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)

While clinical progress in the treatment of soft-tissue sarcoma is rather slow, some major contributions to the understanding of oncogenesis of these rare tumors have been achieved in the last decade. The central role of cell cycle regulation has been demonstrated in hereditary (p53, RB) and somatic mutations or variant expression of genes associated with cell cycle regulation (p53, BCL2, MDM2). For a subset of soft tissue sarcomas harboring chromosomal translocations, fusion genes resulting from these specific translocations were cloned and characterized. The clinical use of these fusion genes may not be restricted to diagnosis and prognosis, since these may serve as specific targets for molecular and immunologic therapy approaches.
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PMID:[What is the value of recent molecular biology knowledge for surgical oncologic therapy of soft tissue sarcoma?]. 993 48

A unique subclone of a bone marrow-derived stromal cell line, BMS2.4, produces soluble factors that inhibit proliferation of several types of hematopoietic cell lines. An understanding of these molecules may be informative about negative regulatory circuits that can potentially limit blood cell formation. We used expression cloning to identify interleukin-6 (IL-6) as one factor that suppressed growth of a pre-B-cell variant line, 1A9-M. Moreover, IL-6 induced macrophage-differentiation and apoptosis of 1A9-M cells. During this process, IL-6 downregulated expression of BCL2 in 1A9-M cells and stimulated BCL-XL expression, but had no effect on p53, Bax, or Bak gene expression. Mechanisms for transduction of IL-6-induced signals were then evaluated in IL-6-stimulated 1A9-M cells. Whereas the signal transducer and activator of transcription 3 (Stat3) was phosphorylated and activated, there was no effect on either Stat1 or Stat5. The importance of BCL2 and Stat3 on IL-6-induced macrophage-differentiation and apoptosis was studied with 1A9-M cells expressing human BCL2 or a dominant-negative form of Stat3, respectively. IL-6-induced apoptosis, but not macrophage-differentiation, was blocked by continuously expressed BCL2. A dominant-negative form of Stat3 inhibited both macrophage-differentiation and apoptosis induced by IL-6. However, diminished Stat3 activity did not prevent IL-6-induced downregulation of the BCL2 gene. Therefore, activation of Stat3 is essential for IL-6-induced macrophage-differentiation and programmed cell death in this model. Whereas overexpression of BCL2 abrogates the apoptotic response, Stat3-independent signals appear to downregulate expression of the BCL2 gene.
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PMID:Both Stat3-activation and Stat3-independent BCL2 downregulation are important for interleukin-6-induced apoptosis of 1A9-M cells. 994 78

Cells of the TP53-deficient human leukemia cell line HL60 continue to progress throughout the cell cycle and arrest in the G2/M phase during protracted exposure to exponentially decreasing low-dose-rate radiation. We have hypothesized that G2/M-phase arrest contributes to the extent of radiation-induced cell death by apoptosis as well as to overall cell killing. To test this hypothesis, we used caffeine and nocodazole to alter the duration of G2/M-phase arrest of HL60 cells exposed to exponentially decreasing low-dose-rate irradiation and measured the activity of G2/M-phase checkpoint proteins, redistribution of cells in the phases of the cell cycle, cell death by apoptosis, and overall survival after irradiation. The results from these experiments demonstrate that concomitant exposure of HL60 cells to caffeine (2 mM) during irradiation inhibited radiation-induced tyrosine 15 phosphorylation of the G2/M-phase transition checkpoint protein CDC2/p34 kinase and reduced G2/M-phase arrest by 40-46% compared to cells irradiated without caffeine. Radiation-induced apoptosis also decreased by 36-50% in cells treated with caffeine and radiation compared to cells treated with radiation alone. Radiation survival was significantly increased by exposure to caffeine. In contrast, prolongation of G2/M-phase arrest by pre-incubation with nocodazole enhanced radiation-induced apoptosis and overall radiation-induced cell killing. To further study the role of cell death by apoptosis in the response to exponentially decreasing low-dose-rate irradiation, HL60 cells were transfected with the BCL2 proto-oncogene. The extent of G2/M-phase arrest was similar for parental, neomycin-transfected control and BCL2-transfected cells during and after exponentially decreasing low-dose-rate irradiation. However, there were significant differences (P < 0.01) in the extent of radiation-induced apoptosis of parental and neomycin- and BCL2-transfected cells after irradiation, with significantly less radiation-induced apoptosis and higher overall survival in BCL2-transfected cells than similarly irradiated control cells. These data demonstrate that radiation-induced G2/M-phase arrest and subsequent induction of apoptosis play an important role in the response of HL60 cells to low-dose-rate irradiation and suggest that it may be possible to increase radiation-induced apoptosis by altering the extent of G2/M-phase arrest. These findings are clinically relevant and suggest a novel therapeutic strategy for increasing the efficacy of brachytherapy and radioimmunotherapy.
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PMID:G2/M-phase arrest and death by apoptosis of HL60 cells irradiated with exponentially decreasing low-dose-rate gamma radiation. 1036 Jul 85

Mantle cell lymphomas (MCLs) are characterized by 11q13 chromosomal translocations and cyclin D1 overexpression. The secondary genetic and molecular events involved in the progression of these tumors are not well known. In this study, we have analyzed 45 MCLs (32 typical and 13 blastoid variants) by comparative genomic hybridization (CGH). To identify the possible genes included in the abnormal chromosome regions, selected cases were analyzed for P53, P16(INK4a), RB, C-MYC, N-MYC, BCL2, BCL6, CDK4, and BMI-1 gene alterations. The most frequent imbalances detected by CGH were gains of chromosomes 3q (49%), 7p (27%), 8q (22%), 12q (20%), 18q (18%), and 9q34 (16%) and losses of chromosomes 13 (44%), 6q (27%), 1p (24%), 11q14-q23 (22%), 10p14-p15 (18%), 17p (16%), and 9p (16%). High-level DNA amplifications were identified in 11 different regions of the genome, predominantly in 3q27-q29 (13%), 18q23 (9%), and Xq28 (7%). The CGH analysis allowed the identification of regional consensus areas in most of the frequently involved chromosomes. Chromosome gains (P =. 02) and losses (P =.01) and DNA amplifications (P =.015) were significantly higher in blastoid variants. The significant differences between blastoid and typical tumors were gains of 3q, 7p, and 12q, and losses of 17p. CGH losses of 17p correlated with P53 gene deletions and mutations. Similarly, gains of 12q and high-level DNA amplifications of 10p12-p13 were associated with CDK4 and BMI-1 gene amplifications, respectively. One of 2 cases with 8q24 amplification showed C-MYC amplification by Southern blot. Alterations in 2p, 3q, 13, and 18q were not associated with N-MYC, BCL6, RB, or BCL2 alterations, respectively, suggesting that other genes may be the targets of these genetic abnormalities in MCLs. Increased number of gains (0 v 1-4 v >4 gains per case) (P =.002), gains of 3q (P =.02), gains of 12q (P =.03), and losses of 9p (P =. 003) were significantly associated with a shorter survival of the patients. These results indicate that an increased number of chromosome imbalances are associated with blastoid variants of MCLs and may have prognostic significance.
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PMID:Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants. 1036 Nov 35

Small cell lung cancer (SCLC) is common in men and women, has a very poor prognosis, and is therefore a major cause of premature mortality. As such, any prospects for improved therapy are of great significance. The promise of telomerase as a therapeutic target is now close to realization with extremely encouraging preclinical studies aimed at the RNA component (hTR) of telomerase. The rational integration of telomerase therapeutics into clinical trials will therefore require tumours to be well characterized for hTR expression. Despite the large number of cancer types now characterized for telomerase or telomerase component gene expression, only a handful of SCLC samples have been analysed. Given the major clinical problem with treating SCLC, we specifically set out to address the issue of hTR expression in neuroendocrine tumours. Our study covers 91 pulmonary neuroendocrine tumours (62 SCLC and 29 carcinoid tumours). We present data to show that upregulation of the RNA component of telomerase occurs in 98% of human SCLCs. Interestingly, the less aggressive carcinoid tumours of the lung had a significantly lower frequency of hTR expression (P < 0.01). Importantly, we compare hTR expression in this series to the well characterized biological targets p53 and BCL2, and show hTR to be expressed more frequently. Therapies directed at the RNA component of human telomerase are in active development and these data show SCLC to be a prime target for such therapies.
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PMID:Is small cell lung cancer the perfect target for anti-telomerase treatment? 1042 23

In the 30 years since the introduction of cisplatin into the clinic, laboratory studies have provided considerable information as to both how the drug exerts its antitumour effects and how some tumours are, or become, resistant. Once inside a cell, the chlorine groups of cisplatin are exchanged for water (aqua) species, which are more chemically reactive. The intracellular target for cisplatin is DNA, where a variety of adducts are formed, some on the same strand of DNA (intrastrand adducts) and others between strands (interstrand adducts). Of the 4 bases, guanine is the preferred site for binding and the most common adduct involves linkages on 2 adjacent guanines on the same strand of DNA. It remains uncertain which of the various types of adduct is the most important in terms of producing antitumour effects. Resistance to cisplatin has been studied extensively using tumour cells repeatedly exposed to the drug in vitro. In these cell models, resistance is generally due to a combination of mechanisms, some resulting in reduced damage to DNA and others following DNA damage. Resistance due to inadequate binding to DNA has been shown to be caused by reduced drug uptake (influx rather than efflux) and inactivation by thiol-containing species such as glutathione and metallothioneins. Resistance occurring post-DNA binding may be due to changes in DNA repair pathways [an increase in nucleotide excision repair (NER) or a loss of DNA mismatch repair (MMR)]. Conversely, the hypersensitivity of some cell lines to cisplatin has been shown to be due to defective NER, through loss or reduced expression of NER proteins such as XPG and XPA. Resistance may also be mediated through alterations in proteins involved in programmed cell death (apoptosis) such as p53 and the BCL2 family. A basic understanding of cisplatin resistance pathways has made a major impact in the development of new platinum analogues capable of circumventing resistance. Examples (which are now undergoing clinical trial) include ZD0473 (which, relative to cisplatin, possesses a reduced reactivity towards inactivating thiol-containing molecules) and the trinuclear platinum BBR3464 (which has markedly different DNA binding properties compared with cisplatin).
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PMID:Preclinical perspectives on platinum resistance. 1086 25

To dissect the p53-dependent apoptotic pathway, events following induction of temperature sensitive (ts) p53val138 were studied in a Ewing tumor cell line. Transcriptional deregulation of p53 targets first observable after 1 h at 32 degrees C preceded activation of caspases and the break-down of mitochondrial respiratory activity. Activation of caspases was first observed 4 h after p53 induction. Using peptide inhibitors we identified activation of caspase 8 upstream of caspases-9 and -3. Although the caspase 8 specific inhibitor z-IETD.fmk did not affect translocation of BAX to the mitochondrial membrane and cytochrome C release it almost completely blocked cleavage of the prototype caspase substrate PARP and DNA fragmentation while enforcing mitochondrial depolarization and production of reactive oxygene species (ROS). Activation of caspase 8 did not involve death-domain receptor signaling. Expression of BCL2 only partially suppressed caspase activation but blocked apoptosis. Replacement of the N-terminus of p53val138 by the related VP16 transactivation domain created a ts p53 with a tanscriptional activity indistinguishable from p53val138 until the time of caspase activation. However, the VP16 - p53 fusion failed to trigger caspases and subsequent induction of the ROS producing gene pig3 paralleled by complete loss of apoptotic activity. These results indicate that p53-dependent transcriptional deregulation, triggering of the caspase cascade and the mitochondrial break-down occur in a timely ordered sequence coordinated by the genuine p53 amino terminus and suggest caspase 8 and PIG3 as key regulatory elements in this process. Oncogene (2000) 19, 4096 - 4107
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PMID:Characterization of distinct consecutive phases in non-genotoxic p53-induced apoptosis of Ewing tumor cells and the rate-limiting role of caspase 8. 1096 70

We report the results of a collaborative study aimed at developing reliable, direct assays for mutation in human cells. The project used common lymphoblastoid cell lines, both with and without mutagen treatment, as a shared resource to validate the development of new molecular methods for the detection of low-level mutations in the presence of a large excess of normal alleles. As the "gold standard, " hprt mutation frequencies were also measured on the same samples. The methods under development included i) the restriction site mutation (RSM) assay, in which mutations lead to the destruction of a restriction site; ii) minisatellite length-change mutation, in which mutations lead to alleles containing new numbers of tandem repeat units; iii) loss of heterozygosity for HLA epitopes, in which antibodies can be used to direct selection for mutant cells; iv) multiple fluorescence-based long linker arm nucleotides assay (mf-LLA) technology, for the detection of substitutional mutations; v) detection of alterations in the TP53 locus using a (CA) array as the target for the screening; and vi) PCR analysis of lymphocytes for the presence of the BCL2 t(14:18) translocation. The relative merits of these molecular methods are discussed, and a comparison made with more "traditional" methods.
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PMID:Molecular methods for the detection of mutations. 1107 20

We have used a sensitive and reproducible method of measuring mRNA expression to compare basal levels of 10 transcripts in the 60 cell lines of the National Cancer Institute's in vitro anticancer drug screen (NCI-ACDS) under conditions of exponential growth. The strongest correlation among these target genes was between levels of CIP1/WAF1 and BAX. Levels of the three major growth arrest and DNA damage-inducible gene transcripts, (GADD34, GADD45, and GADD153), which are coordinately regulated in response to many stresses, were also correlated across the 60 cell lines. Although the stress induction of several of the transcripts studied here has been shown to be dependent on wild-type p53 status, basal levels of only CIP1/WAF1 and BAX were found to correlate with p53 status. As expected, basal expression of O6 alkyl guanine alkyl-transferase correlated well with resistance to O6-alkylating agents (r = -0.44) but not with resistance to alkylators with different mechanisms of action (r = -0.04). When basal expression levels of the 10 genes across the NCI-ACDS panel were compared with sensitivities to a panel of 122 standard chemotherapy agents, the most striking relationship was a strong negative correlation (r = -0.3) between basal BCL-X levels and sensitivity to drugs in all of the mechanistic classes except one class of antimetabolites. Sensitivities to a maximally diverse sample of 1200 from 70,000 compounds tested in the NCI-ACDS of agents were also negatively correlated with BCL-X levels. A novel application of factor analysis revealed that the newly discovered associations were independent of previously demonstrated sensitivity factors such as p53 mutation status and native population doubling time. A similar pattern of correlation was seen for Bcl-X(L) protein levels. Conversely, BAX and BCL2, two other genes associated with regulation of apoptosis, showed no overall correlation with drug sensitivities. This suggests that BCL-X may play a unique role in general resistance to cytotoxic agents, with the cell lines demonstrating relative resistance to 70,000 cytotoxic agents in the NCI-ACDS being characterized by high BCL-X expression.
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PMID:An informatics approach identifying markers of chemosensitivity in human cancer cell lines. 1108 34

Transient expression of the tumor suppressor gene p53 via adenoviral-mediated gene transfer induces apoptosis in glioma cells expressing mutant p53, while causing cell cycle arrest in cells with wild-type p53. To determine whether a change in p53 status of a wild-type p53-expressing cell line such as U-87 MG would alter its apoptotic resistant phenotype in response to Ad-p53 infection, we generated cell lines U-87-175.4 and U-87-175.13 via retroviral-mediated gene transfer of the p53 (175H) mutant into the U-87 MG parental line. Control cell lines U-87-Lux.6 and U-87-Lux.8 were also generated and express the reporter gene luciferase. Both U-87-175.4 and U-87-175.13, but not control cell lines, exhibited morphology characteristic of apoptosis after Ad-p53 infection. Furthermore, expression of other p53 mutants (248W, 273H) in U-87 MG also sensitized cells to Ad-p53-induced apoptosis. Apoptosis was confirmed by TUNEL and cell cycle analysis. Several p53 response genes were examined in cells infected with Ad-p53, and among these, BCL2, p21WAF1/CIP1, CPP32/caspase 3, and PARP showed differences in expression between U87-175 and U87-Lux cell lines. Taken together, our data demonstrate that the introduction of p53 mutants in U-87 MG promotes an apoptotic response in association with adenoviral-mediated wild-type p53 gene transfer. These results underscore the importance of glioma p53 genotype for predicting tumor response to p53-based gene therapy.
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PMID:Introduction of mutant p53 into a wild-type p53-expressing glioma cell line confers sensitivity to Ad-p53-induced apoptosis. 1129 82


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