Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The candidate tumour suppressor gene, LUCA-15, maps to the lung cancer tumour suppressor locus 3p21.3. Overexpression of an alternative RNA splice variant of LUCA-15 has been shown to retard human Jurkat T cell proliferation and to accelerate CD95-mediated apoptosis. An antisense cDNA to the 3'-UTR of this splice variant was able to suppress CD95-mediated apoptosis. Here, we report that overexpression of LUCA-15 itself suppresses CD95-mediated apoptosis in Jurkat cells. This suppression occurs prior to the final execution stage of the CD95 signalling pathway, and is associated with up-regulation of the apoptosis inhibitory protein Bcl-2. LUCA-15 overexpression is also able to inhibit apoptosis induced by the protein kinase inhibitor staurosporine, but is not able to significantly suppress apoptosis mediated by the topoisomerase II inhibitor etoposide. These findings suggest that LUCA-15 is a selective inhibitor of cell death, and confirm the importance of the LUCA-15 genetic locus in the control of apoptosis.
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PMID:LUCA-15 suppresses CD95-mediated apoptosis in Jurkat T cells. 1142 Jun 83

Fas (APO-1/CD95/TNFRSF6) is a member of the tumor necrosis/nerve growth factor receptor family that signals apoptotic cell death in sensitive cells. Expression of Fas and its agonistic ligand (FasL/TNFSF6) was investigated in ex vivo pediatric brain tumor specimens of various histologic types. Fas expression was identified in all of the 18 tumors analyzed by flow cytometry and immunohistochemistry. FasL expression was identified in most of the 13 tumors analyzed by both Western analysis and immunohistochemistry. Nine of these tumor specimens were treated with either the agonistic anti-Fas antibody (APO-1) in combination with protein A or FasL in short-term cytotoxicity assays. Sensitivity to apoptosis induced by the topoisomerase II inhibitor, etoposide, was also assessed. Despite the presence of Fas, all the specimens analyzed demonstrated a high degree of resistance to Fas-mediated apoptosis. These 9 specimens also showed a high degree of resistance to etoposide. Only 2 of the 9 specimens were susceptible to etoposide-induced cell death, whereas only 3 were sensitive to Fas-mediated apoptosis. One brain tumor was sensitive to both Fas ligation and etoposide treatment. This contrasted with the high degree of susceptibility to both etoposide- and Fas-induced apoptosis observed in the reference Jurkat cell line. The results suggest that Fas expression may be a general feature of tumors of the CNS and that a significant degree of resistance to Fas-mediated apoptosis may exist in ex vivo pediatric brain tumor specimens.
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PMID:Ex vivo pediatric brain tumors express Fas (CD95) and FasL (CD95L) and are resistant to apoptosis induction. 1158 92

Functional screening of a human bone marrow cDNA library for suppressors of CD95-mediated apoptosis has led to the identification of a 326 bp fragment (Je2), which not only suppresses CD95-induced apoptosis in Jurkat T-cells, but maps to 3p21.3, to an intronic region of the candidate TSG LUCA-15 locus. Here we report that overexpression of Je2 in CEM-C7 T-cell line is able to suppress CD95-mediated apoptosis, and apoptosis induced by TNFalpha and the glucocorticoid analogue dexamethasone, but was not able to suppress death induced by the topoisomerase II inhibitor etoposide. Je2 inhibition of apoptosis is also associated with a change in the pattern of expression of LUCA-15-encoded proteins. Je2 might therefore function to inhibit apoptosis by destabilising message expression of LUCA-15 and promoting the degradation of its RNA and protein. This suppression of apoptosis by Je2 also appears to be associated with up-regulation of the apoptosis inhibitory protein Bcl-x(L). This study confirms that Je2 is a selective inhibitor of cell death and further implicates LUCA-15 gene locus in the control of apoptosis.
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PMID:Candidate tumour suppressor LUCA-15 can regulate multiple apoptotic pathways. 1220 75

The anthracycline doxorubicin (adriamycin) is an important chemotherapeutic agent used in the treatment of solid epithelial and mesenchymal tumors as well as leukemias. A variety of mechanisms has been proposed to be involved in doxorubicin-induced cytotoxicity such as DNA intercalation, oxidative stress, DNA strand breakage by inhibition of topoisomerase II, activation of death receptors, and altered p53 expression. Concerning doxorubicin resistance and p53 status data reported are contradictory. Here, we show that mouse fibroblasts deficient in p53 (p53(-/-)) are more resistant to doxorubicin than p53 wild-type (p53 wt) cells. This is in contrast to other genotoxic agents (UV-light, alkylating drugs) for which p53(-/-) fibroblasts proved to be more sensitive. Resistance of p53(-/-) cells to doxorubicin is related to reduced induction of apoptosis. This is not likely to be due to altered apoptotic signaling since the expression of Bax and Bcl-2 was unchanged and the induction of Fas/CD95/APO-1 receptor and caspase-8 was the same in p53(-/-) and p53 wt cells on treatment with doxorubicin. However, we observed a clearly lower level of doxorubicin-induced DNA strand breaks in p53(-/-) cells compared to the wt. P170 glycoprotein was equally expressed and the accumulation and elimination of the drug occurred with identical kinetics in both cell types. p53 deficient cells were cross-resistant to another topoisomerase II inhibitor etoposide, which also provoked increased DNA strand breakage in p53 wt cells. Based on the data we conclude that the p53 status significantly impacts the generation of DNA strand breaks because of drug-induced topoisomerase inhibition rather than death receptor signaling. Since human tumors are frequently mutated in p53 the findings bear clinical implications.
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PMID:Resistance of p53 knockout cells to doxorubicin is related to reduced formation of DNA strand breaks rather than impaired apoptotic signaling. 1250 67

Topoisomerase inhibitors are among the most efficient inducers of apoptosis. The main pathways leading from topoisomerase-mediated DNA damage to cell death involve activation of caspases in the cytoplasm by proapoptotic molecules released from mitochondria. In some cells, apoptotic response also involves the death receptor Fas (APO-1/CD95). The engagement of these apoptotic effector pathways is tightly controlled by upstream regulatory pathways that respond to DNA lesions-induced by topoisomerase inhibitors in cells undergoing apoptosis. These include the proapoptotic Chk2, c-Abl and SAPK/JNK pathways, the survival PI(3)kinase-Akt-dependent pathway and the transcription factors p53 and NF-kappaB. Initiation of cellular responses to DNA lesions-induced by topoisomerase inhibitors is ensured by the protein kinases DNA-PK, ATM and ATR, which bind to DNA breaks. These kinases commonly called "DNA sensors" mediate their effects (DNA repair, cell cycle arrest and/or apoptosis) by phosphorylating a large number of substrates, including several downstream kinases such as c-Abl and the checkpoint protein Chk2. c-Abl induces apoptosis by activating cell death pathways (e.g., SAPK, p53 and p73) and inhibiting cell survival pathways [e.g., PI(3)kinase]. The DNA-damage regulating kinase Chk2, in addition to its role in cell cycle arrest and/or DNA repair, can induce apoptosis by phosphorylation/activation of the promyelocytic leukemia (PML) protein and p53. Finally, we will review the recent observations that support a role for topoisomerases in chromatin fragmentation during the execution phase of apoptosis.
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PMID:Apoptosis induced by topoisomerase inhibitors. 1276 73

To explore the molecular mechanisms underlying the actions of Taxol and the functionally related molecule epothilone B (EpoB), we have analyzed the gene expression profiles in A549 cells in response to increasing concentrations of these microtubule-stabilizing drugs. An almost identical expression pattern was observed in cells treated with either Taxol or EpoB. Low concentrations of the drugs induced aberrant mitosis including asymmetric and multipolar cell divisions. At drug concentrations that triggered G(2)-M arrest, cells escaped from a prolonged mitotic arrest without cell division, resulting in tetraploid G(1) cells. This mitotic slippage is correlated with diminished expression of cdc2 kinase, topoisomerase IIalpha, BUB3, and BUB2-like protein 1, as well as with an increased expression of 14-3-3-sigma. Poly(ADP-ribose) polymerase cleavage, an early indicator of apoptosis, occurred in cells undergoing mitotic slippage and in aneuploid cells resulting from aberrant mitosis. In contrast, cells arrested in mitosis demonstrated no signal for apoptosis but had an increased expression of survivin, an inhibitor of apoptosis. Induction of aneuploid or tetraploid G(1) cells was accompanied by increased expression of CD95, p21, and BTG2 that may contribute to cell death because their expression was diminished in an EpoB-resistant cell line. In contrast, expression of GADD45 and PTGF-beta could promote cell survival. We conclude that abnormal mitotic exit is required for apoptotic cell death induced by microtubule-stabilizing drugs.
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PMID:Gene expression and mitotic exit induced by microtubule-stabilizing drugs. 1463 18

Exposure to topoisomerase II inhibitors is linked to the generation of leukemia involving translocations of the MLL gene, normally restricted to an 8.3 kbp tract, the breakpoint cluster region (BCR). Using an in vitro assay, apoptotic activators, including radiation and anti-CD95 antibody, trigger site-specific cleavage adjacent to exon 12 within the MLL BCR and promote translocation of the MLL gene in cells that can survive. To explore the mechanism of cleavage and rearrangement in more detail, the entire MLL BCR was placed into the pREP4 episomal vector and transfected into human lymphoblastoid TK6 cells. Episomes containing either the MLL BCR, or deletion constructs of 367 bp or larger, were cleaved at the same position as genomic MLL after exposure to apoptotic stimuli. Further analysis of sequence motifs surrounding the cleaved region of MLL showed the presence of both a predicted nuclear matrix attachment sequence and a potential strong binding site for topoisomerase II, flanking the site of cleavage. Inactivation of topoisomerase II by the catalytic inhibitor merbarone did not inhibit MLL cleavage, suggesting that the initial cleavage step for MLL rearrangement is not mediated by topoisomerase II.
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PMID:Cleavage of the MLL gene by activators of apoptosis is independent of topoisomerase II activity. 1619 84

CD95 (Fas/Apo-1) triggers apoptotic cell death via a caspase-dependent pathway. Inhibition of caspase activation blocks proapoptotic signaling and thus, prevents execution of apoptosis. Besides induction of apoptotic cell death, CD95 has been reported to trigger necrotic cell death in susceptible cells. In this study, we investigated the interplay between apoptotic and necrotic cell death signaling in T cells. Using the agonistic CD95 antibody, 7C11, we found that caspase inhibition mediated by the pancaspase inhibitor, zVAD-fmk, prevented CD95-triggered cell death in Jurkat T cells but not in A3.01 T cells, although typical hallmarks of apoptosis, such as DNA fragmentation or caspase activation were blocked. Moreover, the caspase-independent cell death in A3.01 cells exhibited typical signs of necrosis as detected by a rapid loss of cell membrane integrity and could be prevented by treatment with the radical scavenger butylated hydroxyanisole (BHA). Similar to CD95-induced cell death, apoptosis triggered by the DNA topoisomerase inhibitors, camptothecin or etoposide was shifted to necrosis when capsase activation was inhibited. In contrast to this, ZVAD was fully protective when apoptosis was triggered by the serpase inhibitor, Nalpha-tosyl-phenyl-chloromethyl ketone (TPCK). TPCK was not protective when administered to anti-CD95/ZVAD-treated A3.01 cells, indicating that TPCK does not possess anti-necrotic activity but fails to activate the necrotic death pathway. Our findings show (a) that caspase inhibition does not always protect apoptotic T cells from dying but merely activates a caspase-independent mode of cell death that results in necrosis and (b) that the caspase-inhibitor-induced shift from apoptotic to necrotic cell death is dependent on the cell type and the proapoptotic stimulus.
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PMID:Caspase inhibition in apoptotic T cells triggers necrotic cell death depending on the cell type and the proapoptotic stimulus. 1636 81


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