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)

A new cell line, CUMC-3, has been derived from an invasive nonkeratinizing squamous cell carcinoma of the uterine cervix in a 32-year-old patient. It has been maintained in long-term culture for 59 months, and passaged over 310 times. Monolayer-cultured cells were polygonal in shape, showing a pavement-like arrangement and a tendency to pile up without contact inhibition. The epithelial nature of the cultured CUMC-3 cells was also confirmed by transmission electron microscopy which demonstrated the presence of desmosomes and tonofilaments. The cells were highly tumorigenic in nude mice and the transplanted tumors were poorly differentiated squamous carcinoma which closely resembled the original tumor. Cultured cells obtained from the CUMC-3-derived nude mouse tumor, CUMC-3N, also were studied for its characterization. Repeated chromosome analysis revealed a stable clone with the modal chromosome number of 78. The metaphase of this cell line had multiple structural aberrations of chromosomes 1, 3, 8, 10, 11, 20, and X and showed several markers of unknown origin. The results of isozyme analyses were distinct from the HeLa cell line. The identical genetic signature was demonstrated both in CUMC-3 and in CUMC-3N cells. Cultured CUMC-3 cells produced human chorionic gonadotropin beta-subunit and tumor antigen of squamous cell carcinoma (TA-4). Cytosol estrogen receptors were found in this cell line but progesterone receptors were not measured. HLA typing of CUMC-3 cells indicated the presence of DR4, DR8, DQw3, and DQw6. The result of oncogene analysis using Southern blotting technique revealed no amplification of oncogene c-myc. Analysis of the DNA samples extracted from the CUMC-3 cells showed the presence of human papillomavirus type 16 DNA. Using the single-strand conformation polymorphism technique, we have screened CUMC-3 cells for p53 mutation in exons 4 to 9. No mobility shift was observed in this cell line. This cell line may be useful in studying the in vitro and in vivo properties of human cervical carcinoma.
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PMID:Establishment and characterization of a cell line (CUMC-3) derived from a human squamous carcinoma of the uterine cervix. 770

A new cell line designated CUME-1 has been established from a poorly differentiated endometrial adenocarcinoma of the uterus. This cell line grew well without interruption for more than 88 months and 110 serial passages were successively carried out. The cells were highly tumorigenic in nude mice (85%). Repeated karyotype analyses from early (4th) to late (55th) passages of this cell line revealed a diploid stable clone in each passages without any noticeable structural or numerical aberrations. But from the 80th passage, a subpopulation with reciprocal translocation between chromosomes 1q and 9q consistently appeared and was observed in about 30% of the cells. This cell line is one of the rare examples of experimentally proved tumorigenic cells of human solid tumor origin that retains the diploid karyotype in vitro. HLA typing indicated the presence of DR4, DR13, DQ3 and DQ6. Cytosol estrogen and progesterone receptors were found both in fresh primary tumor and in this cell line. Gonadotropin-releasing hormone (Gn-RH) receptor mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) in cultured cells. Using the single-strand conformation polymorphism (SSCP) technique, we have screened CUME-1 cells for p53 mutation in exons 4 to 9. No mobility shift was observed. This cell line may be useful in studying the in vitro chromosomal evolution of the cell line and the in vivo properties of human endometrial adenocarcinoma.
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PMID:Establishment and characterization of a highly tumorigenic human diploid endometrial cancer cell line. 935 88

The death receptor (DR) KILLER/DR5 gene has recently been identified as a doxorubicin-regulated transcript that was also induced by exogenous wild-type p53 in p53-negative cells. KILLER/DR5 gene encodes a DR containing cell surface protein that is highly homologous to DR4, another DR of the tumor necrosis factor (TNF) receptor family. Both DR4 and KILLER/DR5 independently bind to their specific ligand TRAIL and engage the caspase cascade to induce apoptosis. TRID (also known as TRAIL-R3) is an antiapoptotic decoy receptor that lacks the cytoplasmic death domain and competes with KILLER/DR5 and DR4 for binding to TRAIL. In this study, we demonstrate that the DR KILLER/DR5 gene is regulated in a p53-dependent and -independent manner during genotoxic and nongenotoxic stress-induced apoptosis. Just like other p53-regulated genes, ionizing radiation induction of KILLER/DR5 occurs in p53 wild-type cells, whereas methyl methanesulfonate regulation of KILLER/DR5 occurs in a p53-dependent and -independent manner. However, unlike other p53-regulated genes, KILLER/DR5 is not regulated following UV irradiation. TNF-alpha, a nongenotoxic cytokine, also induced the expression of KILLER/DR5 in a number of cancer cell lines, irrespective of p53 status. TNF-alpha did not alter the KILLER/DR5 mRNA stability, suggesting that the TNF-alpha regulation of KILLER/DRS expression appears transcriptional. We also provide evidence that KILLER/DR5 is regulated in a trigger and cell type-specific manner and that its induction by TNF-alpha, p53, or DNA damage is not the consequence of apoptosis induced by these agents. Unlike KILLER/DR5, none of the other KILLER/DR5 family members, including DR4, TRID, or the ligand TRAIL, displayed genotoxic stress or TNF-alpha regulation in a p53 transcription-dependent manner. Thus, KILLER/DR5 appears a bona fide downstream target of p53 that is also regulated in a cell type-specific, trigger-dependent, and p53-independent manner.
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PMID:p53-dependent and -independent regulation of the death receptor KILLER/DR5 gene expression in response to genotoxic stress and tumor necrosis factor alpha. 956 66

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

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors are members of the tumor necrosis factor superfamily. TRAIL selectively kills cancer cells but not normal cells. We report here the cloning of the mouse homologue of the TRAIL receptor KILLER/DR5 (MK). The cDNA of MK is 1146 bp in length and encodes a protein of 381 amino acids. MK contains an extracellular cysteine-rich domain, a transmembrane domain, and a cytoplasmic death-domain characteristic of Fas, tumor necrosis factor, and human TRAIL receptors. MK is highly homologous and binds TRAIL with similar affinity as human DR4 and KILLER/DR5. MK induces apoptosis in mouse and human cells and inhibits colony growth of NIH3T3 cells. Expression of MK is p53-dependent and up-regulated by tumor suppressor p53 and by DNA damaging agents in mouse cells undergoing apoptosis. This is the first report describing a mouse TRAIL receptor gene and also demonstrating that the p53-dependent regulation of KILLER/DR5-mediated apoptosis is conserved between human and mouse.
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PMID:Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor. 1038 28

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

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a potent inducer of death of cancer but not normal cells, which suggests its potential use as a tumor-specific antineoplastic agent. TRAIL binds to the proapoptotic death receptors DR4 and the p53-regulated proapoptotic KILLER/DR5 as well as to the decoy receptors TRID and TRUNDD. In the present studies, we identified a subgroup of TRAIL-resistant cancer cell lines characterized by low or absent basal DR4 or high expression of the caspase activation inhibitor FLIP. Four of five TRAIL-sensitive cell lines expressed high levels of DR4 mRNA and protein, whereas six of six TRAIL-resistant cell lines expressed low or undetectable levels of DR4 (chi 2; P < 0.01). FLIP expression appeared elevated in five of six (83%) TRAIL-resistant cell lines and only one of five (20%) TRAIL-sensitive cells (chi 2; P < 0.05). Two TRAIL-resistant lines that expressed DR4 contained an A-to-G alteration in the death domain encoding arginine instead of lysine at codon 441. The K441R polymorphism is present in 20% of the normal population and can inhibit DR4-mediated cell killing in a dominant-negative fashion. The expression level of KILLER/DR5, TRID, TRUNDD or TRID, and TRUNDD did not correlate with TRAIL sensitivity (P > 0.05). These results suggest that the major determinants for TRAIL sensitivity may be the expression level of DR4 and FLIP. TRAIL-resistant cells became susceptible to TRAIL-mediated apoptosis in the presence of doxorubicin. In TRAIL-sensitive cells, caspases 8, 9, and 3 were activated after TRAIL treatment, but in TRAIL-resistant cells, they were activated only by the combination of TRAIL and doxorubicin. Our results suggest: (a) evaluation of tumor DR4 and FLIP expression and host DR4 codon 441 status could be potentially useful predictors of TRAIL sensitivity, and (b) doxorubicin, in combination with TRAIL, may effectively promote caspase activation in TRAIL-resistant tumors.
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PMID:Molecular determinants of response to TRAIL in killing of normal and cancer cells. 1069 May 8

Death receptors of the Tumor Necrosis Factor (TNF) family form membrane-bound self-activating signaling complexes that initiate apoptosis through cleavage of proximal caspases including CASP8 and 10. Here we show that overexpression of the cytoplasmic domain (CD) of the DR4 TRAIL receptor (TNFRSF10A, TRAIL R1) in human breast, lung, and colon cancer cell lines, using an adenovirus vector (Ad-DR4-CD), leads to p53-independent apoptotic cell death involving cleavage of CASP8 and 10 proximally and CASP3, 6, and 7 distally. DR4-CD overexpression also leads to cleavage of poly(ADP-ribose) polymerase (PARP) and the DNA fragmentation factor (DFF45; ICAD). Importantly, normal lung fibroblasts are resistant to DR4-CD overexpression and show no evidence of PARP-, CASP8- or CASP3-cleavage despite similar levels of adenovirus-delivered DR4-CD protein as the cancer cells. These results suggest that DR4 may signal death through known caspases and that further studies are required to evaluate Ad-DR4-CD as a novel anti-cancer agent. Finally, we show that overexpression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (CDKN1A), or its N-terminal 91 amino acids containing cell cycle-inhibitory activity, inhibits DR4-CD-dependent proximal caspase cleavage. The blockage of initiator caspase activation provides a novel insight into how p21 may suppress apoptosis and enhance cell survival.
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PMID:p21(WAF1/CIP1) inhibits initiator caspase cleavage by TRAIL death receptor DR4. 1069 97


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