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)

We observed that photodynamic therapy (PDT) induces the expression and phosphorylation of the inhibitor of apoptosis (IAP) protein survivin in murine and human cancer cells and tumors. Survivin inhibits caspase-9, blocks apoptosis, and is associated with resistance to chemotherapy and radiation. Survivin is a client protein for the 90-kDa heat shock protein (Hsp-90), and the binding of survivin to Hsp-90 assists in the maturation, proper folding, assembly, and transport of this IAP protein. A derivative of the antibiotic geldanamycin, 17-allylamino-17-demethoxygeldanamycin (17-AAG), interferes with proper binding of client proteins, such as survivin, to Hsp-90 and leads to misfolding of client proteins, ubiquination, and proteasome degradation. We hypothesized that PDT efficacy may be reduced by treatment-mediated expression and phosphorylation of survivin, and therefore, targeting the survivin pathway could increase PDT responsiveness. To address this hypothesis, we examined cellular and molecular responses following exposure to PDT, 17-AAG, and the combination of PDT plus 17-AAG in human BT-474 breast cancer cells using Photofrin and NPe6 as photosensitizers. Cells treated with the combination of PDT and 17-AAG exhibited decreased expression of the Hsp-90 client proteins phosphorylated survivin, phosphorylated Akt, and Bcl-2. The decreased expression of these client proteins was accompanied by higher apoptotic indexes and increased cytotoxicity. To confirm a specific role for survivin in modulating PDT, we used a human melanoma cell line, YUSAC2/T34A-C4, stably transfected with an inducible dominant-negative survivin gene under the control of a tetracycline-regulated (tet-off) promoter. PDT treatment of melanoma cells expressing the dominant-negative survivin resulted in increased cleavage of the caspase substrate poly(ADP-ribose) polymerase, apoptosis, and cytotoxicity when compared with results following PDT of the same melanoma cell line expressing wild-type survivin. These results show for the first time that targeting survivin and possibly other Hsp-90 client proteins improves in vitro PDT responsiveness and suggest that manipulation of the antiapoptotic pathway maintained by survivin may enhance PDT-mediated cancer therapy.
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PMID:Survivin, a member of the inhibitor of apoptosis family, is induced by photodynamic therapy and is a target for improving treatment response. 1751 Apr 30

Bcr-Abl is the cause of Philadelphia-positive (Ph(+)) leukemias and also constitutes their principal therapeutic target, as exemplified by dramatic effects of imatinib mesylate. However, mono-targeting of Bcr-Abl does not always achieve complete leukemia eradication, and additional strategies those enable complete elimination of leukemic cells are desired to develop. Here we demonstrate that INNO-406, a much more active Bcr-Abl tyrosine kinase inhibitor than imatinib, augments the activities of several proapoptotic Bcl-2 homology (BH)3-only proteins (Bim, Bad, Bmf and Bik) and induces apoptosis in Ph(+) leukemia cells via Bcl-2 family-regulated intrinsic apoptosis pathway. ABT-737, an inhibitor of antiapoptotic Bcl-2 and Bcl-X(L), greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315I mutation. In contrast, co-treatment with INNO-406 and other pharmacologic inducers of those BH3-only proteins, such as 17-allylaminogeldanamycin, an heat shock protein-90 inhibitor, or PS-341, a proteasome inhibitor, did not further increase the BH3-only protein levels or sensitize leukemic cells to INNO-406-induced apoptosis, suggesting a limit to how much expression levels of BH3-only proteins can be increased by anticancer agents. Thus, double-barrelled molecular targeting for Bcr-Abl-driven oncogenic signaling and the cell protection by antiapoptotic Bcl-2 family proteins may be the rational therapeutic approach for eradicating Ph(+) leukemic cells.
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PMID:Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia. 1751 Jun 58

alphaA-crystallin (Cryaa/HSPB4) is a small heat shock protein and molecular chaperone that prevents nonspecific aggregation of denaturing proteins. Several point mutations in the alphaA-crystallin gene cause congenital human cataracts by unknown mechanisms. We took a novel approach to investigate the molecular mechanism of cataract formation in vivo by creating gene knock-in mice expressing the arginine 49 to cysteine mutation (R49C) in alphaA-crystallin (alphaA-R49C). This mutation has been linked with autosomal dominant hereditary cataracts in a four-generation Caucasian family. Homologous recombination in embryonic stem cells was performed using a plasmid containing the C to T transition in exon 1 of the cryaa gene. alphaA-R49C heterozygosity led to early cataracts characterized by nuclear opacities. Unexpectedly, alphaA-R49C homozygosity led to small eye phenotype and severe cataracts at birth. Wild type littermates did not show these abnormalities. Lens fiber cells of alphaA-R49C homozygous mice displayed an increase in cell death by apoptosis mediated by a 5-fold decrease in phosphorylated Bad, an anti-apoptotic protein, but an increase in Bcl-2 expression. However, proliferation measured by in vivo bromodeoxyuridine labeling did not decline. The alphaA-R49C heterozygous and homozygous knock-in lenses demonstrated an increase in insoluble alphaA-crystallin and alphaB-crystallin and a surprising increase in expression of cytoplasmic gamma-crystallin, whereas no changes in beta-crystallin were observed. Co-immunoprecipitation analysis showed increased interaction between alphaA-crystallin and lens substrate proteins in the heterozygous knock-in lenses. To our knowledge this is the first knock-in mouse model for a crystallin mutation causing hereditary human cataract and establishes that alphaA-R49C promotes protein insolubility and cell death in vivo.
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PMID:Mechanism of small heat shock protein function in vivo: a knock-in mouse model demonstrates that the R49C mutation in alpha A-crystallin enhances protein insolubility and cell death. 1805 99

Hydrogen sulfide (H(2)S) is an endogenously produced gaseous signaling molecule with diverse physiological activity. The potential protective effects of H(2)S have not been evaluated in the liver. The purpose of the current study was to investigate if H(2)S could afford hepatoprotection in a murine model of hepatic ischemia-reperfusion (I/R) injury. Hepatic injury was achieved by subjecting mice to 60 min of ischemia followed by 5 h of reperfusion. H(2)S donor (IK1001) or vehicle were administered 5 min before reperfusion. H(2)S attenuated the elevation in serum alanine aminotransferase (ALT) by 68.6% and aspartate aminotransferase (AST) by 70.8% compared with vehicle group. H(2)S-mediated cytoprotection was associated with an improved balance between reduced glutathione (GSH) vs. oxidized glutathione (GSSG), an attenuated formation of lipid hydroperoxides, and an increased expression of thioredoxin-1 (Trx-1). Furthermore, H(2)S inhibited the progression of apoptosis after I/R injury by increasing the protein expression of heat shock protein (HSP-90) and Bcl-2. These results indicate that H(2)S protects the murine liver against I/R injury through an upregulation of intracellular antioxidant and antiapoptotic signaling pathways.
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PMID:Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and antiapoptotic signaling. 1856 6

Glioblastoma (GBM) is the most common type of primary brain cancer and carries a dismal prognosis primarily due to the emergence of resistance towards extant radiation, conventional and targeted chemotherapies. Although GBM resists therapy-induced apoptosis, tumors show a seemingly paradoxical propensity for florid intratumoral necrogenesis. This necrosis manifests pathologically as microscopic foci or confluent expanses of necrotic tumor. While it is now well recognized that necrosis is an active cell death process and that apoptosis and necrosis death modalities are intertwined on multiple levels, the precise molecular mechanisms and genetic elements underlying these forms of cell death in GBM remain areas of active investigation. In recent oncogenomic studies, we identified a novel GBM oncoprotein, Bcl2-Like 12 (Bcl2L12), which is significantly expressed in the majority of primary GBM tumor specimens and distantly related to canonical Bcl-2 proteins. Due to its distinctive impact on cell death signaling, Bcl2L12 phenocopies pro-necrotic and anti-apoptotic propensities of high grade glioma: Mechanistically, we determined that unlike prototypic Bcl-2 family members, Bcl2L12 does not safeguard mitochondrial membrane integrity, but instead potently inhibits apoptosis at the level of post-mitochondrial effector caspase-3/7 activation. A combination of enforced expression, RNAi-mediated extinction, co-localization and protein interaction studies revealed that Bcl2L12 inhibits caspases 3 and 7 via distinct mechanisms. Direct physical interaction underlies Bcl2L12's inhibition of caspase-7 processing, whereas Bcl2L12-induced transcriptional upregulation of the small heat shock protein alpha B-crystallin is instrumental to neutralization of caspase-3 activation. Mirroring the cellular phenotype elicited by energy depletion, genetic or pharmacologic inhibition of post-mitochondrial apoptosis signaling molecules, Bcl2L12 promotes necrogenesis in glial cells in the context of a proapoptotic stimulus establishing that it represents a novel regulator of the balance between apoptosis and necrosis in GBM.
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PMID:What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator. 1876 59

Bortezomib has been introduced recently in the therapy of multiple myeloma (MM), a disease that is frequently associated with progressive renal failure. Because bortezomib-based therapy has been reported to lead to a rapid recovery of kidney function in patients with MM, we decided to study its direct effects in proximal tubular epithelial cells (PTCs) compared with glomerular mesangial cells (GMCs). After 24 h of stimulation, 50 nM bortezomib led to a 6.37-fold induction of apoptosis and markedly activated caspase-9 and -3 in GMCs but not in PTCs. In PTCs but not in GMCs, bortezomib led to a strong time-dependent degradation of IkappaB-alpha and to a long-lasting phosphorylation of both NF-kappaBp65 and extracellular signal-regulated kinase 1/2. Microarray analysis in bortezomib-treated PTCs revealed a time-dependent predominance of antiapoptotic genes compared with proapoptotic genes. Bortezomib (50 nM) induced heat shock protein (Hsp) 70 mRNA and protein levels in PTCs, whereas basal and bortezomib-stimulated Hsp70 protein expression was much weaker in GMCs. Moreover, bortezomib induced Bcl-2-associated athanogene (BAG) 3 mRNA and protein expression but inhibited BAG5 mRNA levels in PTCs. These data suggest that the reduced susceptibility of PTCs to bortezomib-induced cell apoptosis is because of cell type-specific effects of this compound on apoptosis/survival genes and pathways. The concept of bortezomib representing a blocker of both NF-kappaB activation and cell survival should be carefully examined in particular renal cell types.
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PMID:Bortezomib-induced survival signals and genes in human proximal tubular cells. 1877 64

BAG3 protein, a member of the BAG co-chaperones family, sustains cell survival in a variety of normal and neoplastic cell types, via its interaction with a variety of partners, such as the heat shock protein (HSP) 70, Bcl-2, Raf-1 and others. Expression of BAG3 is induced by some stressful stimuli, such as heat shock, heavy metal exposure. We have reported that proteasome inhibitors can also induce BAG3 expression at the transcriptional level and the induction of BAG3 compromises proteasome inhibitors-mediated apoptosis. However, the molecular mechanism of BAG3 upregulation has not been elucidated. In the current study, we provide evidence that heat shock transcription factor 1 (HSF1) is involved in BAG3 induction by proteasome inhibitor MG132. Using a series of varying lengths of 5'-flanking region of the BAG3 gene into luciferase reporter vectors, we found that MG132 stimulated the promoter activity via the -326/-233 and -825/-689 regions, which contains one putative heat shock-responsive element (HSE) for HSF1-binding, respectively. Site-directed deletion of the sites abrogated the enhanced reporter activity in response to MG132 treatment. Chromatin immunoprecipitation assay demonstrated that HSF1 directly bound to the MG132-responsive site on the BAG3 promoter. Activation of HSF1 occurred with MG132 along with BAG3 upregulation. Furthermore, knockdown HSF1 by small interfering RNA attenuated the BAG3 upregulation due to MG132.These results indicate that the proteasome inhibitor MG132 induces BAG3 expression through HSF1 activation.
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PMID:Proteasome inhibitor MG132 induces BAG3 expression through activation of heat shock factor 1. 1900 20

We have isolated a high-light and heat-shock inducible gene, Arabidopsis heat shock transcription factor (HsfA2), which induces expression of various types of target gene such as heat shock protein 18.2-CI (Hsp18.1-CI), galactinol synthase 1 (GolS1), and Bcl-2-associated athanogene 6 (Bag6). Here we investigated the regulatory system of target genes operating via HsfA2. A transient reporter assay using a luciferase reporter construct with different fragments of the Hsp18.1-CI, the GolS1, or the Bag6 promoter showed that two modules of a TATA-proximal heat shock element (HSE) are essential for transcriptional activation by HsfA2. Electrophoretic mobility shift assay demonstrated that the increase in protein complex formation onto the HSE was markedly suppressed during high-light stress and recovery from the stress in knockout HsfA2 plants. HsfA2 appears to function not only in the triggering of response to environmental stress, but also in the amplification of the signal in the response.
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PMID:Analysis of the regulation of target genes by an Arabidopsis heat shock transcription factor, HsfA2. 1935 26

Bax, a Bcl-2 interacting protein, plays a central role in several stimuli-induced apoptosis pathways through its functional and physical interactions with various biologically important proteins. Identification of the Bax-modulating protein network should be useful to further our understanding of Bax-mediated apoptosis. For the first time, we performed proteome-wide quantification and identification of differentially expressed proteins between Bax+/- and Bax-/- HCT116 clones using a newly developed quantitative mass spectrometric analysis strategy. This strategy is based on forward and reverse differential isotope labeling of the proteome digests of two comparative cells, followed by two-dimensional liquid chromatography separation and automated peptide deposition to matrix-assisted laser desorption ionization sample plates for MS quantification and MS/MS peptide sequence identification. We quantified and identified 200 differentially expressed proteins involved in various cellular processes. Through bioinformatic analysis, four groups of differentially expressed proteins were highlighted for the association with Bax: mitochondria permeability transition channel proteins, Bax regulator proteins, heat shock protein family members, and oxidative stress-triggered proteins. These results indicate the functional diversity of Bax and provide new research directions to study the biology of Bax-regulated apoptosis.
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PMID:Targeted quantitative mass spectrometric identification of differentially expressed proteins between Bax-expressing and deficient colorectal carcinoma cells. 1942 6

Cancer progression is associated with reduced apoptosis and increased proliferation. We hypothesized that upregulation of the Bag family of survival cochaperones and its molecular partners of the Bcl-2 and heat shock protein (HSP) families would correlate with disease progression and survival in ovarian cancer. Bag-1, Bag-4, HSP27, HSP70, Bcl-2, and Bcl-X(L) expression was immunohistochemically analyzed in effusions (188) and patient-matched solid tumors (43 primary carcinomas, 81 solid metastases). Results were analyzed for anatomic site-related differences, and association with clinicopathologic parameters and survival. Bag-1, Bag-4, and HSP70 were detected in the tumor cell nuclei and cytoplasm, whereas HSP27, Bcl-2, and Bcl-X(L) had exclusively cytoplasmic localization. Antiapoptotic protein expression in effusions differed significantly from primary tumors and metastases. Cytoplasmic Bag-1 (P=0.002), nuclear and cytoplasmic HSP70 (P<0.001), and Bcl-2 (P=0.001) expression was higher in primary carcinomas and solid metastases compared with effusions, whereas Bcl-X(L) (P=0.01), nuclear Bag-1 (P<0.001), nuclear Bag-4 (P=0.01), and cytoplasmic Bag-4 (P=0.002) were upregulated in effusions. Bcl-X(L) expression was associated with poor response to chemotherapy at diagnosis (P=0.02) and HSP27 expression was associated with high-grade tumors (P=0.01). Increased cytoplasmic HSP70 staining in effusions correlated with poor overall survival for the entire cohort (P=0.01). In primary carcinomas, higher Bcl-2 expression correlated with worse overall (P=0.04) and progression-free (P=0.02) survival. Antiapoptotic proteins are differentially expressed in effusions compared with solid tumors, whereas primary carcinomas and solid metastases have comparable expression patterns. HSP70 expression in effusions may be a prognostic marker of poor survival, with a similar role for Bcl-2 in primary carcinomas.
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PMID:Expression and clinical role of antiapoptotic proteins of the bag, heat shock, and Bcl-2 families in effusions, primary tumors, and solid metastases in ovarian carcinoma. 1962 Sep 38


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