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)

Nasal natural killer (NK)-cell lymphoma was resistant to various antitumor agents. Although high expression of p-glycoprotein has been reported, other molecular mechanism of the chemo-resistance is largely unknown. Activation of STAT3 and expression of major apoptosis-related proteins Bcl-2, Bcl-x, and Mcl-1 were analyzed by immunohistochemistry. Effects of STAT3 inhibitor AG490 on NK-YS cell line were analyzed by Western blotting and flow cytometric apoptosis assay. STAT3 was activated in six of the nine nasal NK-cell lymphomas (67%). In contrast, STAT3 activation was detected in 35% of diffuse large B-cell lymphoma (DLBCL) and in 10% of follicular lymphoma (FL). Frequent activation of STAT3 was significantly correlated with Mcl-1 expression in nasal NK-cell lymphoma, i.e., Mcl-1 was positive in five of six STAT3-active cases and negative in all three STAT3-inactive ones. In DLBCL, not only six out of seven STAT3-active cases (86%) but also eight out of thirteen STAT3-inactive cases (62%) were positive for Mcl-1 expression. Latent membrane protein-1 was positive in four nasal NK-cell lymphomas, among which three cases showed intermediate STAT3 activation. Inhibition of STAT3 activation by JAK inhibitor AG490 decreased Mcl-1 expression and induced apoptosis in STAT3-active NK-YS cells. Serum starvation rather increased the Mcl-1 level in NK-YS cells, and this effect was also canceled by AG490. These results suggest that activation of STAT3-Mcl-1 axis may play a role in the chemotherapy resistance of nasal NK-cell lymphoma. The pathway may be one of the future therapeutic targets of this intractable disease.
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PMID:Frequent STAT3 activation is associated with Mcl-1 expression in nasal NK-cell lymphoma. 1996 19

In cell lines, the Epstein-Barr virus (EBV)-encoded protein latent membrane protein 2A (LMP2A) protects B-cells from apoptosis by blocking B-cell receptor (BCR) signalling. However, EBV-infected B-cells in vivo are extremely different from cell lines. This study used a murine transgenic model in which B-cells express LMP2A and a BCR specific for hen egg lysozyme to determine whether LMP2A protects resting and antigen-activated B-cells from apoptosis. LMP2A allows BCR signal transduction and induces constitutive activation of NF-kappaB to increase Bcl-2 levels that afford LMP2A-mediated protection from apoptosis in the absence or presence of antigen. In contrast, low levels of NF-kappaB inhibitor only affected Bcl-2 and Bcl-xL levels and increased apoptosis in LMP2A-negative B-cells after BCR cross-linking. These data suggest that LMP2A uniquely makes resting B-cells sensitive to NF-kappaB inhibition and apoptosis and suggest that NF-kappaB may be a novel target to eradicate latently EBV-infected B-cells.
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PMID:Epstein-Barr virus LMP2A imposes sensitivity to apoptosis. 2048 64

Various approaches have been taken to study the function of prion proteins. Biochemical methods were applied to search for a binding partner of PrPC which is attached to the cell surface by a glycosylphosphatidylinositol GPI anchor (1). The glial fibrillary acidic protein was one of the first possible binding partners to be described (2) followed by Bcl-2 (3,4), molecular chaperones (5), amyloid precursor-like protein 1 (6), the 37-kDa laminin receptor (7) and a 66-kDa membrane protein which has not been characterized in more detail (8). However, it has not been possible to show any biological significance for PrPC binding of these proteins. Based on biochemical analyses of chicken PrPC, Harris et al. (9) hypothesized that PrPC may play a role in the regulation of the expression of cholinergic receptors at the neuromuscular endplate.
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PMID:Prion protein as copper-binding protein at the synapse. 2137 96

Nasal-type NK/T cell lymphoma (NK/TCL) is an increasingly recognized disease entity of aggressive clinical behavior. The objective of this study was to investigate the correlation between the clinical features of NK/TCL and patient prognosis. Immunohistochemical detection of Epstein-Barr virus (EBV)-associated latent membrane protein (LMP)-1, Cyclin D1 and Bcl-2 protein expression, as well as TUNEL staining, were performed. Of the 58 cases studied, 47 (81%) displayed positive expression of LMP-1 protein, which was associated with the presence of B symptoms and patient prognosis. In addition, high expression of Cyclin D1 and Bcl-2 protein was observed to correlate with poor prognosis and decreased survival. More importantly, LMP-1 and Cyclin D1 appeared to be co-expressed. This, along with other parameters such as clinical stage at diagnosis and enlarged lymph nodes, could be used as an independent prognostic factor for clinical outcome, as the survival rate of NK/TCL patients was closely associated with LMP-1/Cyclin D1 co-expression, advanced clinical stage and lymph node infiltration.
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PMID:Expression of LMP-1 and Cyclin D1 protein is correlated with an unfavorable prognosis in nasal type NK/T cell lymphoma. 2147 18

Higd-1a (hypoxia induced gene domain family-1a) is a mitochondrial inner membrane protein with a conformation of N-terminal outside-C-terminal outside and loop inside. There are four Higd genes, Higd-1a, -1b, -1c and -2a, in the mouse. Higd-1a and -2a are expressed primarily in the brain, heart, kidney and leukocytes. HIF (hypoxia-inducible factor) overexpression induced the endogenous expression and promoter activity of Higd-1a. Mutation of the HRE (hypoxia-response element) site at -32bp in the Higd-1a promoter reduced the promoter activity, suggesting that transcription of Higd-1a is regulated by binding of the transcription factor HIF to the HRE. Higd-1a promoted cell survival under hypoxia. RAW264.7 cells stably transfected with Higd-1a underwent less apoptosis than control cells in a hypoxic condition, and hypoxia-induced apoptosis was strongly enhanced when endogenous Higd-1a was silenced by siRNA. The survival effect of Higd-1a was completely abolished by deletion of the 26 N-terminal amino acids, and we showed that Higd-1a increased survival by inhibiting cytochrome C release and reducing the activities of caspases. However, expression of Bcl-2, Bax, Bad, and BNIP3 and translocation of AIF were unaffected under the same conditions. Higd-2a also enhanced cell survival under hypoxia. Cells transfected with Higd-2a underwent less apoptosis than control cells in hypoxic conditions, and hypoxia-induced apoptosis increased when endogenous Higd-2a was depleted. Together these observations indicate that Higd-1a is induced by hypoxia in a HIF-dependent manner and its anti-apoptotic effect results from inhibiting cytochrome C release and reducing caspase activities.
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PMID:The survival effect of mitochondrial Higd-1a is associated with suppression of cytochrome C release and prevention of caspase activation. 2185 40

Despite making up only a minor fraction of the total cellular glutathione, recent studies indicate that the mitochondrial glutathione pool is essential for cell survival. Selective depletion of mitochondrial glutathione is sufficient to sensitize cells to mitochondrial oxidative stress (MOS) and intrinsic apoptosis. Glutathione is synthesized exclusively in the cytoplasm and must be actively transported into mitochondria. Therefore, regulation of mitochondrial glutathione transport is a key factor in maintaining the antioxidant status of mitochondria. Bcl-2 resides in the outer mitochondrial membrane where it acts as a central regulator of the intrinsic apoptotic cascade. In addition, Bcl-2 displays an antioxidant-like function that has been linked experimentally to the regulation of cellular glutathione content. We have previously demonstrated a novel interaction between recombinant Bcl-2 and reduced glutathione (GSH), which was antagonized by either Bcl-2 homology-3 domain (BH3) mimetics or a BH3-only protein, recombinant Bim. These previous findings prompted us to investigate if this novel Bcl-2/GSH interaction might play a role in regulating mitochondrial glutathione transport. Incubation of primary cultures of cerebellar granule neurons (CGNs) with the BH3 mimetic HA14-1 induced MOS and caused specific depletion of the mitochondrial glutathione pool. Bcl-2 was coimmunoprecipitated with GSH after chemical cross-linking in CGNs and this Bcl-2/GSH interaction was antagonized by preincubation with HA14-1. Moreover, both HA14-1 and recombinant Bim inhibited GSH transport into isolated rat brain mitochondria. To further investigate a possible link between Bcl-2 function and mitochondrial glutathione transport, we next examined if Bcl-2 associated with the 2-oxoglutarate carrier (OGC), an inner mitochondrial membrane protein known to transport glutathione in liver and kidney. After cotransfection of CHO cells, Bcl-2 was coimmunoprecipitated with OGC and this novel interaction was significantly enhanced by glutathione monoethyl ester. Similarly, recombinant Bcl-2 interacted with recombinant OGC in the presence of GSH. Bcl-2 and OGC cotransfection in CHO cells significantly increased the mitochondrial glutathione pool. Finally, the ability of Bcl-2 to protect CHO cells from apoptosis induced by hydrogen peroxide was significantly attenuated by the OGC inhibitor phenylsuccinate. These data suggest that GSH binding by Bcl-2 enhances its affinity for the OGC. Bcl-2 and OGC appear to act in a coordinated manner to increase the mitochondrial glutathione pool and enhance resistance of cells to oxidative stress. We conclude that regulation of mitochondrial glutathione transport is a principal mechanism by which Bcl-2 suppresses MOS.
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PMID:Bcl-2 is a novel interacting partner for the 2-oxoglutarate carrier and a key regulator of mitochondrial glutathione. 2211 89

Among lymphoproliferative disorders, lymph node infarction appears to be most frequently seen in diffuse large B-cell lymphoma, followed by follicular lymphoma, with other types being rare. We experienced one such case, classical Hodgkin's lymphoma (cHL) associated with lymph node infarction, in which Reed-Sternberg (RS) cells were positive for CD15, CD30, fascin, PAX-5, p53, latent membrane protein-1 (LMP-1), Bcl-2, and EBV-encoded small non-polyadenylated RNAs. Furthermore, RS cells in the infarcted area were still positive for CD30, fascin, p53, and Bcl-2. For definitive diagnosis of nodal lymphomas including Hodgkin's lymphoma, identification of the effacement of normal nodal architecture is essential. Although this could not be evaluated in our case because of predominant reactive follicular hyperplasia with interfollicular distribution of RS cells, the presence of large cells with RS cell-related molecules together with the distorted distribution of cCD3-positive cells and CD20-positive cells led us to make a definitive diagnosis of cHL. It is, therefore, considered that immunohistochemical evaluation of the infarcted lymph node is, at least on some occasions, still informative for more accurate diagnosis of lymphoid neoplasia. Hodgkin's lymphoma should also be considered when one encounters lymph node infarction.
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PMID:Lymph node infarction in classical Hodgkin's lymphoma. 2270 29

NKT cells are a unique subset of T cells that recognize glycolipid Ags presented in the context of CD1d molecules. NKT cells mount strong antitumor responses and are a major focus in developing effective cancer immunotherapy. It is known that CD1d molecules are constantly internalized from the cell surface, recycled through the endocytic compartments, and re-expressed on the cell surface. However, little is known about the regulation of CD1d-mediated Ag processing and presentation in B cell lymphoma. Prosurvival factors of the Bcl-2 family, such as Bcl-xL, are often upregulated in B cell lymphomas and are intimately linked to sphingolipid metabolism, as well as the endocytic compartments. We hypothesized that Bcl-xL can regulate CD1d-mediated Ag presentation to NKT cells. We found that overexpression or induction of Bcl-xL led to increased Ag presentation to NKT cells. Conversely, the inhibition or knockdown of Bcl-xL led to decreased NKT cell activation. Furthermore, knockdown of Bcl-xL resulted in the loss of CD1d trafficking to lysosome-associated membrane protein 1(+) compartments. Rab7, a late endosomal protein, was upregulated and CD1d molecules accumulated in the Rab7(+) late endosomal compartment. These results demonstrate that Bcl-xL regulates CD1d-mediated Ag processing and presentation to NKT cells by altering the late endosomal compartment and changing the intracellular localization of CD1d.
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PMID:Bcl-xL regulates CD1d-mediated antigen presentation to NKT cells by altering CD1d trafficking through the endocytic pathway. 2507 Aug 54

The voltage-dependent anion channel (VDAC) or porin is a major membrane protein integrated into the mitochondrial outer membrane in eukaryotes. It is encoded as three isoforms (VDAC1 to 3), which play differential roles in metabolism and cell death. As a channel, VDAC mediates metabolites, ions and water movements through the outer membrane in physiological conditions, but it can also participate to mitochondrial membrane permeabilization, an apoptotic checkpoint in stress and pathological conditions. Indeed, due to its subcellular location, VDAC interacts with many molecules as diverse as NAD+, lipids and cytosolic proteins such as hexokinase, tubulin, GSK3, Bax and Bcl-2 family members and mitochondrial proteins, such as the adenine nucleotide translocase (ANT). All these interactions can influence VDAC role in cell fate determination. In the recent past, major efforts focused on VDAC1 channel function and regulation by calcium and reactive oxygen species, and comparatively, fewer studies have been undertaken on VDAC2 and 3 and their pathophysiological involvement. Here, we review recent insights into the role of VDAC isoforms in cell death, and its regulation by phosphorylation or protein-lipid interactions and discuss the putative consequences of this post-translational modification on cell fate, notably in the context of lipid accumulation. This might have important implications for the understanding of basic mechanisms of mitochondrial lipid sensing and might contribute to define a novel therapeutic target for future investigation.
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PMID:VDAC phosphorylation, a lipid sensor influencing the cell fate. 2508 40

Vascular cell adhesion molecule 1 (VCAM1) is a member of the Immunoglobulin superfamily and encodes a cell surface sialoglycoprotein expressed in cytokine-activated endothelium. This type I membrane protein mediates leukocyte-endothelial cell adhesion, facilitates the downstream signaling, and may play a role in the development of artherosclerosis and rheumatoid arthritis. Accumulating evidence has demonstrated that VCAM1 exerts an anti-apoptotic effect in several tumor tissues such as ovarian cancer and breast cancer. Intracerebral hemorrhage (ICH) is the second most common subtype of stroke with high morbidity and mortality, which imposes a big burden on individuals and the whole society. These together prompted us to question whether VCAM1 has some association with neuron apoptosis during the pathological process of ICH. An ICH rat model was established and assessed by behavioral tests in order to explore the role of VCAM1 after ICH. Up-regulation of VCAM1 was observed in brain areas surrounding the hematoma following ICH by western blotting and immunohistochemistry. Immunofluorescence manifested VCAM1 was strikingly increased in neurons, but not in astrocytes and microglia. Furthermore, we detected that neuronal apoptosis marker active caspase-3 had co-localizations with VCAM1. At the same time, Bcl-2 was also co-localized with VCAM1. Taken together, our findings suggested that VCAM1 might be involved in the neuronal apoptosis and pathophysiology of ICH.
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PMID:Up-regulation of VCAM1 Relates to Neuronal Apoptosis After Intracerebral Hemorrhage in Adult Rats. 2586 55


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