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 advent of DNA microarray technology will likely have a major impact on the molecular classification and understanding of human cancer. Obtaining a global perspective of proteins expressed in cancer cells is considerably more challenging. Here we describe a microarray-based platform that can be used to measure protein levels and activities in a complex biological milieu such as a cellular lysate. Using a protein microarray made up of 1920 elements (146 distinct antibodies) we were able to monitor alterations of protein levels in LoVo colon carcinoma cells treated with ionizing radiation. The protein microarray approach revealed radiation-induced up-regulation of apoptotic regulators including p53, DNA fragmentation factor 40/caspase activated DNase, DNA fragmentation factor 45/inhibitor of caspase activated DNase, tumor necrosis factor-related apoptosis-inducing ligand, death receptor 5, decoy receptor 2, FLICE-like inhibitory protein, signal transducers and activators of transcription 1alpha, and uncoupling protein 2, among others. Consistent with this observation, an increased percentage of apoptosis was observed in irradiated LoVo cells. Interestingly, we also observed radiation-induced down-regulation of carcinoembryonic antigen, a prototypic cancer biomarker. Selected proteins assessed by microarray were validated by traditional immunoblotting. Taken together, our work suggests that protein/antibody microarrays will facilitate high-throughput proteomic studies of human cancer and carcinogenesis.
 ...
PMID:Profiling of cancer cells using protein microarrays: discovery of novel radiation-regulated proteins. 1160 98

The death receptor 5 (DR5) is a receptor for tumor necrosis factor-related apoptosis-inducing ligand and is able to induce apoptosis in various tumor cells. The expression of DR5 is up-regulated at the transcriptional level by p53, genotoxic stress and so on. To investigate the structure of the DR5 gene promoter, we screened and sequenced a genomic clone containing the 5'-flanking region of the DR5 gene. RNase protection assays showed two major transcription start sites around -122 and -137 upstream of the translation initiation codon ATG. Transient transfections with serial 5'-deletion mutants identified the minimal promoter element spanning -198 to -116. Site-directed mutagenesis demonstrated that the DR5 gene promoter has no typical TATA-box, but has two Sp1 sites responsible for the basal transcription activity of the DR5 gene promoter.
 ...
PMID:Promoter structure and transcription initiation sites of the human death receptor 5/TRAIL-R2 gene. 1169 76

Many malignant glioma cells express death receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), yet some of these cells are resistant to TRAIL. Here, we examined signaling events in TRAIL-induced apoptosis and searched for therapeutic agents that could overcome TRAIL resistance in glioma cells. TRAIL induced apoptosis through death receptor 5 (DR5) and was mediated by caspase-8-initiated extrinsic and intrinsic mitochondrial pathways in sensitive glioma cell lines. TRAIL also triggered apoptosis in resistant glioma cell lines through the same pathways, but only if the cells were pretreated with chemotherapeutic agents, cisplatin, camptothecin and etoposide. Previous studies suggested that this was due to an increase in DR5 expression in wild-type TP53 cells, but this mechanism did not account for cells with mutant TP53. Here, we show that a more general effect of these agents is to downregulate caspase-8 inhibitor c-FLIP(S) (the short form of cellular Fas-associated death domain-fike interleukin-1-converting enzyme-inhibitory protein) and up-regulate Bak, a pro-apoptotic Bcl-2 family member, independently of cell's TP53 status. Furthermore, we showed that TRAIL alone or in combination with chemotherapeutic agents, induced apoptosis in primary tumor cultures from patients with malignant gliomas, reinforcing the potential of TRAIL as an effective therapeutic agent for malignant gliomas.
 ...
PMID:TRAIL triggers apoptosis in human malignant glioma cells through extrinsic and intrinsic pathways. 1465 59

The transcription factor nuclear factor kappaB (NF-kappaB) regulates the expression of both anti-apoptotic and proapoptotic genes. Death receptor 5 (DR5, TRAIL-R2) is a proapoptotic protein considered to be a potential target for cancer therapy, and its expression is mediated by NF-kappaB. The mechanism of NF-kappaB-induced DR5 expression is, however, unknown. Herein, we determined that etoposide-induced DR5 expression requires the first intronic region of the DR5 gene. Mutation of a putative NF-kappaB binding site in this intron eliminates DR5 promoter activity, as do mutations in the p53 binding site in this region. Reduction in p53 expression also blocks p65 binding to the intronic region of the DR5 gene, indicating cooperation between p53 and p65 in DR5 expression. In contrast, the anti-apoptotic stimulus, epidermal growth factor (EGF), fails to increase DR5 expression but effectively activates NF-kappaB and induces p65 binding to the DR5 gene. EGF, however, induces the association of histone deacetylase 1 (HDAC1) with the DR5 gene, whereas etoposide treatment fails to induce this association. Indeed, HDAC inhibitors activate NF-kappaB and p53 and upregulate DR5 expression. Blockage of DR5 activation decreased HDAC inhibitor-induced apoptosis, and a combination of HDAC inhibitors and TRAIL increased apoptosis. This provides a mechanism for regulating NF-kappaB-mediated DR5 expression and could explain the differential roles NF-kappaB plays in regulating apoptosis.
 ...
PMID:Transcription factor NF-kappaB differentially regulates death receptor 5 expression involving histone deacetylase 1. 1596 98

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has recently attracted attention as a potential therapeutic agent in the treatment of cancer. We assessed the roles of p53, TRAIL receptors, and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (c-FLIP) in regulating the cytotoxic effects of recombinant TRAIL (rTRAIL) alone and in combination with chemotherapy [5-fluorouracil (5-FU), oxaliplatin, and irinotecan] in a panel of colon cancer cell lines. Using clonogenic survival and flow cytometric analyses, we showed that chemotherapy sensitized p53 wild-type, mutant, and null cell lines to TRAIL-mediated apoptosis. Although chemotherapy treatment did not modulate mRNA or cell surface expression of the TRAIL receptors death receptor 4, death receptor 5, decoy receptor 1, or decoy receptor 2, it was found to down-regulate expression of the caspase-8 inhibitor, c-FLIP. Stable overexpression of the long c-FLIP splice form but not the short form was found to inhibit chemotherapy/rTRAIL-induced apoptosis. Furthermore, siRNA-mediated down-regulation of c-FLIP, particularly the long form, was found to sensitize colon cancer cells to rTRAIL-induced apoptosis. In addition, treatment of a 5-FU-resistant cell line with 5-FU down-regulated c-FLIP expression and sensitized the chemotherapy-resistant cell line to rTRAIL. We conclude that TRAIL-targeted therapies may be used to enhance conventional chemotherapy regimens in colon cancer regardless of tumor p53 status. Furthermore, inhibition of c-FLIP may be a vital accessory strategy for the optimal use of TRAIL-targeted therapies.
 ...
PMID:Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP. 1637 18

Sulforaphane (SFN), a naturally occurring isothiocyanate, is an attractive agent because of its potent anticancer effects. SFN suppresses the proliferation of various cancer cells in vitro and in vivo. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is also one of the most promising candidates for cancer therapeutics owing to its ability to selectively induce apoptosis in tumor cells. In this study, we report that SFN enhances TRAIL-induced apoptosis in human osteosarcoma cells, Saos2 and MG63. The apoptosis induced by co-treatment with SFN and TRAIL was markedly blocked by a dominant negative form of the TRAIL receptor or caspase inhibitors. The combined use of SFN and TRAIL effectively induced Bid cleavage and the activation of caspases 8, 10, 9 and 3 at ineffective concentrations for each agent. SFN upregulated the expression of death receptor 5 (DR5), a receptor for TRAIL, at mRNA and protein levels in a dose-dependent manner. In addition, the SFN-mediated sensitization to TRAIL was reduced by DR5 siRNA, suggesting that the sensitization was at least partially mediated through the induction of DR5 expression. Furthermore, SFN sensitized TRAIL-induced apoptosis in a p53-independent manner. On the other hand, SFN neither induced DR5 protein expression or enhanced TRAIL-induced apoptosis in normal human peripheral blood mononuclear cells. Thus, combined treatment with SFN and TRAIL might be a promising therapy for osteosarcoma.
 ...
PMID:Sulforaphane enhances TRAIL-induced apoptosis through the induction of DR5 expression in human osteosarcoma cells. 1657 51

We previously established the murine adrenal chromaffin cell line tsAM5D, which was immortalized with the temperature-sensitive simian virus 40 large T-antigen. tsAM5D cells have the capacity to differentiate into neuron-like cells in response to neurotrophic factors when the culture temperature is shifted from 33 to 39 degrees C. In this model system, the temperature shift in the absence of neurotrophic factors led to cell death. Hoechst staining analysis revealed that typical apoptotic nuclei appeared in a time-dependent manner after the temperature shift. Upon shifting to 39 degrees C, the degradation of T-antigen was accompanied by the transcriptional activation of p53 protein. Among the p53 target genes, death receptor 5 (DR5), which is the receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), showed the highest level of induction. Interestingly, TRAIL-neutralizing antibody protected tsAM5D cells from the temperature shift-induced apoptotic cell death by blocking the activation of caspase-8 and -3, indicating the involvement of TRAIL-mediated death signaling in the temperature shift-induced apoptosis. Glial cell line-derived neurotrophic factor (GDNF) inhibited the TRAIL-mediated activation of caspase-8 in tsAM5D cells exposed to 39 degrees C and cooperated with basic fibroblast growth factor and ciliary neurotrophic factor. Interestingly, the temperature shift induced oligomerization of DR5, which is the earliest process necessary for transduction of the death signal. This oligomerization was inhibited by treatment with GDNF plus ciliary neurotrophic factor but not by that with GDNF alone or GDNF plus basic fibroblast growth factor. These results are discussed with respect to the intracellular mechanism underlying the protective function of neurotrophic factors against TRAIL-mediated death signaling.
 ...
PMID:Protective effects of neurotrophic factors on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of murine adrenal chromaffin cell line tsAM5D. 1677 3

p53 deficiency is common in almost all human tumors and contributes to an aggressive chemo- or radiotherapy-resistant phenotype, therefore providing a target for drug development. Molecular targeting to restore wild-type p53 activity has been attempted in drug development and has led to the identification of CP-31398, PRIMA1, and the Nutlins. However, strategies targeting p53-activated transcriptional responses or p53 family member expression in p53-deficient tumors have yet to be explored. Here we demonstrate the use of noninvasive bioluminescence imaging in a high-throughput cell-based screen of small molecules that activate p53 responses and cell death in human tumor cells carrying a mutant p53. We isolated a number of small molecules that activate p53 reporter activity, increase expression of p53 target genes such as p21(WAF1) or death receptor 5 (KILLER/DR5) of TNF-related apoptosis-inducing ligand (TRAIL), and induce apoptosis in p53-deficient cells. Some of the compounds activate a p53 response by increasing p73 expression, and knockdown of transactivating isoforms of p73 by small interfering RNA reduces their induction of p53-responsive transcriptional activity. Some compounds do not induce significant p73 expression but induce a high p53-responsive transcriptional activity in the absence of p53. In vivo experiments demonstrate potent antitumor effects of selected compounds, using either HCT116/p53(-/-) or DLD1 human colon tumor xenografts. The results establish the feasibility of a cell-based drug screening strategy targeting the p53 transcription factor family of importance in human cancer and provide lead compounds for further development in cancer therapy.
 ...
PMID:Small-molecule modulators of p53 family signaling and antitumor effects in p53-deficient human colon tumor xenografts. 1683 97

The naturally occurring tumour necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis through two death receptors, death receptor 4 (DR4) and death receptor 5 (DR5), that are expressed on the cell membrane. Binding of the ligand to the death receptors leads to activation of the extrinsic apoptosis pathway. Chemotherapy on the other hand stimulates the intrinsic apoptosis pathway via activation of p53 in response to cellular damage. Many cancer cells have mutations in p53 causing resistance to chemotherapy-induced apoptosis. Concomitant signalling through the extrinsic pathway may overcome this resistance. Moreover, enthusiasm for TRAIL as an anticancer agent is based on the demonstration of rhTRAIL-induced selective cell death in tumour cells and not in normal cells. In this review, we provide an overview of the TRAIL pathway, the physiological role of TRAIL and the factors regulating TRAIL sensitivity. We also discuss the clinical development of novel agents, i.e. rhTRAIL and agonistic antibodies, that activate the death receptors.
 ...
PMID:The clinical trail of TRAIL. 1688 4

Reactivation of mutant p53 in tumours is a promising strategy for cancer therapy. Here we characterise the novel p53 rescue compound P53R3 that restores sequence-specific DNA binding of the endogenously expressed p53(R175H) and p53(R273H) mutants in gel-shift assays. Overexpression of the paradigmatic p53 mutants p53(R175H), p53(R248W) and p53(R273H) in the p53 null glioma cell line LN-308 reveals that P53R3 induces p53-dependent antiproliferative effects with much higher specificity and over a wider range of concentrations than the previously described p53 rescue drug p53 reactivation and induction of massive apoptosis (PRIMA-1). Furthermore, P53R3 enhances recruitment of endogenous p53 to several target promoters in glioma cells bearing mutant (T98G) and wild-type (LNT-229) p53 and induces mRNA expression of numerous p53 target genes in a p53-dependent manner. Interestingly, P53R3 strongly enhances the mRNA, total protein and cell surface expression of the death receptor death receptor 5 (DR5) whereas CD95 and TNF receptor 1 levels are unaffected. Accordingly, P53R3 does not sensitise for CD95 ligand- or tumour necrosis factor alpha-induced cell death, but displays synergy with Apo2L.0 in 9 of 12 glioma cell lines. Both DR5 surface induction and synergy with Apo2L.0 are sensitive to siRNA-mediated downregulation of p53. Thus this new p53 rescue compound may open up novel perspectives for the treatment of cancers currently considered resistant to the therapeutic induction of apoptosis.
 ...
PMID:A novel p53 rescue compound induces p53-dependent growth arrest and sensitises glioma cells to Apo2L/TRAIL-induced apoptosis. 1820 4


1 2 3 4 5 Next >>