permeabilization (LMP). Translocation of the lysosomal proteases cathepsin B and cathepsin D into the cytosol was observed after treatment with these drugs, and apoptosis was inhibited by pepstatin A, an inhibitor of cathepsin D. Apoptosis depended on Bax, suggesting that LMP induced a mitochondrial apoptotic pathway. We conclude that a large number of potential anticancer drugs induce p53-independent apoptosis and that LMP is a mediator of many such responses.
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PMID:Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis. 1561 92

We determined one mechanism by which the putative phosphoinositide-dependent kinase (PDK)-1 inhibitor 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}acetamide (OSU-03012) killed primary human glioma and other transformed cells. OSU-03012 caused a dose-dependent induction of cell death that was not altered by p53 mutation, expression of ERBB1 vIII, or loss of phosphatase and tensin homolog deleted on chromosome 10 function. OSU-03012 promoted cell killing to a greater extent in glioma cells than in nontransformed astrocytes. OSU-03012 and ionizing radiation caused an additive, caspase-independent elevation in cell killing in 96-h viability assays and true radiosensitization in colony formation assays. In a cell type-specific manner, combined exposure to OSU-03012 with a mitogen-activated protein kinase kinase 1/2 inhibitor, phosphoinositide 3-kinase/AKT inhibitors, or parallel molecular interventions resulted in a greater than additive induction of cell killing that was independent of AKT activity and caspase function. OSU-03012 lethality as a single agent or when combined with signaling modulators was not modified in cells lacking expression of BIM or of BAX/BAK. OSU-03012 promoted the release of cathepsin B from the lysosomal compartment and release of AIF from mitochondria. Loss of BH3-interacting domain (BID) function, overexpression of BCL(XL), and inhibition of cathepsin B function suppressed cell killing and apoptosis-inducing factor (AIF) release from mitochondria. In protein kinase R-like endoplasmic reticulum kinase-/- cells, the lethality of OSU-03012 was attenuated which correlated with reduced cleavage of BID and with suppression of cathepsin B and AIF release into the cytosol. Our data demonstrate that OSU-03012 promotes glioma cell killing that is dependent on endoplasmic reticulum stress, lysosomal dysfunction, and BID-dependent release of AIF from mitochondria, and whose lethality is enhanced by irradiation or by inhibition of protective signaling pathways.
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PMID:OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells. 1662 74

Previous studies found that kainic acid (KA)-induced apoptosis involved the lysosomal enzyme cathepsin B, suggesting a possible mechanism of autophagy in excitotoxicity. The present study was sought to investigate activation and contribution of autophagy to excitotoxic neuronal injury mediated by KA receptors. The formation of autophagosomes was observed with transmission electron microscope after excitotoxin exposure. The contribution of autophagic mechanisms to KA-induced upregulation of microtubule-associated protein 1A/1B light chain 3 (LC3), lysosome- associated membrane protein 2 (LAMP2) and cathepsin B, release of cytochrome c, activation of caspase-3, down-regulation of Bcl-2, upregulation of Bax, p53, puma and apoptotic death of striatal neurons were assessed with co-administration of the autophagy inhibitor 3-methyladenine (3-MA). These studies showed that KA brought about an increase in the formation of autophagosomes and autolysosomes in the cytoplasm of striatal cells. KA-induced increases in the ratio of LC3-II/LC3-I, LAMP2, cathepsin B, release of cytochrome c and activation of caspase-3 were blocked by pre-treatment with 3-MA. 3-MA also reversed KA-induced down-regulation of Bcl-2 and upregulation of Bax protein levels, LC3, p53 and puma mRNA levels in the striatum. KA-induced internucleosomal DNA fragmentation and loss of striatal neurons were robustly inhibited by 3-MA. These results suggest that over-stimulation of KA receptors can activate autophagy. The autophagic mechanism participates in programmed cell death through regulating the mitochondria-mediated apoptotic pathway.
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PMID:An autophagic mechanism is involved in apoptotic death of rat striatal neurons induced by the non-N-methyl-D-aspartate receptor agonist kainic acid. 1809 25

Fanconi anemia (FA) cells are generally hypersensitive to DNA cross-linking agents, implying that mutations in the different FANC genes cause a similar DNA repair defect(s). By using a customized cDNA microarray chip for DNA repair- and cell cycle-associated genes, we identified three genes, cathepsin B (CTSB), glutaredoxin (GLRX), and polo-like kinase 2 (PLK2), that were misregulated in untreated primary fibroblasts from three unrelated FA-D2 patients, compared to six controls. Quantitative real-time RT PCR was used to validate these results and to study possible molecular links between FA-D2 and other FA subtypes. GLRX was misregulated to opposite directions in a variety of different FA subtypes. Increased CTSB and decreased PLK2 expression was found in all or almost all of the analyzed complementation groups and, therefore, may be related to the defective FA pathway. Transcriptional upregulation of the CTSB proteinase appears to be a secondary phenomenon due to proliferation differences between FA and normal fibroblast cultures. In contrast, PLK2 is known to play a pivotal role in processes that are linked to FA defects and may contribute in multiple ways to the FA phenotype: PLK2 is a target gene for TP53, is likely to function as a tumor suppressor gene in hematologic neoplasia, and Plk2(-/-) mice are small because of defective embryonal development.
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PMID:Microarray mRNA expression analysis of Fanconi anemia fibroblasts. 1854 20


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