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)

Malignant cell accumulation in B-cell chronic lymphocytic leukemia (B-CLL) is primarily caused by defective apoptosis rather than increased proliferation. To further understand the role of Bcl-2 family members, known regulators of apoptosis, in the abnormal B-CLL survival, we have measured their mRNA levels in fresh B-CLL cells and in cultures undergoing spontaneous apoptosis. Using RNA protection assays we found constitutive expression of most bcl-2 members with high levels of bcl2, bcl-w, bad, bak, bax, and the bcl-2/bax ratio, compared to normal PBL. Spontaneous apoptosis of B-CLL cells by in vitro culture resulted in decreased bcl-2, bcl-w, bfl-1, mcl-1, bak, bax, and bcl-2/bax expression. The pro-apoptotic member bik was only expressed in 5/19 cases and was not modulated during apoptosis, suggesting that bik is not involved in this process. Thus, several Bcl-2 family genes are regulated during B-CLL spontaneous apoptosis and their relative levels may contribute to in vivo progression of the disease.
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PMID:Bcl-2 family gene modulation during spontaneous apoptosis of B-chronic lymphocytic leukemia cells. 1497 37

The proteins of the Bcl-2 family are important regulators of programmed cell death. Structural studies of Bcl-2 family members have provided many important insights into their molecular mechanism of action and how members of this family interact with one another. To date, structural studies have been performed on six Bcl-2 family members encompassing both anti- (Bcl-x(L), Bcl-2, KSHV-Bcl-2, Bcl-w) and pro-apoptotic (Bax, Bid) members. They all show a remarkably similar fold despite an overall divergence in amino acid sequence and function (pro-apoptotic versus anti-apoptotic). The three-dimensional structures of Bcl-2 family members consist of two central, predominantly hydrophobic alpha-helices surrounded by six or seven amphipathic alpha-helices of varying lengths. A long, unstructured loop is present between the first two alpha-helices. The structures of the Bcl-2 proteins show a striking similarity to the overall fold of the pore-forming domains of bacterial toxins. This finding led to experiments which demonstrated that Bcl-x(L), Bcl-2, and Bax all form pores in artificial membranes. A prominent hydrophobic groove is present on the surface of the anti-apoptotic proteins. This groove is the binding site for peptides that mimic the BH3 region of various pro-apoptotic proteins such as Bak and Bad. Structures of Bcl-x(L) in complex with these BH3 peptides showed that they bind as an amphipathic alpha-helix and make extensive hydrophobic contacts with the protein. These data have not only helped to elucidate the interactions important for hetero-dimerization of Bcl-2 family members but have also been used to guide the discovery of small molecules that block Bcl-x(L) and Bcl-2 function. In the recently determined structure of the anti-apoptotic Bcl-w protein, the protein was also found to have a hydrophobic groove on its surface capable of binding BH3-containing proteins and peptides. However, in the native protein an additional carboxy-terminal alpha-helix interacts with the hydrophobic groove. This is reminiscent of how the carboxy-terminal alpha-helix of the pro-apoptotic protein Bax binds into its hydrophobic groove. This interaction may play a regulatory role and for Bax may explain why it is found predominately in the cytoplasm prior to activation. The hydrophobic groove of the pro-apoptotic protein, Bid protein, is neither as long nor as deep as that found in Bcl-x(L), Bcl-2, or Bax. In addition, Bid contains an extra alpha-helix, which is located between alpha1 and alpha2 with respect to Bcl-x(L), Bcl-2, and Bax. Although there are still many unanswered questions regarding the exact mechanism by which the Bcl-2 family of proteins modulates apoptosis, structural studies of these proteins have deepened our understanding of apoptosis on the molecular level.
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PMID:Structural biology of the Bcl-2 family of proteins. 1499 93

Apoptosis plays an important role during development and in the maintenance of multicellular organisms. Bcl-2 family members affect cell death in either a positive or negative fashion. Although some redundancy exists between family members, expression of certain family members is important during development in an organ-specific manner. The founding family member bcl-2 tends to be highly expressed in the embryo and declines postnatally following differentiation and maturation. Altered expression of bcl-2, as well as other family members, has been observed in disease states potentially affecting treatment modalities. Here we examine the distribution and role death repressors bcl-2, bcl-x(L) and bcl-w as well as death effectors bax and bak play regulating apoptosis in a tissue-specific manner. Understanding the normal role of these proteins during embryogenesis and in the mature organ will give us important insight into what goes awry in various disease states.
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PMID:Bcl-2 family members and disease. 1499 1

The molecular regulation of seizure-induced neuronal death may involve interactions between proteins of the Bcl-2 and 14-3-3 families. To further examine these pathways we performed subcellular fractionation on hippocampi obtained following a brief period of status epilepticus in the rat. Western blotting determined seizures induced caspase-8 cleavage and increased Bcl-w levels within the cytoplasm. Bax, Bad and Bid were largely present within the cytoplasm before and after seizures, although some Bax and, following seizures, truncated Bid was detected in mitochondria. Levels of 14-3-3 were significantly reduced in the cytoplasm and microsomal fractions. These data establish the expression and distribution profile of key Bcl-2 family proteins and the signaling chaperone 14-3-3 in the rat and provide additional evidence for the activation of programmed cell death pathways by seizures.
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PMID:Subcellular distribution of Bcl-2 family proteins and 14-3-3 within the hippocampus during seizure-induced neuronal death in the rat. 1503 20

As immunosuppressive agents, glucocorticoids (GCs) act by inhibiting the expression of cytokines and adhesion molecules at the transcriptional and post-transcriptional levels. In addition, GCs exerted their effects by modulating apoptosis. In view of the central role of the Bcl-2 family protein in regulating apoptosis, it was tempting to speculate that GCs modulated apoptosis through modulation of the expression of proapoptotic (Bax, Bcl-X(S), Bak) and prosurvival (Bcl-2, Bcl-X(L), Bcl-w) Bcl-2 family members. Prosurvival Bcl-2 family members in various cell types antagonized GC-induced apoptosis, thereby suggesting a causal relationship between GC-induced apoptosis and Bcl-2 proteins. The antagonism of apoptosis afforded by prosurvival Bcl-2 proteins appeared to be specific for the GCs, as Bcl-2 and Bcl-x(L) blocked GC-induced apoptosis in T cell hybridomas but did not affect Fas or activation-induced apoptosis. Although it is speculated that GC-induced apoptosis may be mediated through the activation of proapoptotic Bcl-2 proteins, recent findings suggest that this may vary depending on the conditions and the cell types used. The mechanism by which Bcl-2 inhibited GC-induced apoptosis remains uncertain. It was suggested that Bcl-2 acted on outer mitochondrial membranes to preserve their function. Bcl-2 overexpression also inhibited GC-induced apoptotic events, including caspase activation and mitochondrial dysfunction. The cross-talk of the GC receptors with other secondary messengers could lead to modulation of the activity of Bcl-2 proteins through modification of their phosphorylation status, without ruling out the possibility of a physical interaction between activated GR with Bcl-2 proteins.
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PMID:On the link between Bcl-2 family proteins and glucocorticoid-induced apoptosis. 1507 61

While there is a host of pro-apoptotic stimuli that target neurons in Alzheimer disease (AD), given the chronicity of the disease and the survival of many neurons, those neurons must either avoid or, at minimum, delay apoptotic death signaling. In this study, we investigated Bcl-w, a novel member of the Bcl-2 family that promotes cell survival. In AD, we found increased levels of Bcl-w associated with neurofibrillary pathology and punctate intracytoplasmic structures whereas, in marked contrast, there are only low diffuse levels of Bcl-w in the neuronal cytoplasm of age-matched control cases. Immunoblot analysis confirmed that Bcl-w levels were significantly increased in AD. By electron microscopy, we determined that the increased Bcl-w expression in AD was ultrastructurally localized to mitochondria and neurofibrillary pathology. To investigate the cause and consequence of Bcl-w up-regulation in neurons, we found that fibrillized amyloid-beta led to increased Bcl-w protein levels in M17 human neuroblastoma cells, and that overexpression of Bcl-w significantly protected neurons against staurosporine- and amyloid-beta-induced apoptosis. Taken together, these series of results suggest that Bcl-w may play an important protective role in neurons in the diseased brain and that this aspect could be therapeutically harnessed to afford neuroprotection.
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PMID:Neuroprotective properties of Bcl-w in Alzheimer disease. 1514 16

This study provides new insights into neuroprotection involving interaction of protein kinase C (PKC) pathway with Bcl-2 family proteins. Using a model of serum deprivation, we investigated the mechanism by which the anti-Parkinson/monoamine oxidase (MAO)-B inhibitor drug, rasagiline, exerts its neuroprotective effect in rat pheochromocytoma PC12 cells. Here, we report that rasagiline (0.1-10 microM) decreased apoptosis via multiple protection mechanisms, including the stimulation of PKC phosphorylation; up-regulation of PKCalpha and PKC mRNAs, induction of Bcl-xL, Bcl-w, and brain-derived neurotrophic factor (BDNF) mRNAs; and down-regulation of Bad and Bax mRNAs. Moreover, rasagiline inhibited the cleavage and activation of procaspase-3 and poly (ADP-ribose) polymerase (PARP), whereas the PKC inhibitor, GF109203X, reversed these actions. Similarly, rasagiline decreased serum-free-induced levels of the important regulator of cell death, Bad, which was also blocked by GF109203X, indicating the involvement of PKC in rasagiline-induced cell survival. Furthermore, these studies have established that PKC- and Bcl-2-dependent neuroprotective activity of rasagiline is dependent on its propargyl moiety, because propargylamine had similar effects with the same potency.
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PMID:Neuroprotection via pro-survival protein kinase C isoforms associated with Bcl-2 family members. 1524 50

The anti-apoptotic proteins Bcl-w and Bcl-2 and the pro-apoptotic protein Bax may mediate cell death or survival via regulation of the mitochondria including second mitochondria-derived activator of caspase (Smac)/direct inhibitor of apoptosis protein (IAP)-binding protein with low pI (DIABLO) release. This study aimed to explore alterations in Bcl-w, Bcl-2, and Bax and the relationship between these proteins and Smac/DIABLO by means of in situ hybridization, immunohistochemical (IHC) staining, and Western blots after low- and high-intensity photothrombotic ring stroke. At 4 h after low-intensity irradiation, we found widespread bcl-w overexpression on both the mRNA and protein levels in the bilateral cortex except the ring lesion region and in subcortical regions. A prolonged elevation of Bcl-2 with relatively unchanged Bax in the mitochondrial fraction was demonstrated from 4 to 72 h. These upregulated anti-apoptotic proteins combined with little Smac/DIABLO release might be associated with increased cell survival and thereby remarkable morphological recovery after low-intensity irradiation. After high-intensity irradiation, we observed decreased bcl-w and bcl-2 mRNA with increased Bcl-2 protein in the cytosolic fraction, whereas the Bax protein remained in scattered ischaemic cells in the ring lesion and the region at risk that corresponded with release of Smac/DIABLO from mitochondria to the cytosol at 1-24 h. These changes might be related to the massive cell death observed after high-intensity irradiation. Taken together, the balance and the location of anti-apoptotic proteins vs. pro-apoptotic proteins could be associated with the translocation of Smac/DIABLO from the mitochondria to the cytosol and therefore closely related to cell death or survival after focal cerebral ischaemia.
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PMID:Dynamic changes of the anti- and pro-apoptotic proteins Bcl-w, Bcl-2, and Bax with Smac/Diablo mitochondrial release after photothrombotic ring stroke in rats. 1534 89

In utero exposure to exogenous anti-androgenic compounds induces a wide range of abnormalities of the reproductive system, including hypospermatogenesis, cryptorchidism and hypospadias. By using rats exposed in utero to the anti-androgenic compound flutamide (0.4, 2 or 10 mg/kg per day), it has been shown that hypospermatogenesis in adult testes could be related to (i) a long-term apoptosis in germ cells but not in somatic Leydig and Sertoli cells as evidenced by the TUNEL approach and (ii) alterations in the mRNA and protein expression of pro- (Bax, Bak, Bid) and anti-apoptotic (Bcl-2, Bcl-w) members of the Bcl-2 family. Indeed, the number of apoptotic germ cells increased with the dose of flutamide administered and the apoptotic germ cells were mainly detected at androgen-dependent stages VII-VIII. Moreover, for the Bcl-2-related proteins that were expressed mainly in the germ cells, a decrease in the levels of anti-apoptotic peptides Bcl-w (60%, P=0.003) and Bcl-2 (90%, P=0.0001) was observed at 2 mg/kg per day flutamide and an increase in levels of the pro-apoptotic Bax (2.3-fold, P=0.0004) was detected at 10 mg/kg per day. In contrast, the levels of pro-apoptotic peptide Bak that was mainly expressed in somatic cells decreased (70%, P=0.0008) at 10 mg/kg per day. Such alterations in Bcl-2-related peptides occurred mainly at the protein level except for Bcl-2 (72%, P=0.0001) and Bak (43%, P=00002) transcripts. Together, these results showed that the apoptosis observed in adult germ cells from rats exposed in utero to flutamide may result from a long-term alteration in the balance between pro- and anti-apoptotic Bcl-2-related molecules in favour of pro-apoptotic proteins. These data further supported the concept of an androgen-dependent fetal programming that is in relation with an alteration of the expression of Bcl-2-related genes/proteins promoting apoptosis in testicular germ cells of adult rats with fetal androgen disruption.
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PMID:The mitochondrial-dependent pathway is chronically affected in testicular germ cell death in adult rats exposed in utero to anti-androgens. 1552 76

In diabetes, peripheral nerves suffer deficient neurotrophic support-a situation which resembles axotomy. This raises the question: does inappropriate establishment of an axotomised neuronal phenotype contribute to diabetic neuropathy, and in extremis, does this provoke apoptosis? We hybridized reverse-transcribed RNA, from the dorsal root ganglia (DRG) of 8-week streptozotocin (STZ)-induced diabetic rats, to Affymetrix Rat Genome U34A chips and scanned the array for expression of (a) genes that are upregulated by axotomy, (b) proapoptotic and (c) anti-apoptotic genes. Expression of the axotomy-responsive genes coding for growth-associated protein 43 (GAP-43), galanin, neuropeptide Y (NPY), pre-pro-vasoactive intestinal polypeptide (pre-pro-VIP), neuronal nitric oxide synthase (nNOS), protease nexin 1, heat-shock protein 27 (HSP 27) and myosin light chain kinase II (MLCK II) was unaffected in ganglia from diabetic rats compared to controls; thus, no axotomised phenotype was established. The expression of the majority of proapoptotic genes in the DRG was also unaltered (bax, bad, bid, bok, c-Jun, p38, TNFR1, caspase 3 and NOS2). Similarly there was no change in expression of the majority of antiapoptotic genes (bcl2, bcl-xL, bcl-w, NfkappaB). These alterations in gene expression make it clear that neither axotomy nor apoptotic phenotypes are established in neurones in this model of diabetes.
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PMID:Expression of axotomy-inducible and apoptosis-related genes in sensory nerves of rats with experimental diabetes. 1558 61


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