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)

Cross-linking of cell surface Fas molecules by Fas ligand or by agonistic anti-Fas Abs induces cell death by apoptosis. We found that a serine protease inhibitor, N-tosyl-L-lysine chloromethyl ketone (TLCK), dramatically enhances Fas-mediated apoptosis in the human T cell line Jurkat and in various B cell lines resistant to Fas-mediated apoptosis. The enhancing effect of TLCK is specific to Fas-induced cell death, with no effect seen on TNF-alpha or TNF-related apoptosis-inducing ligand-induced apoptosis. TLCK treatment had no effect on Fas expression levels on the cell surface, and neither promoted death-inducing signaling complex formation nor decreased expression levels of cellular inhibitors of apoptosis (FLICE inhibitory protein, X chromosome-linked inhibitor of apoptosis, and Bcl-2). Activation of the Fas-mediated apoptotic pathway by anti-Fas Ab is accompanied by aggregation of Fas molecules to form oligomers that are stable to boiling in SDS and beta-ME. Fas aggregation is often considered to be required for Fas-mediated apoptosis. However, sensitization of cells to Fas-mediated apoptosis by TLCK or other agents (cycloheximide, protein kinase C inhibitors) causes less Fas aggregation during the apoptotic process compared with that in nonsensitized cells. These results show that Fas aggregation and Fas-mediated apoptosis are not directly correlated and may even be inversely correlated.
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PMID:Fas aggregation does not correlate with Fas-mediated apoptosis. 1141 35

Depsipeptide is in clinical trials for chronic lymphocytic leukemia (CLL) on the basis of earlier observations demonstrating selective in vitro activity in CLL. We sought to determine the relationship of histone H3 and H4 acetylation, inhibition of histone deacetylase, and apoptosis observed in CLL cells to justify a pharmacodynamic end point in these clinical trials. We demonstrate that in vitro depsipeptide induces histone H3 and H4 acetylation and histone deacetylase enzyme inhibition at concentrations corresponding to the LC50 (concentration producing 50% cell death) for cultured CLL cells (0.038 microM depsipeptide). The changes in histone acetylation are lysine specific, involving H4 K5, H4 K12, and H3 K9, and to a lesser extent H4 K8, but not H4 K16 or H3 K14. Depsipeptide-induced apoptosis is caspase dependent, selectively involving the tumor necrosis factor (TNF) receptor (extrinsic pathway) initiating caspase 8 and effector caspase 3. Activation of caspase 8 was accompanied by the down-regulation of cellular FLICE-inhibitory protein (c-FLIP, I-FLICE) without evidence of Fas (CD95) up-regulation. Changes in other apoptotic proteins, including Bcl-2, Bax, Mcl-1, and X-linked inhibitor of apoptosis (XIAP), were not observed. Our results demonstrate a relationship between target enzyme inhibition of histone deacetylase, histone H3 and H4 acetylation, and apoptosis involving the TNF-receptor pathway of apoptosis that is not used by other therapeutic agents in CLL. These data suggest use of histone H3 and H4 acetylation, inhibition of histone deacetylase, and down-regulation of FLIP as pharmacodynamic end points for further evaluation of this drug in patients.
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PMID:Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein. 1264 37

Although the transplantation of alginate-poly-L-lysine-alginate encapsulated islets of Langerhans usually is successful, graft survival is still limited. Molecular analysis by RT-PCR of the encapsulated islets may provide insight into the mechanisms that affect islets during graft failure. However, RT-PCR on encapsulated islets is not possible because the poly-L-lysine of the capsule interferes with both cDNA synthesis and PCR amplification. We applied a method that mechanically removes the microcapsules from the islets after a short trypsin-EDTA treatment (decapsulation), thereby enabling RT-PCR analysis. The results of this study show that the decapsulation procedure does not affect islet vitality and has only minor effects on islet function and morphology. The decapsulation does not affect GAPDH, beta-actin, Bcl-2, or Bax gene expression. This method is an improvement over the time-consuming manual dissection of microcapsules because it allows for the rapid and relatively harmless removal of capsules on a larger scale. Decapsulation offers the possibility of applying RT-PCR, as well as other methods, which cannot be performed on encapsulated islets.
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PMID:Effective removal of alginate-poly-L-lysine microcapsules from pancreatic islets by use of trypsin-EDTA. 1456 13

Osteoclasts (OCs) undergo rapid apoptosis without trophic factors, such as macrophage colony-stimulating factor (M-CSF). Their apoptosis was associated with a rapid and sustained increase in the pro-apoptotic BH3-only Bcl-2 family member Bim. This was caused by the reduced ubiquitylation and proteasomal degradation of Bim that is mediated by c-Cbl. Although the number of OCs was increased in the skeletal tissues of bim-/- mice, the mice exhibited mild osteosclerosis due to reduced bone resorption. OCs differentiated from bone marrow cells of bim-/- animals showed a marked prolongation of survival in the absence of M-CSF, compared with bim+/+ OCs, but the bone-resorbing activity of bim-/- OCs was significantly reduced. Overexpression of a degradation-resistant lysine-free Bim mutant in bim-/- cells abrogated the anti-apoptotic effect of M-CSF, while wild-type Bim did not. These results demonstrate that ubiquitylation-dependent regulation of Bim levels is critical for controlling apoptosis and activation of OCs.
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PMID:Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim. 1465 36

Bcl-x(L) is a potent inhibitor of apoptosis. While Bcl-x(L) can be bound to mitochondria, a substantial fraction, depending on the cell type or tissue, is found in the cytosol of healthy cells. Gel filtration and crosslinking experiments reveal that, unlike monomeric Bax, Bcl-x(L) migrates in a complex of approximately 50 kDa in the cytosol. Co-immunoprecipitation experiments indicate that Bcl-x(L) in the cytosol forms homodimers. The C-terminal hydrophobic tails of two Bcl-x(L) molecules are involved in homodimer formation, and analysis of mutants demonstrates that the C-terminal lysine residue and the G138 residue lining the BH3-binding pocket are required for homodimerization. The flexible loop preceding the C-terminal tail in Bcl-x(L) is longer than that of several monomeric Bcl-2 family members and is a requisite for the homodimer formation. Bad binding to Bcl-x(L) dissociates the homodimers and triggers Bcl-x(L) binding to mitochondrial membranes. The C-terminal tail of Bcl-x(L) is also required to mediate Bcl-x(L)/Bax heterodimer formation. Both mitochondrial import and antiapoptotic activity of different Bcl-x(L) mutants correlate with their ability to form homodimers.
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PMID:Bcl-x(L) sequesters its C-terminal membrane anchor in soluble, cytosolic homodimers. 1513 99

Necrotizing enterocolitis (NEC) is characterized by the upregulation of proinflammatory proteins, nitrosative stress, and increased enterocyte apoptosis. We examined the expression and regulation of the Bcl-2/adenovirus EIB 19-kDa-interacting protein 3 (BNIP3), a pro-apoptotic gene regulated by nitric oxide (NO) in hepatocytes, in NEC. Newborn rats subjected to hypoxia and fed a conventional formula by gavage (FFH) developed NEC and demonstrated elevated expression of BNIP3 mRNA and protein in mucosal scrapings of the ileal samples and in the liver. In contrast, control rats [breast-fed (BF) without hypoxia] did not develop NEC or elevated BNIP3 expression in these tissues. BNIP3 expression paralleled the histological manifestation of NEC. Supplementation of the formula with L-Nomega-(1-iminoethyl)lysine, an inducible NO synthase inhibitor, reduced BNIP3 expression in FFH animals to the levels found in BF animals. Both hypoxia and peroxynitrite upregulated BNIP3 protein expression in human intestinal cells. Finally, ileal samples obtained from infants undergoing surgical resection for acute NEC demonstrated higher levels of BNIP3 protein. Because hypoxia and formation of reactive nitrogen species may promote gut barrier failure, we propose that upregulation of the cell death-related protein BNIP3 is one possible mechanism associated with enterocyte cell death observed in the intestine with NEC.
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PMID:Intestinal and hepatic expression of BNIP3 in necrotizing enterocolitis: regulation by nitric oxide and peroxynitrite. 1600 67

The aim of this study was to determine the expression of Bcl-2 gene and prognostic importance of Bcl-2 expression in paraffin embedded blocks of patients diagnosed with non-small cell lung cancer (NSCLC). This study included the retrospective analysis of overall 46 patients diagnosed with NSCLC in our clinic between 1996 and 1999. In 16 (34.8%) patients, the diagnosis was made on biopsy of bronchial mucosa and in 30 (65.2%) patients, on materials obtained by surgical resection (lobectomy and pneumonectomy). We reviewed the sections 4-6 microns in size and stained with Hemotoxylin-Eosine (HE) obtained from paraffin embedded blocks and fixed by 10% formalin. These sections are transferred on to slides covered with poly-L-lysine, then de-paraffinization was made. In all cases, immunohistochemical staining with Bcl-2 antibodies was performed. Positive staining was observed in 9 (19.6%) patients, but not in 37 (80.4%) patients. Out of 32 cases with squamous cell tumor, 8 (25%) were observed to have positive staining in their sections, but 24 (75%) were not so. No staining was observed in 11 cases whose cell type was adenoma and two cases whose cell type was adenosquamos (100%). Staining was present in the section of one case with large cell (100%). Median survival time was 36.6 months in cases in which staining was observed and 6.10 months in cases in which staining was not observed, with a significant difference (p< 0.05). In conclusion, the rate of survival was higher in cases in which staining was present.
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PMID:Distribution of Bcl-2 gene expression and its prognostic value in non-small cell lung cancer. 1645 30

Pharmacological manipulation of gene expression is considered a promising avenue to reduce postischemic brain damage. Histone deacetylases (HDACs) play a central role in epigenetic regulation of transcription, and inhibitors of HDACs are emerging as neuroprotective agents. In this study, we investigated the effect of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) on histone acetylation in control and ischemic mouse brain. We report that brain histone H3 acetylation was constitutively present at specific lysine residues in neurons and astrocytes. It is noteworthy that in the ischemic brain tissue subjected to 6 h of middle cerebral artery occlusion, histone H3 acetylation levels drastically decreased, without evidence for a concomitant change of histone acetyl-transferase or deacetylase activities. Treatment with SAHA (50 mg/kg i.p.) increased histone H3 acetylation within the normal brain (of approximately 8-fold after 6 h) and prevented histone deacetylation in the ischemic brain. These effects were accompanied by increased expression of the neuroprotective proteins Hsp70 and Bcl-2 in both control and ischemic brain tissue 24 h after the insult. It is noteworthy that at the same time point, mice injected with SAHA at 25 and 50 mg/kg had smaller infarct volumes compared with vehicle-receiving animals (28.5% and 29.8% reduction, p < 0.05 versus vehicle, Student's t test). At higher doses, SAHA was less efficient in increasing Bcl-2 and Hsp70 expression and did not afford significant ischemic neuroprotection (13.9% infarct reduction). Data demonstrate that pharmacological inhibition of HDACs promotes expression of neuroprotective proteins within the ischemic brain and underscores the therapeutic potential of molecules inhibiting HDACs for stroke therapy.
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PMID:Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain. 1694 32

The tripeptide-copper complex, described as a growth factor for various kinds of differentiated cells, stimulates the proliferation of dermal fibroblasts and elevates the production of vascular endothelial growth factor, but decreased the secretion of transforming growth factor-beta1 by dermal fibroblasts. Dermal papilla cells (DPCs) are specialized fibroblasts, which are important in the morphogenesis and growth of hair follicles. In the present study, the effects of L-alanyl-L-histidyl-L-lysine-Cu2+ (AHK-Cu) on human hair growth ex vivo and cultured dermal papilla cells were evaluated. AHK-Cu (10(-12) - 10(-9) M) stimulated the elongation of human hair follicles ex vivo and the proliferation of DPCs in vitro. Annexin V-fluorescein isothiocyanate/propidium iodide labeling and flow cytometric analysis showed that 10(-9) M AHK-Cu reduced the number of apoptotic DPCs, but this decrease was not statistically significant. The ratio of Bcl-2/Bax was elevated, and the levels of the cleaved forms of caspase-3 and PARP were reduced by treatment with 10(-9) M AHK-Cu. The present study proposed that AHK-Cu promotes the growth of human hair follicles, and this stimulatory effect may occur due to stimulation of the proliferation and the preclusion of the apoptosis of DPCs.
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PMID:The effect of tripeptide-copper complex on human hair growth in vitro. 1770 34

Human TFPI-2 is an extracellular matrix-associated Kunitz-type serine proteinase inhibitor. We previously demonstrated that a human fibrosarcoma cell line, HT-1080, does not express TFPI-2, but genetic restoration of TFPI-2 expression in these cells markedly inhibited their growth and metastasis in vivo. In the present study, either full-length recombinant TFPI-2, or its mutated first Kunitz-type domain (R24K KD1), were offered to HT-1080 cells, and the degree of apoptosis assessed by nuclear fragmentation, ethidium bromide and acridine orange staining, fluorescence activated cell sorting, immunoblotting and gene expression profiling. R24K KD1 induced apoptosis in 69% of HT-1080 cells in a 48 h period compared to 39% for TFPI-2, while a KD1 preparation lacking a reactive site arginine/lysine residue (R24Q KD1) produced only an 18% apoptosis rate, suggesting that the observed apoptosis was related to proteinase inhibition. Immunoblotting experiments indicated increased caspase 3 and 9 activation, up-regulation of pro-apoptotic Bax and suppression of anti-apoptotic Bcl-2 protein. Finally, microarray analyses of R24K KD1-treated cells indicated elevated expression of several pro-apoptotic genes and under-expression of anti-apoptotic genes. Collectively, our results demonstrate that treatment of HT-1080 cells exogenously with either TFPI-2 or R24K KD1 activates caspase-mediated, pro-apoptotic signaling pathways resulting in apoptosis.
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PMID:Human tissue factor pathway inhibitor-2 induces caspase-mediated apoptosis in a human fibrosarcoma cell line. 1840 18


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