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)

Apoptosis is a distinctive form of cell death that reflects cleavage of a subset of intracellular polypeptides by proteases known as caspases. Two major intracellular caspase cascades, one activated predominantly by death receptor ligands and the other triggered by various cellular stresses, including DNA damage and microtubule disruption, have been delineated. Activation of these protease cascades is tightly regulated by a number of polypeptides, including Bcl-2 family members, inhibitor of apoptosis proteins, and several protein kinases. The demonstration that many antineoplastic agents induce apoptosis in susceptible cells raises the possibility that factors affecting caspase activation and activity might be important determinants of anticancer drug sensitivity. Here, we review recent studies describing the regulation of apoptotic pathways and identify potential implications of these findings for resistance to antineoplastic agents.
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PMID:Apoptosis and the response to anticancer therapy. 1167 85

The aim of the preliminary study was to evaluate the role of apoptosis and proliferation of myocytes in order to predict the prognosis and optimal treatment of patients with end-stage dilated cardiomyopathy. Endomyocardial biopsy was performed during open-heart surgery (reductive annuloplasty of double orifice) in 19 patients with end-stage dilated cardiomyopathy. The terminal deoxynucleotidyl transferase d-UTP-biotin nick-end labelling (TUNEL) method was used for the detection of apoptosis, and immunohistochemical methods were used for the evaluation of inhibitor of apoptosis such as proto-oncogene Bcl-2 (B-cell lymphoma gene), and proliferative markers such as proliferation cell nuclear antigen (PCNA) and Ki-67 proliferative antigen. The increased percentage of apoptotic myocytes and decreased expression of bcl-2 is associated with earlier death after surgery. Increased expression of proliferation markers of myocytes in patients who survived seven years after surgery compared to those who died within three years suggest that adult cardiomyocytes are not terminally differentiated and this might represent potential growth reserve of the diseased heart. Based on our preliminary study we may conclude that myocytes' apoptosis and proliferative activity might help us to predict the prognosis and optimal treatment of patients with end-stage dilated cardiomyopathy.
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PMID:Myocytes' apoptosis and proliferation in endomyocardial biopsy as prognostic factors in terminal heart failure. 1167 24

Successful cancer therapy requires the selective killing of cancer cells. Many molecular components of the pathways that lead to cell death have recently been identified and a number of these, including p53, Apaf-1, and members of the inhibitor of apoptosis protein and Bcl-2 gene families, have been found to be altered or disregulated in many cancers. These recent advances and the ongoing elucidation of how these pathways work is providing clues as to how therapeutically resistant cancers might be attacked.
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PMID:Cell death and cancer therapy. 1171 Jul 30

CpG DNA has been recognized as a powerful stimulant of dendritic cells (DCs). In this study, we demonstrate that CpG DNA inhibits spontaneous apoptosis of DCs. CpG DNA up-regulated cellular inhibitor of apoptosis proteins (cIAPs) as well as Bcl-2 and Bcl-x(L), but down-regulated active caspase-3. Although CpG DNA activated p38 mitogen-activated protein kinase, extracellular signal-related kinase, and phosphatidylinositide-3'-OH kinase (PI3K), only the blocking of PI3K inhibited the CpG DNA-induced DC survival. Moreover, while the expression of Bcl-2 and Bcl-x(L) depends on both PI3K and p38 mitogen-activated protein kinase, the up-regulation of cIAPs and the down-regulation of active caspase-3 by CpG DNA require PI3K activation, suggesting PI3K-dependent up-regulation of cIAPs in the antiapoptotic activity of CpG DNA in DCs. This study indicates that CpG DNA provides a survival signal to DCs, which might be one of mechanisms by which bacterial DNA stimulates and maintains the innate immune responses.
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PMID:Cutting Edge: CpG DNA inhibits dendritic cell apoptosis by up-regulating cellular inhibitor of apoptosis proteins through the phosphatidylinositide-3'-OH kinase pathway. 1175 39

The Kaposi's sarcoma-associated herpesvirus (KSHV) (or human herpesvirus 8) open reading frame (ORF) K15 encodes a putative integral transmembrane protein in the same genomic location as latent membrane protein 2A of Epstein-Barr virus. Ectopic expression of K15 in cell lines revealed the presence of several different forms ranging in size from full length, approximately 50 kDa, to 17 kDa. Of these different species the 35- and 23-kDa forms were predominant. Mutational analysis of the initiator AUG indicated that translation initiation from this first AUG is required for K15 expression. Computational analysis indicates that the different forms detected may arise due to proteolytic cleavage at internal signal peptide sites. We show that K15 is latently expressed in KSHV-positive primary effusion lymphoma cell lines and in multicentric Castleman's disease. Using a yeast two-hybrid screen we identified HAX-1 (HS1 associated protein X-1) as a binding partner to the C terminus of K15 and show that K15 interacts with cellular HAX-1 in vitro and in vivo. Furthermore, HAX-1 colocalizes with K15 in the endoplasmic reticulum and mitochondria. The function of HAX-1 is unknown, although the similarity of its sequence to those of Nip3 and Bcl-2 infers a role in the regulation of apoptosis. We show here that HAX-1 can form homodimers in vivo and is a potent inhibitor of apoptosis and therefore represents a new apoptosis regulatory protein. The putative functions of K15 with respect to its interaction with HAX-1 are discussed.
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PMID:K15 protein of Kaposi's sarcoma-associated herpesvirus is latently expressed and binds to HAX-1, a protein with antiapoptotic function. 1175 70

The long median survival time of patients with follicular non-Hodgkin's lymphoma (NHL), means that the efficacy of new treatments are difficult to assess in the short term. Bcl-2 is an inhibitor of apoptosis and overexpression of the bcl-2 gene in the blood or bone marrow is a feature in up to 85% of patients with follicular NHL. Levels of bcl-2(+) cells in the peripheral blood or bone marrow therefore are a useful measure of disease status in such patients and can be detected by polymerase chain reaction (PCR). Complete bcl-2 clearance from the bone marrow (molecular remission) following autologous stem cell transplant (ASCT) for follicular NHL is considered to be an important prognostic factor for disease-free survival. Tumour cell contamination of the stem cell grafts used in ASCT is commonly associated with relapse. This can be addressed by purging the stem cell harvest prior to transplantation. Various methods of in vitro purging after stem cell collection have been shown to reduce the level of contamination but yield is invariably reduced and grafts remain bcl-2 positive. However, in vivo purging with rituximab during the process of collection has been used to obtain bcl-2-negative stem cell harvests without compromising the yield. Rituximab is a monoclonal antibody licensed for treatment of relapsed and refractory low-grade or follicular NHL. Rituximab targets the CD20 antigen, which is found on cells of the B cell lineage. When used for in vivo purging it depletes the peripheral blood of CD20-positive cells and prevents contamination by lymphoma cells. Molecular remission, as measured by bone-marrow bcl-2 clearance, has been achieved in 7/7 patients with follicular NHL at 1 year after treatment with ASCT using rituximab as an 'in vivopurse', followed by rituximab maintenance. Early clinical outcomes are also encouraging.
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PMID:Bcl-2 clearance: optimising outcomes in follicular non-Hodgkin's lymphoma. 1184 Jan 56

Kaurane diterpenes have been identified from numerous medicinal plants, which have been used for treatment of inflammation and cancer, however, their molecular mechanism of action remains unclear. We have previously shown that kamebakaurin and other three kaurane diterpenes selectively inhibit activation of transcription factor NF-kappaB, a central mediator of apoptosis and immune responses. We here demonstrate that kamebakaurin is a potent inhibitor of NF-kappaB activation by directly targeting DNA-binding activity of p50. Kamebakaurin prevented the activation of NF-kappaB by different stimuli in various cell types. Kamebakaurin did not prevent either stimuli-induced degradation of IkappaB-alpha or nuclear translocation of NF-kappaB, however, it significantly interfered DNA binding activity of activated NF-kappaB in cell and in vitro and preferentially prevented p50-mediated DNA-binding activity of NF-kappaB rather than that of RelA as measured using in vitro translated p50 and RelA proteins. Moreover, a p50 mutant with a Cys-62 --> Ser mutation was not inhibited with kamebakaurin, indicating that the effect of kamebakaurin was probably due to its interaction with cysteine 62 in p50. The covalent modification of p50 by kamebakaurin was further demonstrated by mass spectrometry analysis that showed an increase in the molecular mass of kamebakaurin-treated p50, and this modification was not reverted by addition of dithiothreitol. These results suggested that kamebakaurin exhibited its inhibitory activity by a direct covalent modification of cysteine 62 in the p50. Also, treatment of cells with kamebakaurin prevented the tumor necrosis factor-alpha (TNF-alpha)-induced expression of antiapoptotic NF-kappaB target genes encoding c-IAP1 (hiap-2) and c-IAP2 (hiap-1), members of the inhibitor of apoptosis family, and Bfl-1/A1, a prosurvival Bcl-2 homologue, and augmented the TNF-alpha-induced caspase 8 activity, thereby resulting in sensitizing MCF-7 cells to TNF-alpha-induced apoptosis. Taken together, kamebakaurin is a valuable candidate for the intervention of NF-kappaB-dependent pathological conditions such as inflammation and cancer.
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PMID:Kaurane diterpene, kamebakaurin, inhibits NF-kappa B by directly targeting the DNA-binding activity of p50 and blocks the expression of antiapoptotic NF-kappa B target genes. 1187 50

We studied the human HL60 leukemia cell line and its multidrug resistant (MDR) variant HL60R. In contrast to the HL60, HL60R showed an inability to undergo apoptosis from doxorubicin (Dox) or other different stimuli, including cisplatin, Fas ligation and serum withdrawal. HL60R cells lost surface Fas expression, but we found no evidence that Fas/FasL mediates the apoptotic effects of Dox in HL60. P-glycoprotein (P-gp) did not seem to play a major role as a specific inhibitor of apoptosis. In fact, the P-gp inhibitor verapamil reversed only partially the resistance to Dox-induced apoptosis of the MDR cells. In addition, it did not modify the rate of apoptosis induced from the other stimuli in the same cells. The expression of p53 or Bcl-2 was not different between HL60 and HL60R. However, in HL60R there was an increase in the mRNAs of inhibitory of apoptosis proteins (IAPs) like neuronal apoptosis inhibitory protein (NAIP), c-IAP-2 and survivin. Treatment with Dox or serum starvation strongly down-regulated X-linked IAP and survivin mRNAs in HL60. Cisplatin decreased NAIP and survivin mRNAs in the same cells. However, in HL60R the levels of these IAP mRNAs were much less affected by the treatments. These results support that IAPs may be involved in tumor resistance to chemotherapeutic drugs or other apoptotic agents.
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PMID:Resistance to diverse apoptotic triggers in multidrug resistant HL60 cells and its possible relationship to the expression of P-glycoprotein, Fas and of the novel anti-apoptosis factors IAP (inhibitory of apoptosis proteins). 1191 75

Over the past few years, many studies have been done on the apoptotic involvement in muscle fiber degeneration in various myopathies, but the occurrence of apoptosis in muscles of mitochondrial encephalomyopathies is still controversial. To confirm whether apoptotic processes are truly related to muscle fiber degeneration in mitochondrial encephalomyopathies, we performed the TUNEL method not only at the light microscopic (LM) but also at the electron microscopic (EM) level for muscles of five MELAS, five CPEO and five MERRF patients and five control muscles. Immunohistochemical studies of Bcl-2, Bax, cytochrome c, Apaf-1, activated caspase-3 and human inhibitor of apoptosis protein XIAP, and immunoblotting of Apaf-1 and XIAP were also carried out. In LM-TUNEL, MELAS, CPEO and MERRF patients had only very small numbers of TUNEL-positive myonuclei: 0.13+/-0.10%, 0.15+/-0.14% and 0.04+/-0.09%, respectively. Almost all of them were seen in ragged-red fibers (RRFs). EM-TUNEL showed no significant increase of DNA fragmentation in RRFs despite mild peripheral chromatin condensation. However, Bax and Apaf-1 expression and cytochrome c release from mitochondria were seen in RRFs. Caspase-3 activation was confirmed in 9.0+/-3.7%, 12.0+/-4.4% and 12.4+/-3.8% of RRFs in MELAS, CPEO and MERRF, respectively, but not in control muscles. Almost all RRFs showed sarcoplasmic expression of XIAP. Thus, there is a possibility that, although apoptotic reactions started in muscles of mitochondrial encephalomyopathies, their execution is rarely completed. Sarcoplasmic expression of XIAP probably leads to the suspension of the apoptotic process in mitochondrial encephalomyopathies.
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PMID:Apoptosis is suspended in muscle of mitochondrial encephalomyopathies. 1201 84

Human cytomegalovirus encodes a powerful cell death suppressor vMIA (viral mitochondria-localized inhibitor of apoptosis), also known as pUL37x1. vMIA, a product of the immediate early gene UL37 exon 1, is predominantly localized in mitochondria, where it appears to form a complex with adenine nucleotide translocator, believed to be a component of the mitochondrial transition pore complex. vMIA suppresses apoptosis by blocking permeabilization of the mitochondrial outer membrane. Expression of vMIA protects cells against apoptosis triggered by diverse stimuli, including ligation of death receptors, exposure to certain cytotoxic drugs, and infection with an adenovirus mutant deficient in E1B19K. Deletion mutagenesis of vMIA revealed two domains that are necessary and, together, sufficient for its anti-apoptotic activity. The first domain contains a mitochondrial targeting signal. The function of the second domain is still unknown. vMIA does not share any significant amino acid sequence homology with Bcl-2, and, unlike Bcl-2 or Bcl-x(L), it does not bind BAX or VDAC. These structural and functional differences between vMIA and Bcl-2 suggest that vMIA represents a separate class of cell death suppressors. Experiments with vMIA-deficient CMV (human cytomegalovirus) mutants provide strong evidence that the anti-apoptotic function of vMIA is required to prevent CMV-induced apoptosis, and is necessary for viral replication. In addition to vMIA, UL37 encodes two longer splice-variant proteins, gpUL37 and GP37(M). Biological functions of these proteins have not yet been identified, and may be unrelated to their anti-apoptotic activity. The identification of vMIA and the finding that its anti-apoptotic function is required for CMV replication provides a rationale for the development of anti-CMV pharmaceuticals that would inactivate vMIA and thus restore apoptosis in cells infected with CMV.
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PMID:vMIA, a viral inhibitor of apoptosis targeting mitochondria. 1202 48


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