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

Glucocorticoids play a role in regulation of T lymphocytes homeostasis and development. In particular, glucocorticoid treatment induces massive apoptosis of CD4(+)CD8(+) double-positive (DP) thymocytes. This effect is due to many mechanisms, mainly driven by modulation of gene transcription. To find out which genes are modulated, we analyzed DP thymocytes treated for 3 h with dexamethasone (a synthetic glucocorticoid) by global gene expression profiling. Results indicate modulation of 163 genes, also confirmed by either RNase protection assay or real-time polymerase chain reaction. In particular, dexamethasone caused down-regulation of genes promoting DP thymocyte survival (e.g., Notch1, suppressor of cytokine signaling 1, and inhibitor of DNA binding 3) or modulation of genes activating cell death through the ceramide pathway (UDP-glucose ceramide glucosyltransferase, sphingosine 1-phosphate phosphatase, dihydroceramide desaturase, isoform 1, and G protein-coupled receptor 65) or through the mitochondrial machinery. Among the latter, there are Bcl-2 family members (Bim, Bfl-1, Bcl-xL, and Bcl-xbeta), genes involved in the control of redox status (thioredoxin reductase, thioredoxin reductase inhibitor, and NADP(+)-dependent isocitrate dehydrogenase) and genes belonging to Tis11 family that are involved in mRNA stability. Our study suggests that dexamethasone treatment of DP thymocytes modulates several genes belonging to apoptosis-related systems that can contribute to their apoptosis.
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PMID:Modulation of pro- and antiapoptotic molecules in double-positive (CD4+CD8+) thymocytes following dexamethasone treatment. 1691 56

Celastrol, a quinone methide triterpenoid, was isolated as an inhibitor of NF-kappaB from Celastrus orbiculatus. This compound dose-dependently inhibited a variety of stimuli-induced NF-kappa B-regulated gene expression and the DNA-binding of NF-kappa B in different cell lines without affecting DNA-binding activity of AP-1. Preincubation of celastrol completely blocked the LPS-, TNF-alpha-, or PMA-induced degradation and phosphorylation of I kappa B alpha. Importantly, celastrol inhibited IKK activity and the constitutively active IKK beta activity in a dose-dependent manner without either affecting the NF-kappa B activation induced by RelA over-expression or directly suppressing the DNA-binding of activated NF-kappa B. However, mutation of cysteine 179 in the activation loop of IKK beta abolished sensitivity towards to celastrol, suggesting that celastrol suppressed the NF-kappa B activation by targeting cysteine 179 in the IKK. To verify that celastrol is a NF-kappa B inhibitor, we investigated its effect on some NF-kappa B target genes expressions. Celastrol prevented not only LPS-induced mRNA expression of iNOS and TNF-alpha, but also TNF-alpha-induced Bfl-1/A1 expression, a prosurvival Bcl-2 homologue. Consistent with these results, celastrol significantly suppressed the production of NO and TNF-alpha in LPS-stimulated RAW264.7 cells, and increased the cytotoxicity of TNF-alpha in HT-1080 cells. We also demonstrated that celastrol showed anti-inflammatory and anti-tumor activities in animal models. Taken together, this study extends our understanding on the molecular mechanisms underlying the anti-inflammatory and anti-cancer activities of celastrol and celastrol-containing medicinal plant, which would be a valuable candidate for the intervention of NF-kappa B-dependent pathological conditions.
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PMID:Inhibition of NF-kappa B activation through targeting I kappa B kinase by celastrol, a quinone methide triterpenoid. 1698

Anti-apoptotic Bcl-2-family proteins (Bcl-2, Bcl-x(L), Bfl-1, Mcl-1, Bcl-W and Bcl-B) have been recently validated as drug discovery targets for cancer, owed to their ability to confer tumor resistance to chemotherapy or radiation. The anti-apoptotic activity of Bcl-2 proteins is due to their ability to heterodimerize with their pro-apoptotic counterparts (proteins such as Bad, Bim or Bid) via a conserved peptide region termed BH3. Thus, molecules that mimic pro-apoptotic BH3 domains represent a direct approach to overcoming the protective effects of anti-apoptotic proteins such as Bcl-2 and Bcl-x(L). Here, we report on the development and evaluation of two novel Lanthanide-based assays that are formatted for high-throughput screening of small molecules capable of antagonizing BH3-Bcl-2 interactions. The assay conditions, robustness and reproducibility (Z' factors) are described. These assays represent useful tools to enable further studies in the search for novel, safe and effective anti-cancer agents targeting Bcl-2-family proteins.
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PMID:Robust lanthanide-based assays for the detection of anti-apoptotic Bcl-2-family protein antagonists. 1699 62

The PTEN tumor suppressor gene modulates cell growth and survival known to be regulated by the activation of the transcription factor NFkappaB, suggesting PTEN might affect the NFkappaB activation pathway. We found that PTEN inhibited NFkappaB activation induced by TNF. The suppression of NFkappaB activation correlated with sequential inhibition of the tumor necrosis factor-induced expression of NFkappaB-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin) gene products. Downregulation of the antiapoptotic genes by PTEN increased TNF-induced apoptosis, as indicated by caspase activation, TUNEL, annexin staining, and esterase assay. We conclude that the ectopic expression of PTEN enhances TNF-induced apoptosis and downregulates the proliferation of glioma cells through the suppression of various molecules including NFkappaB, and various mediators of cellular survival and proliferation, and that this targets might be essential for its central role in the growth and survival of glioma cancer cells.
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PMID:PTEN enhances TNF-induced apoptosis through modulation of nuclear factor-kappaB signaling pathway in human glioma cells. 1701 14

Significant advancements in our understanding of cell-survival signalling in AD (Alzheimer's disease) stem from recent investigations into the metabolism, trafficking and fate of the essential omega-3 fatty acid DHA (docosahexaenoic acid) (C(22:6), n=3). Brain synaptic terminals and neuronal plasma membranes are highly enriched in DHA, and deficiencies in this polyunsaturated fatty acid are characteristic of AD-affected brain. Oxidative stress, targeting phospholipids containing DHA, and age-related DHA depletion are associated with the progressive erosion of normal cognitive function in AD. Current studies support the idea that DHA itself and novel DHA-derived neural synapse- and membrane-derived lipid messengers have considerable potential to modulate cell survival signalling in stressed cultured neural cell models in vitro and in mammalian models of learning, memory and AD in vivo. Key players in this intrinsic rescue system include the alpha-secretase-processed neurotrophin sAPPalpha [soluble APPalpha (amyloid precursor protein alpha)] peptide, the DHA-derived 10,17S-docosatriene NPD1 (neuroprotectin D1), a tandem brain cytosolic phospholipase A(2) and 15-lipoxygenase enzymatic system that biosynthesizes NPD1, and a small family of anti-apoptotic neuroprotective genes that encode Bcl-2, Bcl-X(L) and Bfl-1 (A1). This paper reviews current ideas regarding DHA and the oxygenated DHA derivative NPD1, intrinsically triggered biolipid neuroprotectants that along with their associated rescue pathways, contribute to life-or-death decisions of brain cells during homoeostasis, aging and neurodegenerative disease.
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PMID:Survival signalling in Alzheimer's disease. 1707 1

Unlike the tocopherols, the tocotrienols, also members of the vitamin E family, have an unsaturated isoprenoid side chain. In contrast to extensive studies on tocopherol, very little is known about tocotrienol. Because the nuclear factor-kappaB (NF-kappaB) pathway has a central role in tumorigenesis, we investigated the effect of gamma-tocotrienol on the NF-kappaB pathway. Although gamma-tocotrienol completely abolished tumor necrosis factor alpha (TNF)-induced NF-kappaB activation, a similar dose of gamma-tocopherol had no effect. Besides TNF, gamma-tocotrienol also abolished NF-kappaB activation induced by phorbol myristate acetate, okadaic acid, lipopolysaccharide, cigarette smoke, interleukin-1beta, and epidermal growth factor. Constitutive NF-kappaB activation expressed by certain tumor cells was also abrogated by gamma-tocotrienol. Reducing agent had no effect on the gamma-tocotrienol-induced down-regulation of NF-kappaB. Mevalonate reversed the NF-kappaB inhibitory effect of gamma-tocotrienol, indicating the role of hydroxymethylglutaryl-CoA reductase. Gamma-tocotrienol blocked TNF-induced phosphorylation and degradation of IkappaBalpha through the inhibition of IkappaBalpha kinase activation, thus leading to the suppression of the phosphorylation and nuclear translocation of p65. gamma-Tocotrienol also suppressed NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, TAK1, receptor-interacting protein, NIK, and IkappaBalpha kinase but not that activated by p65. Additionally, the expressions of NF-kappaB-regulated gene products associated with antiapoptosis (IAP1, IAP2, Bcl-xL, Bcl-2, cFLIP, XIAP, Bfl-1/A1, TRAF1, and Survivin), proliferation (cyclin D1, COX2, and c-Myc), invasion (MMP-9 and ICAM-1), and angiogenesis (vascular endothelial growth factor) were down-regulated by gamma-tocotrienol. This correlated with potentiation of apoptosis induced by TNF, paclitaxel, and doxorubicin. Overall, our results demonstrate that gamma-tocotrienol inhibited the NF-kappaB activation pathway, leading to down-regulation of various gene products and potentiation of apoptosis.
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PMID:Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. 1711 79

Whether resveratrol, a component of red grapes, berries, and peanuts, could suppress the proliferation of multiple myeloma (MM) cells by interfering with NF-kappaB and STAT3 pathways, was investigated. Resveratrol inhibited the proliferation of human multiple myeloma cell lines regardless of whether they were sensitive or resistant to the conventional chemotherapy agents. This stilbene also potentiated the apoptotic effects of bortezomib and thalidomide. Resveratrol induced apoptosis as indicated by accumulation of sub-G(1) population, increase in Bax release, and activation of caspase-3. This correlated with down-regulation of various proliferative and antiapoptotic gene products, including cyclin D1, cIAP-2, XIAP, survivin, Bcl-2, Bcl-xL, Bfl-1/A1, and TRAF2. In addition, resveratrol down-regulated the constitutive activation of AKT. These effects of resveratrol are mediated through suppression of constitutively active NF-kappaB through inhibition of IkappaBalpha kinase and the phosphorylation of IkappaBalpha and of p65. Resveratrol inhibited both the constitutive and the interleukin 6-induced activation of STAT3. When we examined CD138(+) plasma cells from patients with MM, resveratrol inhibited constitutive activation of both NF-kappaB and STAT3, leading to down-regulation of cell proliferation and potentiation of apoptosis induced by bortezomib and thalidomide. These mechanistic findings suggest that resveratrol may have a potential in the treatment of multiple myeloma.
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PMID:Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. 1716 50

This study investigated radioresistance mechanisms in the doxorubicin-resistant acute myelogenous leukemia (AML)-2/DX100. AML-2/DX100 also showed resistance to radiation. AML-2/DX100 characterized by down-regulated catalase expression was supersensitive to exogenous hydrogen peroxide whereas they increased defense mechanisms against endogenous reactive oxygen species (ROS) as compared with AML-2/WT. In AML-2/WT, radiation increased Bax expression and its translocation to mitochondria but had little effect on translocation of Bcl-2 and consequently induced the release of cytochrome c from the mitochondria with the subsequent caspase-3 activation. On the contrary, in AML-2/DX100, radiation neither increased Bax expression nor its translocation to mitochondria while it increased Bcl-2 translocation to mitochondria. A specific p38 MAPK inhibitor SB203580 increased radioresistance in AML-2/WT but little in AML-2/DX100. It inhibited radiation-induced Bax translocation in AML-2/WT but not in AML-2/DX100, indicating that p38 MAPK is working after irradiation in AML-2/WT but not in AML-2/DX100. Electrophoretic mobility shift assay and Western blot analysis revealed that NF-kappaB in AML-2/DX100 was more activated with degradation of cytosolic IkappaBalpha than was that of AML-2/WT. cDNA microarray showed that Bfl-1/A1 and granzyme H in AML-2/DX100 were highly up-regulated (6.21-fold) and down-regulated (6.49-fold), respectively, as compared with each of AML-2/WT, which were confirmed by RT-PCR assay. Taken together, these results indicate that radioresistance mechanisms of AML-2/DX100 could be related to alterations in ROS-scavenging activity, in mitochondrial translocation of Bax and Bcl-2, and in expression of pro-apoptotic (granzyme H) and anti-apoptotic (Bfl-1/A1) genes. It has been shown that balance of p38 MAPK and NF-kappaB signals is a determinant in radiosensitivity of AML-2/WT and AML-2/DX100.
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PMID:Balance of NF-kappaB and p38 MAPK is a determinant of radiosensitivity of the AML-2 and its doxorubicin-resistant cell lines. 1721 10

Defects in apoptosis mechanisms play important roles in malignancy and autoimmunity. Orphan nuclear receptor Nur77/TR3 has been demonstrated to bind antiapoptotic protein Bcl-2 and convert it from a cytoprotective to a cytodestructive protein, representing a phenotypic conversion mechanism. Of the 6 antiapoptotic human Bcl-2 family members, we found that Nur77/TR3 binds strongest to Bcl-B, showing selective reactivity with Bcl-B, Bcl-2, and Bfl-1 but not Bcl-X(L), Mcl-1, or Bcl-W. Nur77 converts the phenotype of Bcl-B from antiapoptotic to proapoptotic. Bcl-B is prominently expressed in plasma cells and multiple myeloma. Endogenous Bcl-B associates with endogenous Nur77 in RPMI 8226 myeloma cells, where RNA interference experiments demonstrated dependence on Bcl-B for Nur77-induced apoptosis. Furthermore, a Nur77-mimicking peptide killed RPMI 8226 myeloma cells through a Bcl-B-dependent mechanism. Because Bcl-B is abundantly expressed in plasma cells and some myelomas, these findings raise the possibility of exploiting the Nur77/Bcl-B mechanism for apoptosis for eradication of autoimmune plasma cells or myeloma.
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PMID:Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma. 1722 26

Elevated expression of the antiapoptotic protein Bfl-1 (A1) was previously reported in several cancer cell lines. Recently, molecular profiling of large B-cell lymphoma identified Bfl-1 as a gene signature in 'OxPhos' diffuse large B-cell lymphoma subtype and in primary mediastinal large B-cell lymphoma, suggesting that in addition to Bcl-2, Bcl-xL and Mcl-1, Bfl-1 may be a relevant target in the design of new strategies for cancer therapy. Using short hairpin RNA strategy, we show here that Bfl-1 silencing in one lymphoblastoid B-cell line and in two diffuse large B-cell lymphoma cell lines potently induces their apoptosis and sensitizes those cell lines to anti-CD20 (Rituximab)-mediated cell death as well as to apoptosis induced by chemotherapeutic molecules such as doxorubicin, vincristine, cisplatin and fludarabine. These results demonstrate for the first time that Bfl-1 is an essential protein for survival of malignant B cells and suggest Bfl-1 may represent a potential target for future drug development against B cell lymphoma.
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PMID:Downregulation of Bfl-1 protein expression sensitizes malignant B cells to apoptosis. 1735 99


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