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)

APO2L (TRAIL) is a novel CD95L (Fas/APO-1-L) homologous cytotoxic cytokine that interacts with various receptors which transmit (DR4, DR5) or inhibit (DcR1, DcR2) an apoptotic signal. Here, we report that human glioma cell lines preferentially express mRNAs for agonistic death receptors DR4 (8/12) and DR5 (11/12) rather than the death-inhibitory decoy receptors DcR1 (4/12) and DcR2 (2/12). Ten of 12 cell lines are susceptible to APO2L-induced apoptosis. The resistant cell lines, U138MG and U373MG, are cross-resistant to CD95L-induced apoptosis. Similar to CD95L-induced apoptosis, APO2L-induced apoptosis is inhibited by ectopic expression of the caspase inhibitor, crm-A, or of bcl-2, or by coexposure to the corticosteroid, dexamethasone, or the lipoxygenase inhibitor, nordihydroguaretic acid. There is no correlation between p53 genetic status of the cell lines and their susceptibility to APO2L-induced apoptosis, but the latter is moderately enhanced by ectopic expression of wild-type p53. APO2L targeting may be a promising approach for selectively targeting apoptosis to human malignant glioma cells.
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PMID:APO2 ligand: a novel lethal weapon against malignant glioma? 961 12

The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) has been shown to induce apoptosis in various tumor cell lines including human non-small cell lung carcinoma (NSCLC) cells, which are resistant to the natural all-trans retinoic acid and to many synthetic receptor-selective retinoids. Although the mechanism of this effect was not elucidated, it was found to be independent of nuclear retinoid receptors. In the present study, we analysed the mechanisms by which CD437 induces apoptosis in two human NSCLC cell lines: H460 with wild-type p53 and H1792 with mutant p53. Both cell lines underwent apoptosis after exposure to CD437, although the cell line with wild-type p53 (H460) was more sensitive to the induction of apoptosis. CD437 increased the activity of caspase in both cell lines, however, the effect was much more pronounced in the H460 cells. The caspase inhibitors (Z-DEVD-FMK and Z-VAD-FMK) suppressed CD437-induced CPP32-like caspase activation and apoptosis in both cell lines. CD437 induced the expression of the p53 gene and its target genes, p21, Bax, and Killer/DR5, only in the H460 cells. These results suggest that CD437-induced apoptosis is more extensive in NSCLC cells that express wild-type p53, possibly due to the involvement of the p53 regulated genes Killer/DR5, and Bax although CD437 can also induce apoptosis by means of a p53-independent mechanism. Both pathways of CD437-induced apoptosis appear to involve activation of CPP32-like caspase.
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PMID:Mechanisms of apoptosis induced by the synthetic retinoid CD437 in human non-small cell lung carcinoma cells. 1032 56

CD437 is a novel retinoid that can induce apoptosis in a variety of tumor cell types by an unknown mechanism. We found that CD437 up-regulated the expression of p21(WAF1/CIP1), Bax, and Killer/DR5 and induced G1 arrest and rapid apoptosis in three human non-small cell lung carcinoma cell lines with wild-type p53 but not in five cell lines with mutant p53, suggesting a role for p53 in the effects of CD437. Using H460 cells in which wild-type p53 protein was degraded by transfection of the human papillomavirus 16 E6 (HPV-16 E6) gene and H460 cells transfected with a control plasmid only, we found that CD437 increased p53, p21(WAF1/CIP1), Bax, and Killer/DR5 in the control transfectants. In contrast, the constitutive p53 protein level was suppressed, and the ability of CD437 to increase p53 and its downstream genes was compromised in E6 transfectants. In addition, CD437 induced G1 arrest and apoptosis in the control transfectants but not in the E6-transfected cells. These results indicate that p53 plays a role in CD437-induced growth inhibition and apoptosis in human non-small cell lung carcinoma cells.
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PMID:Implication of p53 in growth arrest and apoptosis induced by the synthetic retinoid CD437 in human lung cancer cells. 1038 41

Both DR4 and DR5 have recently been identified as membrane death receptors that are activated by their ligand TRAIL to engage the intracellular apoptotic machinery. TRID (also named as TRAIL-R3) is an antagonist decoy receptor and lacks the cytoplasmic death domain. TRID protects from TRAIL-induced apoptosis by competing with DR4 and DR5 for binding to TRAIL. TRID has been shown to be overexpressed in normal human tissues but not in malignantly transformed cell lines. DR5 is a p53-regulated gene and we have recently reported that DR5 expression is induced in response to genotoxic stress in both a p53-dependent and independent manner (Sheikh et al., 1998). In the current study, we demonstrate that TRID gene expression is also induced by the genotoxic agents ionizing radiation and methyl methanesulfonate (MMS) in predominantly p53 wild-type cells, whereas UV-irradiation does not induce TRID gene expression. Consistent with these results, exogenous wild-type p53 also upregulates the expression of endogenous TRID in p53-null cells. Thus, TRID appears to be a p53 target gene that is regulated by genotoxic stress in a p53-dependent manner. Using primary gastrointestinal tract (GIT) tumors and their matching normal tissue, we also demonstrate for the first time that TRID expression is enhanced in primary tumors of the GIT. It is, therefore, possible that TRID overexpressing GIT tumors may gain a selective growth advantage by escaping from TRAIL-induced apoptosis.
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PMID:The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract. 1043 97

Recent investigation further defines the role of p53 and of signaling events upstream and downstream of p53 in apoptosis following drug-induced DNA damage. The transcription factors NF-kappaB and AP-1 can be activated, and then directly transactivate FasL in response to chemotherapeutic agents. Death receptors for FasL (Fas) and for TRAIL (DR4, DR5) are emerging as important regulators of drug-induced apoptosis in human cancers, mediated by caspase activation. Apoptosis has been accepted as the predominant mechanism of drug-induced cell death in preclinical experimental models and in clinically sensitive tumors. However, drug-induced cell death can include acute or delayed apoptosis, necrosis, or a delayed mitotic death, and require further delineation for their relative contribution to tumor responses in vivo.
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PMID:Apoptosis and drug response. 1055 11

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent endogenous activator of the cell death pathway and functions by activating the cell surface death receptors 4 and 5 (DR4 and DR5). TRAIL is nontoxic in vivo and preferentially kills neoplastically transformed cells over normal cells by an undefined mechanism. Radiotherapy is a common treatment for breast cancer as well as many other cancers. Here we demonstrate that ionizing radiation can sensitize breast carcinoma cells to TRAIL-induced apoptosis. This synergistic effect is p53-dependent and may be the result of radiation-induced up-regulation of the TRAIL-receptor DR5. Importantly, TRAIL and ionizing radiation have a synergistic effect in the regression of established breast cancer xenografts. Changes in tumor cellularity and extracellular space were monitored in vivo by diffusion-weighted magnetic resonance imaging (diffusion MRI), a noninvasive technique to produce quantitative images of the apparent mobility of water within a tissue. Increased water mobility was observed in combined TRAIL- and radiation-treated tumors but not in tumors treated with TRAIL or radiation alone. Histological analysis confirmed the loss of cellularity and increased numbers of apoptotic cells in TRAIL- and radiation-treated tumors. Taken together, our results provide support for combining radiation with TRAIL to improve tumor eradication and suggest that efficacy of apoptosis-inducing cancer therapies may be monitored noninvasively, using diffusion MRI.
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PMID:Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy. 1067 30

KILLER/DR5, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor gene, has been shown to be induced by DNA damaging agents and radiation in a p53-dependent manner. Although TRAIL is a potential therapeutic agent for cancer, the induction mechanism of its receptors is poorly understood. Here we show the identification of three p53 DNA-binding sites in the KILLER/DR5 genomic locus located upstream (BS1; -0.82 Kb) of the ATG site, within Intron 1 (BS2; +0.25 Kb downstream of the ATG) and within Intron 2 (BS3; +1.25 Kb downstream of the ATG). A modified p53-binding and immunoselection protocol using a wild-type p53-expressing adenovirus vector (Ad-p53) was used to identify the binding sites and to show that each binding site can bind specifically to wild-type p53 protein (wt-p53). A reporter assay revealed that only BS2 could enhance luciferase expression driven by a basal promoter. We constructed a reporter plasmid carrying the genomic regulatory region of KILLER/DR5 including the three p53 DNA-binding sites but no additional basal promoter. The genomic fragment showed basal transcriptional activity which was induced by wt-p53 but not by mutant p53, and human papilloma virus E6 inhibited the p53-dependent activation. Mutation of BS2 abrogated not only the binding activity of wt-p53 but also the induction of the KILLER/DR5 genomic promoter-reporter gene, indicating that BS2 is responsible for the p53-dependent transactivation of KILLER/ DR5. In p53-wild-type but not -mutant or -null cell lines, doxorubicin treatment stabilized p53 protein, and increased specific binding to BS2 as revealed by EMSA, and upregulated the KILLER/DR5 promoter-luciferase reporter gene. These results suggest that the transactivation of KILLER/DR5 is directly regulated by exogenous or endogenous wt-p53 and establishes KILLER/DR5 as a p53 target gene that can signal apoptotic death.
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PMID:Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site. 1077 7

A search of the Genebank database revealed that there are two distinct gene sequences with the common name of TRAIL-R2/Killer/DR5. Using reverse transcription-polymerase chain reaction (RT-PCR), we confirmed the existence of two isoforms of TRAIL-R2/Killer/DR5 mRNA, which we have designated the long and short isoforms based on their electrophoretic mobility. We found that both the long and short mRNA isoforms are ubiquitously expressed in human tissues and cell lines. The long form generally predominates, but the proportion of the two isoforms varies depending on the tissue type. Treatment of MCF-7 human breast cancer cells with the DNA damaging drugs adriamycin, campthothecin, or etoposide causes a coordinated up-regulation of both isoforms. Treatment of the p53-mutant T-47D breast cancer cell line with adriamycin also results in up-regulation of both isoforms, suggesting that adriamycin up-regulates TRAIL-R2/Killer/DR5 expression independent of functional p53. The expression of both mRNA isoforms are increased in MCF-7 cells cultured in charcoal-stripped fetal bovine serum compared to normal serum, suggesting that sex steroid hormones may play a role in the negative regulation of their expression. This was confirmed in MCF-7 cells cultured in stripped serum supplemented with 17beta-estradiol, which also resulted in a decrease in the mRNA expression of both isoforms. These results demonstrate that the TRAIL-R2/Killer/DR5 gene gives rise to two distinct forms of mRNA, and that these two forms are coordinately regulated by DNA damage and 17beta-estradiol in human breast cancer cells. The functional significance of the two isoforms remains to be determined.
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PMID:Coordinated regulation of two TRAIL-R2/KILLER/DR5 mRNA isoforms by DNA damaging agents, serum and 17beta-estradiol in human breast cancer cells. 1093 93

The cell surface decoy receptor proteins TRID (also known as DcR1 or TRAIL-R3) and TRUNDD (DcR2, TRAIL-R4) inhibit caspase-dependent cell death induced by the cytotoxic ligand TRAIL in part because of their absent or truncated cytoplasmic death domains, respectively. We previously identified the death domain containing proapoptotic TRAIL death receptor KILLER/DR5 (TRAIL-R2) as an upregulated transcript following exposure of cancer cells, with wild-type but not with mutant or degraded p53 proteins, to a cytotoxic dose of adriamycin. In the present studies we provide evidence that expression of the TRAIL decoy receptors TRUNDD and TRID increases following infection of cancer cells with p53-expressing adenovirus (Ad-p53), in a manner similar to other p53 target genes such as KILLER/DR5 and p21WAF1/CIP1. Subsequent overexpression of TRUNDD in colon cancer cell lines caused a significant delay in killing induced by TRAIL. Furthermore, cotransfection of TRUNDD with either p53 or KILLER/DR5 (at a 4:1 DNA ratio) in colon cancer cells decreased cell death caused by either gene. This protective effect of TRUNDD was not dependent on the presence of TRAIL, and overexpression of TRUNDD did not alter the protein levels of either p53 or KILLER/ DR5. Further deletion studies showed that whereas protection by TRUNDD against TRAIL-mediated apoptosis did not require an intact intracellular domain (ICD), the first 43 amino acids of the ICD of TRUNDD were needed for protection against cell death induced by p53 or KILLER/DR5. Our results suggest a model in which the TRAIL decoy receptors may be induced by p53, thereby attenuating an apoptotic response that appears to involve KILLER/DR5. Therefore, the p53-dependent induction of TRUNDD may provide a mechanism to transiently favor cell survival over cell death, and overexpression of TRUNDD may be another mechanism of escape from p53-mediated apoptosis in gene therapy experiments.
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PMID:The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis. 1093 23

Recently, several tumor necrosis factor receptor 1 (TNF-R1) and Fas-related death receptors have been discovered and include DR3, DR4, DR5 and DR6. These receptors contain an extracellular region containing varying numbers of cysteine-rich domains and an intracellular region that contains the death domain. The death receptors are activated in a ligand-dependent or independent manner and transduce apoptotic signals via their respective intracellular death domains. In addition to death receptors, several decoy molecules have also been identified and include DcR1/TRID, DcR2/TRUNDD, DcR3 and osteoprotegrin (OPG). The decoy molecules do not transduce apoptotic signals but rather compete with the death receptors for ligand binding and thereby inhibit ligand-induced apoptosis. Recent evidence suggests that p53 upregulates the expression of death receptors Fas and DR5, and thus, may mediate apoptosis in part via Fas and/or DR5. However, p53 also regulates the expression of TRAIL decoy receptors DcR1/TRID and DR2/TRUNDD. Although the significance of p53-dependent regulation of decoy receptors remains unclear, evidence suggests that DcR1/TRUNDD appears to inhibit 53-mediated apoptosis. It is, therefore, possible that p53 may blunt its DR5-dependent apoptotic effects by controlling the levels of decoy receptors.
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PMID:Death and decoy receptors and p53-mediated apoptosis. 1094 51


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