Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukemia inhibitory factor (LIF) affects the growth of carcinoma cells, and we thus analyzed its underlying mechanisms. Carcinoma cells constitutively express LIF mRNA, and 23 lines (92.0%) and all (100%) of 25 lines express LIF receptor mRNAs of LIFRbeta and gp130, respectively. Exogenous addition of LIF promoted significant cell proliferation in 4 lines (MCF-7, ZR-75-1, Hs-700T and Panc-1) and suppressed cell growth in 3 lines (AZ-521, GBK-1 and HT-29). LIF significantly induced an immediate early response of genes c-fos and junB 3 hr after stimulation, but not of c-jun during the process of proliferation of MCF-7 and Hs-700T cells, with maximum levels at 30-60 min. The cell-cycle-related gene cyclin E was also induced in MCF-7 and Hs-700T cells, whereas cyclinA, cdk2, c-myc, c-myb and p53 mRNAs were not induced. On the other hand, LIF inhibited growth and increased the rate of cell death of AZ-521 and GBK-1 cells. LIF increased the number of TUNEL-positive cells in AZ-521 cells and DNA fragmentation in AZ-521 and GBK-1 cells. LIF induced apoptosis related genes c-myc and ICE during suppression of cell growth, but p53, p21, c-fos, cyclin A and cyclin E were not induced. Our results suggest that LIF is linked to cell proliferation and apoptosis in some human carcinoma cell lines. It is considered that this is related to differences in signal transduction and induction of oncogenes.
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PMID:Leukemia inhibitory factor induces apoptosis and proliferation of human carcinoma cells through different oncogene pathways. 925 11

Human chorionic gonadotropin (hCG) inhibits the progression of 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinomas. In order to determine whether this phenomenon was mediated by induction of programmed cell death or apoptosis, 45-day-old virgin Sprague-Dawley rats received 8 mg DMBA/100 g body weight; 20 days later they were injected daily with 100 IU hCG for 40 days (DMBA + hCG group). Age-matched untreated, hCG- and DMBA + saline treated rats were used as controls. Tissues were collected at the time of DMBA administration and at 5, 10, 20 and 40 days of hCG injection. RNA from mammary glands, adenocarcinomas and ovaries was probed for transforming growth factors (TGF) alpha and beta, and the apoptotic genes TRPM2, ICE, bcl2, bcl-XL, bcl-XS, p53 and c-myc. The mammary glands of hCG-treated animals with or without DMBA exhibited elevated expression of TRPM2, ICE, bcl-XS, c-myc and p53; and elevation in the apoptotic index. Mammary adenocarcinomas developed in those animals treated with hCG showed an elevation in the expression of p53, c-myc and ICE genes in comparison with the levels detected in the adenocarcinomas developed by the animals treated with DMBA alone. No significant alterations in the expression of any of the genes tested was observed in ovarian RNAs. These results led us to conclude that hCG induces programmed cell death in the mammary gland initiated in the carcinogenic process, that this process is p53 dependent, and is modulated by c-myc expression. Our data also indicate the possibility that a cell death program dependent on the bcl2 family exists, because of the potential involvement of p53, bcl-XS and Bax in apoptosis. This additional mechanism of tumor inhibition makes hCG treatment a useful approach for the prevention and therapy of breast cancer.
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PMID:Chorionic gonadotropin inhibits rat mammary carcinogenesis through activation of programmed cell death. 932 78

Treatment of U-937 promonocytic cells with the DNA topoisomerase II inhibitor etoposide rapidly caused death by apoptosis, as determined by changes in chromatin structure, production of DNA breaks, nucleosome-sized DNA degradation, decrease in mitochondrial membrane potential and phosphatidyl serine translocation in the plasma membrane, and at the same time induced intracellular acidification. Both the execution of the apoptotic process and the intracellular acidification were reduced by the addition of forskolin plus theophylline or other cAMP increasing agents. These agents also attenuated the induction of apoptosis by camptothecin, heat-shock, cadmium chloride and X-radiation. Although etoposide slightly increased the production of reactive oxygen intermediates, this increase was not prevented by forskolin plus theophylline, and the addition of antioxidant agents failed to inhibit apoptosis. Etoposide caused a great increase in NF-(kappa)B binding activity, which was not prevented by forskolin plus theophylline, while AP-1 binding was little affected by the topoisomerase inhibitor. The treatments did not significantly alter the levels of Bcl-2 and Bax. By contrast, the expression of c-myc, which was very high in untreated U-937 cells and only partially inhibited by etoposide, was rapidly and almost totally abolished by the cAMP increasing agents. Finally, it was observed that etoposide caused a transient dephosphorylation of retinoblastoma (Rb), which was associated with cleavage of poly(ADP-ribose) polymerase (PARP). Both Rb dephosphorylation and PARP cleavage were inhibited by forskolin plus theophylline. The inhibition of Rb (type I) phosphatase and ICE/CED-3-like protease activities, and the abrogation of c-myc expression, are mechanisms which could explain the anti-apoptotic action of cAMP increasing agents in myeloid cells.
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PMID:cAMP increasing agents attenuate the generation of apoptosis by etoposide in promonocytic leukemia cells. 945 37

We show, in this study, that type I IFN induction of the cyclin-dependent kinase (cdk) inhibitor p21WAF1 in the human Burkitt lymphoma B cell-line Daudi and ensuing cell cycle arrest correlate with the terminal differentiation of these cells, and is ultimately followed by apoptosis and cell death. The expression of p21WAF1 paralleled the onset of G1 arrest and the reduction of surface IgM expression which was used as a marker of the differentiation response, and the IFN treated cells acquired a typical plasma cell-like morphology. The type II IFN IFNgamma, which does not inhibit the growth of Daudi cells, did not induce the expression of p21WAF1, nor affect the expression of surface IgM. The induction of p21WAF1 which paralleled the inhibition of the phosphorylation of the retinoblastoma protein, pRB, was preceded by the strong reduction in c-myc levels. We propose that the coupled down-regulation of c-myc and induction of p21WAF1 may be crucial to the induction of differentiation and G1 arrest in Daudi cells by type I IFN. Growth arrest and differentiation was followed by apoptosis and cell death, and was accompanied by the induction of the activity of the apoptotic ICE-family protease CPP32. G1 arrest and differentiation followed by apoptotic cell death are characteristics of terminal differentiation. Thus, our data suggest that the induction of p21WAF1 and G1 arrest mediated by type I IFN in Daudi cells is part of terminal differentiation response in these cells, highlighting a role for type I IFN as B cell terminal differentiation factors.
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PMID:Type I interferon induction of the Cdk-inhibitor p21WAF1 is accompanied by ordered G1 arrest, differentiation and apoptosis of the Daudi B-cell line. 958 86

The glycoprotein hormone, human chorionic gonadotropin (hCG) inhibits mammary tumorigenesis through induction of differentiation, and inhibits the proliferation of human breast epithelial cells (HBEC) in vitro. The present study was designed to determine whether the inhibitory effects of hCG was associated with the modulation of apoptotic gene expression. MCF-10F, a normal immortalized HBEC, BP1-E, a benzo(a)pyrene (BP) transformed cell line, and the urothelial cell line T24, were treated with 100 IU/ml of a commercially available preparation of hCG. Cell growth analysis and RNA extraction for determination of apoptotic gene expression were performed at 24 and 120 hrs of hCG treatment. Both hCG-treated and control cells grew at similar rates for the first 24 hours. A significant reduction in the number of viable MCF-10F and BP1-E cells occurred by 120 hours of treatment, whereas the number of both hCG treated and control T24 cells were similar. Northern blot analysis revealed that the 24 hour-hCG treatment induced an elevation in the expression of the apoptotic genes TRPM2, ICE, TGF-beta, p53, bax, and p21WAF1/CIP1 in MCF-10F cells. By 120 hours of treatment MCF-10F cells maintained the same level of gene expression observed at 24 hours, except for a reduction in c-myc and bax. Control cells exhibited an elevation in the expression of TRPM2, TGF-beta, p53, bax, and p21WAF1/CIP1, whose levels became similar to those observed in hCG-treated cells. The 24 hour-treated BP1-E cells showed activation of ICE, bax and p21WAF1/CIP1. However, TRPM2 expression was moderately activated. By 120 hours TRPM2, ICE, TGF-beta, c-myc and p21WAF1/CIP1 were elevated in both treated and control cells except bax which was slightly down-regulated. The levels of bc12 were significantly decreased by hCG treatment. Gene expression was not modified by hCG treatment in T24 cells. Our findings suggest that hCG induced an acceleration in the expression of apoptotic genes, which became evident before detection of cell growth inhibition. Gene activation differed among immortalized, and chemically transformed cells, suggesting that hCG might utilize both p53 dependent and p53 independent pathways for inhibiting cell cycle progression. The importance of these findings lies in the potential use of agents like hCG for the chemoprevention and chemotherapy of breast cancer.
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PMID:Growth inhibition and activation of apoptotic gene expression by human chorionic gonadotropin in human breast epithelial cells. 989 38

Apoptosis is a mechanism of cell death that occurs in normal development and on the regulation of vertebrate tissues and organ cellularity. Neurons undergo p53-dependent and p53-independent apoptosis, depending upon the stimulus that triggers DNA fragmentation. Many neurons in the developing nervous system suffer apoptosis, with the cyclin D1 being an essential mediator of neuronal cell death. Other characteristics of apoptosis are: condensation of the nucleus, fragmentation of chromatin at nucleosome linkage sites, membrane blebbing, and the formation of apoptotic bodies. Among the possible molecular mechanisms are: (a) activation of proteases, as ICE (Il-1 beta converting enzyme); (b) calpain is activated in several cells, with PARP (Poly-ADP-ribose polymerase) and a small U1 Ribonucleoprotein, being substrates for ICE and its homologs such as ICH and others proteins. The p53 gene encodes a transcription factor that contributes to several different cellular activities, including apoptosis, the cellular response to radiation, and the activation of proteins such as GADD, Bcl-2 (represses to apoptosis) and Bax. P53 exerts a role as inductor of apoptosis by transactivating expression of the Bax gene. The p53 gene tumor suppressor limits cellular proliferation by including either the arrest of cell cycle in G1, or apoptosis, depending on the cellular context. The p21 is an inhibitor of cyclin-dependent kinase, which is transactivated by p53. During apoptosis, there is an activation of both, c-myc, and the transcription factor NF-kB, which is a important regulator of apoptosis. As an example of signalization of apoptosis we have selected to illustrate the problem related to the system Fas/APO in thymocytes.
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PMID:[Molecular bases of the programmed cell death process: implications of tumor suppressor protein p53 and other proteins in the control of cell cycle. Mechanisms of apoptotic action. Review]. 992 5

There is increasing evidence that basic fibroblast growth factor (bFGF) plays an important role in cell proliferation, differentiation, and survival in various systems. In the eye, although a truncated, dominant negative bFGF receptor in transgenic mice induced defective lens development and caused lens fiber cells to display characteristics of apoptosis, there is little direct evidence of the effect of bFGF on lens epithelial cell apoptosis. Our study examines the effects of bFGF on programmed cell death induced by serum deprivation using a human lens epithelial cell line. Cells supplemented with 20% fetal bovine serum were used as normal controls. Over a period of 7 days, the addition of 100 ng/ml bFGF effectively suppressed serum-deprived apoptosis. The expression of gamma-crystallin and major intrinsic protein, which are markers of lens cell differentiation, was not detected. Also there was no significant difference in cell proliferation between serum-deprived cells with or without bFGF. ICE (caspase-1) was expressed under both the conditions, but the level of expression between the two groups was not substantially different. bcl-2 and c-myc were upregulated only in bFGF-treated cells. Thus we speculate that the inhibitory effect of bFGF on apoptosis is through the upregulation of the inhibitor of apoptosis, instead of downregulation of the initiator. This effect appears to be independent of lens cell differentiation and proliferation.
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PMID:bFGF suppresses serum-deprivation-induced apoptosis in a human lens epithelial cell line. 1032 60

The role of ceramide in triggering apoptosis is still a matter of debate. While in some experimental systems, ceramide was shown to mediate Fas-induced cell death, in other instances it was claimed to induce the expression of Fas ligand (FasL), killing cells in a caspase-dependent fashion. We found that, in mature A20 B cells, ceramide-induced apoptosis is independent of the caspase pathway, since we observed no ICE-like, CPP32-like and Mch2 activities and no PARP proteolysis. Moreover, we were unable to protect these cells from ceramide-induced apoptosis using caspase inhibitors, while they blocked Fas-induced apoptosis and no FasL induction could be detected following ceramide treatment. These results suggest that ceramide does not induce apoptosis through the Fas/FasL pathway. We also found that overexpression of Nur77, a zinc-finger transcription factor described to upregulate FasL, antagonizes ceramide-induced apoptosis, but not Fas-induced apoptosis. This further supports the hypothesis that Fas and ceramide death pathways are independent in A20 cells. Ceramide-induced cell death was associated with increased c-myc, p53, Bax and p27kip1 levels; in contrast, cells transfected with Nur77 (A20Nur77), resistant to ceramide-induced apoptosis, showed a marked downregulation of p53 after ceramide treatment, with neither Bax nor p27kip1 induction. In conclusion, our results suggest that, in the A20 B cell line, Fas and ceramide trigger two distinct pathways and that Nur77 overexpression confers protection against ceramide-mediated apoptosis which correlates with inhibition of p53, Bax and p27kip1 induction.
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PMID:Ceramide-induced cell death is independent of the Fas/Fas ligand pathway and is prevented by Nur77 overexpression in A20 B cells. 1074 71

The ability of bone cements to modify the apoptotic program in activated immune cells and the mechanisms by which they act were evaluated. Mononuclear cells were collected from healthy individuals, cultured for 4 and 24 h with phytohemoagglutinina-P and cement extracts and then tested to assess: (a) cell viability; (b) early apoptotic events, by Annexin V/propidium iodide staining; and (c) the expression of pro- (p53, c-myc, ICE) and anti-apoptotic (bcl-2) genes. After 4 h three cements were able to increase significantly the percentage of apoptotic cells, while after 24 h no differences were found. The proportion of dead cells was not significantly changed at either culture time. The simultaneous expression of both pro-apoptotic (ICE, c-myc, p53) and antiapoptotic genes (bcl-2) was investigated only with regard to the materials which induced significant changes in apoptosis: two cements induced the p53 expression, while the third down-regulated bcl-2. As apoptosis regulates the balance of immune response, the authors recommend that the interaction between materials and immune cells should be assessed, so that the use of pro-apoptotic materials may be avoided in patients with immune defects.
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PMID:Modulation of pro- and anti-apoptotic genes in lymphocytes exposed to bone cements. 1098 78

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


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