Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine how hyaluronidase increases certain cancer cell sensitivity to tumor necrosis factor (TNF) cytotoxicity, we report here the isolation and characterization of a hyaluronidase-induced murine WW domain-containing oxidoreductase (WOX1). WOX1 is composed of two N-terminal WW domains, a nuclear localization sequence, and a C-terminal alcohol dehydrogenase (ADH) domain. WOX1 is mainly located in the mitochondria, and the mitochondrial targeting sequence was mapped within the ADH domain. Induction of mitochondrial permeability transition by TNF, staurosporine, and atractyloside resulted in WOX1 release from mitochondria and subsequent nuclear translocation. TNF-mediated WOX1 nuclear translocation occurred shortly after that of nuclear factor-kappaB nuclear translocation, whereas both were independent events. WOX1 enhanced TNF cytotoxicity in L929 cells via its WW and ADH domains as determined using stable cell transfectants. In parallel with this observation, WOX1 also enhanced TRADD (TNF receptor-associated death domain protein)-mediated cell death in transient expression experiments. Antisense expression of WOX1 raised TNF resistance in L929 cells. Enhancement of TNF cytotoxicity by WOX1 is due, in part, to its significant down-regulation of the apoptosis inhibitors Bcl-2 and Bcl-x(L) (>85%), but up-regulation of pro-apoptotic p53 ( approximately 200%) by the ADH domain. When overexpressed, the ADH domain mediated apoptosis, probably due to modulation of expression of these proteins. The WW domains failed to modulate the expression of these proteins, but sensitized COS-7 cells to TNF killing and mediated apoptosis in various cancer cells independently of caspases. Transient cotransfection of cells with both p53 and WOX1 induced apoptosis in a synergistic manner. WOX1 colocalizes with p53 in the cytosol and binds to the proline-rich region of p53 via its WW domains. Blocking of WOX1 expression by antisense mRNA abolished p53 apoptosis. Thus, WOX1 is a mitochondrial apoptogenic protein and an essential partner of p53 in cell death.
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PMID:Hyaluronidase induction of a WW domain-containing oxidoreductase that enhances tumor necrosis factor cytotoxicity. 1105 90

Apoptosis induction by the pure antiestrogen faslodex, also known as ICI 182780 (ICI), is associated with an effective down-regulation of Bcl-2 expression in the human breast cancer cell line MCF-7. Recent observations point out that beside members of the Bcl-2 family also the TNFR1 signaling pathway may be involved in apoptosis induction by antiestrogens. In this report we have analyzed the expression of members of the TNFR1 signaling pathway during the apoptotic process induced by the pure antiestrogen faslodex and by tamoxifen (Tam) in MCF-7 breast cancer cells. Treatment with 10(-7) M ICI or 10(-7) M Tam leads to a time dependent increase of TNFR1 and TRADD steady-state mRNA levels in MCF-7 cells. In contrast, Bcl-2 expression was strongly decreased following administration of ICI but only weakly after administration of Tam. Western blot analysis and studies by the use of fluorescence microscopy and flow cytometry revealed a time dependent induction of TNFR1 protein and cell surface expression in MCF-7 cells in response to treatment with ICI. To investigate if TNFR1 is functionally involved in apoptosis induction by antiestrogens, we tested whether TNFR1 blocking antibodies can counteract the growth inhibitory action of Tam and ICI. Coincubation of MCF-7 cells with antiestrogens (ICI or Tam) and blocking TNFR1 antibodies lead to an increase in cell viability. Our results provide evidence for a cross talk between the TNFR1 signaling pathway and antiestrogens during the process of apoptosis induction in MCF-7 breast cancer cells. The superiority of the pure antiestrogen ICI to induce apoptosis in MCF-7 cells may result from its capability to modulate the induction of apoptosis via Bcl-2 as well as TNF-associated signal transduction pathways.
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PMID:Treatment with the pure antiestrogen faslodex (ICI 182780) induces tumor necrosis factor receptor 1 (TNFR1) expression in MCF-7 breast cancer cells. 1111 59

We have previously reported that mice with cardiac-specific overexpression of tumor necrosis factor (TNF)- alpha develop myocardial inflammation, cardiac hypertrophy, and dilated cardiomyopathy. TNF- alpha is reported to induce apoptosis in cultured cardiac myocytes. To investigate the role of apoptosis in this transgenic model, wild-type controls (WT) and transgenic mice (TG) at the age of 1, 8, and 40 weeks were analyzed. Increased incidence of apoptosis in TG was indicated by DNA laddering. TUNEL assays revealed that the frequencies of apoptotic cells were increased in the TG myocardium at all ages. However, as revealed by histochemical and immunofluorescent methods, most of the apoptotic cells appeared to be non-myocytes even in the mice with overt congestive heart failure. To elucidate the signaling pathways responsible for TNF- alpha induced apoptosis, expression of apoptosis-related genes were evaluated by multi-probe RNase protection assays. Transcripts for death-domain-related proteins, including TNFR1, Fas, FADD, TRADD, and RIP, were constitutively expressed in WT and upregulated in the TG myocardium. Expression of caspase-1 through -8 was also enhanced in TG. While both anti- and pro-apoptotic Bcl-2 family genes were constitutively expressed in WT, TNF- alpha overexpression strongly induced anti-apoptotic A1 in the myocardium. Furthermore, TNF- alpha overexpression activated NF- kappa B, a mediator of anti-apoptotic pathways, in the myocardium. Thus, overexpression of TNF- alpha activated both anti- and pro-apoptotic pathways in the myocardium, resulting in an increase of apoptosis, primarily in non-myocytes. These results suggest that TNF- alpha by itself is not sufficient to induce apoptosis in cardiac myocytes in vivo.
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PMID:Overexpression of tumor necrosis factor- alpha activates both anti- and pro-apoptotic pathways in the myocardium. 1143 39

The prostate apoptosis response-4 (par-4) gene was isolated in a differential screen for immediate-early genes that are up-regulated during apoptosis of prostate cancer cells. Unlike most other immediate-early genes, par-4 is exclusively induced during apoptosis. The expression or induction of par-4 is not restricted to prostatic cells. The par-4 gene is widely expressed in diverse normal tissues and cell types and conserved during evolution. Par-4 protein contains a leucine zipper domain that is essential for sensitization of cells to apoptosis. Functional studies indicate that par-4 expression is necessary to induce apoptosis. Par-4 protein may induce apoptosis by a p53-independent pathway that involves cytoplasmic inactivation of atypical protein kinase C isoforms resulting in down-regulation of MAP kinase activity and an up-regulation of p38 kinase activity. However, Par-4 is detected in the cytoplasm and in the nucleus, suggesting both cytoplasmic and nuclear roles for the pro-apoptotic protein. Interestingly, Par-4 is predicted to contain a death domain homologous to that of Fas or TRADD, and may therefore trigger a death cascade analogous to that of the death domain proteins. Par-4-dependent apoptosis is abrogated by Bcl-2 and by caspase inhibitors. Identification of the components of the p53-independent apoptosis pathway induced by Par-4 may help to further elucidate the mechanism of Par-4 action. Moreover, in view of the pro-apoptotic function of Par-4, its role in diseases, such as cancer and neurogenerative disorders, whose pathophysiology involves apoptotic cell death needs further investigation.
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PMID:Apoptosis mediated by a novel leucine zipper protein Par-4. 1464 2

Ras farnesyltransferase inhibitor (FTI) exhibit antiproliferative and antiangiogenic effects through a mechanism that is poorly understood. Because of the known role of Ras in the activation of transcription factor NF-kappaB and because NF-kappaB-regulated genes can control cell survival and angiogenesis, we postulated that FTI mediates its effects in part by modulating NF-kappaB activation. Therefore, in the present study we investigated the effect of FTI, SCH 66336, on NF-kappaB and NF-kappaB-regulated gene expression activated by a variety of inflammatory and carcinogenic agents. We demonstrate by DNA-binding assay that NF-kappaB activation induced by tumor necrosis factor (TNF), phorbol 12-myristate 13-acetate, cigarette smoke, okadaic acid, and H(2)O(2) was completely suppressed by SCH 66336; the suppression was not cell type-specific. This FTI suppressed the activation of IkappaBalpha kinase (IKK), thus abrogating the phosphorylation and degradation of IkappaBalpha. Additionally, TNF-activated Ras and SCH 66336 inhibited the activation. Also, overexpression of Ras (V12) enhanced TNF-induced NF-kappaB activation, and adenoviral dominant-negative Ras (N17) suppressed the activation, thus suggesting the critical role of Ras in TNF signaling. SCH 66336 also inhibited the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK but not that activated by the p65 subunit of NF-kappaB. The TNF-induced NF-kappaB-regulated gene products cyclin D1, COX-2, MMP-9, survivin, IAP1, IAP2, XIAP, Bcl-2, Bfl-1/A1, TRAF1, and FLIP were all down-regulated by SCH 66336, which potentiated apoptosis induced by TNF and doxorubicin. Overall, our results indicate that SCH 66336 inhibited activation of NF-kappaB and NF-kappaB-regulated gene expressions induced by carcinogens and inflammatory stimuli, which may provide a molecular basis for the ability of SCH 66336 to suppress proliferation and angiogenesis.
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PMID:Protein farnesyltransferase inhibitor (SCH 66336) abolishes NF-kappaB activation induced by various carcinogens and inflammatory stimuli leading to suppression of NF-kappaB-regulated gene expression and up-regulation of apoptosis. 1509 May 42

Guggulsterone, derived from Commiphora mukul and used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, has been recently shown to antagonize the farnesoid X receptor and decrease the expression of bile acid-activated genes. Because activation of NF-kappaB has been closely linked with inflammatory diseases affected by guggulsterone, we postulated that it must modulate NF-kappaB activation. In the present study, we tested this hypothesis by investigating the effect of this steroid on the activation of NF-kappaB induced by inflammatory agents and carcinogens. Guggulsterone suppressed DNA binding of NF-kappaB induced by tumor necrosis factor (TNF), phorbol ester, okadaic acid, cigarette smoke condensate, hydrogen peroxide, and interleukin-1. NF-kappaB activation was not cell type-specific, because both epithelial and leukemia cells were inhibited. Guggulsterone also suppressed constitutive NF-kappaB activation expressed in most tumor cells. Through inhibition of IkappaB kinase activation, this steroid blocked IkappaBalpha phosphorylation and degradation, thus suppressing p65 phosphorylation and nuclear translocation. NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK was also blocked by guggulsterone but without affecting p65-mediated gene transcription. In addition, guggulsterone decreased the expression of gene products involved in anti-apoptosis (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), proliferation (cyclin D1 and c-Myc), and metastasis (MMP-9, COX-2, and VEGF); this correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents. Overall, our results indicate that guggulsterone suppresses NF-kappaB and NF-kappaB-regulated gene products, which may explain its anti-inflammatory activities.
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PMID:Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. 1532 87

A loss of TNF receptors expression has been found in advanced lung cancers, and human A549 lung adenocarcinoma cells are resistant to the cytotoxic effects of TNF-alpha and cisplatin. Here, the mechanisms of the drug resistance of A549 were extensively studied by gene modulation of the cells by solamargine (SM) which was isolated from Solanum incanum herb. SM induced morphological changes of chromatin condensation, DNA fragmentation, and sub-G(1) peak in a DNA histogram of A549 cells, indicating cell death by apoptosis. SM elevated the expressions of TNF-R1 and -R2 and overcame the resistance of A549 cells to TNF-alpha and -beta. The recruitment of TRADD, FADD, and activation of caspase-8 and -3 in SM-treated A549 cells evidenced the activation of TNFRs signal transduction. In addition, release of cytochrome c from mitochondria, down-expression of Bcl-2 and Bcl-x(L), up-regulation of Bax, and caspase-9 activities were observed in SM-treated A549 cells. Combinational treatment of SM and cisplatin synergistically enhanced caspase-8, -9, and -3 activities in A549 cells. Thus, SM sensitizes A549 cells through TNFRs and mitochondria-mediated pathways and may have anticancer potential against TNFs- and cisplatin-resistance lung cancer cells.
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PMID:Action of solamargine on TNFs and cisplatin-resistant human lung cancer cells. 1533 28

Solamargine (SM), isolated from Solanum incanum herb, displayed a superior cytotoxicity in four human lung cancer cell lines. The half-inhibitory concentrations (IC50), of the cell viability assay for H441, H520, H661 and H69 cells were 3, 6.7, 7.2 and 5.8 microM, respectively. SM-induced apoptosis of these cells by PS externalization in a dose-dependent manner and increased sub-G1 fraction were observed. Quenching of the expression of tumor necrosis factor receptors (TNFRs) during the progress of human lung carcinogenesis has been previously reported. SM may induce cell apoptosis via modulating the expression of TNFRs and their subsequent TRADD/FADD signal cascades. Subsequently, SM treatment increased the binding activities of TNF-alpha and TNF-beta to the lung cancers, and the intrinsic TNFs-resistant cancer cells became susceptible to TNF-alpha and -beta. In addition, SM caused release of cytochrome c, downregulation of anti-apoptotic Bcl-2 and Bcl-xL, increase of caspase-3 activity, and DNA fragmentation. Thus, SM could modulate the expressions of TNFRs and Bcl-2, and might be a potential anticancer agent for TNFs and Bcl-2 related resistance of human lung cancer cells.
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PMID:Action of solamargine on human lung cancer cells--enhancement of the susceptibility of cancer cells to TNFs. 1552 63

Evodiamine, an alkaloidal component extracted from the fruit of Evodiae fructus (Evodia rutaecarpa Benth., Rutaceae), exhibits antiproliferative, antimetastatic, and apoptotic activities through a poorly defined mechanism. Because several genes that regulate cellular proliferation, carcinogenesis, metastasis, and survival are regulated by nuclear factor-kappaB (NF-kappaB), we postulated that evodiamine mediates its activity by modulating NF-kappaB activation. In the present study, we investigated the effect of evodiamine on NF-kappaB and NF-kappaB-regulated gene expression activated by various carcinogens. We demonstrate that evodiamine was a highly potent inhibitor of NF-kappaB activation, and it abrogated both inducible and constitutive NF-kappaB activation. The inhibition corresponded with the sequential suppression of IkappaBalpha kinase activity, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acetylation. Evodiamine also inhibited tumor necrosis factor (TNF)-induced Akt activation and its association with IKK. Suppression of Akt activation was specific, because it had no effect on JNK or p38 MAPK activation. Evodiamine also inhibited the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK but not that activated by the p65 subunit of NF-kappaB. NF-kappaB-regulated gene products such as Cyclin D1, c-Myc, COX-2, MMP-9, ICAM-1, MDR1, Survivin, XIAP, IAP1, IAP2, FLIP, Bcl-2, Bcl-xL, and Bfl-1/A1 were all down-regulated by evodiamine. This down-regulation potentiated the apoptosis induced by cytokines and chemotherapeutic agents and suppressed TNF-induced invasive activity. Overall, our results indicated that evodiamine inhibits both constitutive and induced NF-kappaB activation and NF-kappaB-regulated gene expression and that this inhibition may provide a molecular basis for the ability of evodiamine to suppress proliferation, induce apoptosis, and inhibit metastasis.
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PMID:Evodiamine abolishes constitutive and inducible NF-kappaB activation by inhibiting IkappaBalpha kinase activation, thereby suppressing NF-kappaB-regulated antiapoptotic and metastatic gene expression, up-regulating apoptosis, and inhibiting invasion. 1571 Jun 1

Zerumbone found in subtropical ginger Zingiber zerumbet Smith exhibits antiproliferative and antiinflammatory activities but underlying molecular mechanisms are poorly understood. As several genes that regulate proliferation and apoptosis are regulated by nuclear factor (NF)-kappaB, we hypothesized that zerumbone mediates its activity through the modulation of NF-kappaB activation. We found that zerumbone suppressed NF-kappaB activation induced by tumor necrosis factor (TNF), okadaic acid, cigarette smoke condensate, phorbol myristate acetate, and H2O2 and that the suppression was not cell type specific. Interestingly, alpha-humulene, a structural analogue of zerumbone lacking the carbonyl group, was completely inactive. Besides being inducible, constitutively active NF-kappaB was also inhibited. NF-kappaB inhibition by zerumbone correlated with sequential suppression of the IkappaBalpha kinase activity, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acylation. Zerumbone also inhibited the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK but not that activated by the p65 subunit of NF-kappaB. NF-kappaB-regulated gene products, such as cyclin D1, COX-2, MMP-9, ICAM-1, c-Myc, survivin, IAP1, IAP2, XIAP, Bcl-2, Bcl-xL, Bfl-1/A1, TRAF1 and FLIP, were all downregulated by zerumbone. This downregulation led to the potentiation of apoptosis induced by cytokines and chemotherapeutic agents. Zerumbone's inhibition of expression of these NF-kappaB-regulated genes also correlated with the suppression of TNF-induced invasion activity. Overall, our results indicated that zerumbone inhibits the activation of NF-kappaB and NF-kappaB-regulated gene expression induced by carcinogens and that this inhibition may provide a molecular basis for the prevention and treatment of cancer by zerumbone.
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PMID:Zerumbone abolishes NF-kappaB and IkappaBalpha kinase activation leading to suppression of antiapoptotic and metastatic gene expression, upregulation of apoptosis, and downregulation of invasion. 1600 45


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