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)

A major concern in cancer therapy is resistance of tumors such as glioblastoma to current treatment protocols. Here, we report that transfer of the gene encoding second mitochondria-derived activator of caspase (Smac) or Smac peptides sensitized various tumor cells in vitro and malignant glioma cells in vivo for apoptosis induced by death-receptor ligation or cytotoxic drugs. Expression of a cytosolic active form of Smac or cell-permeable Smac peptides bypassed the Bcl-2 block, which prevented the release of Smac from mitochondria, and also sensitized resistant neuroblastoma or melanoma cells and patient-derived primary neuroblastoma cells ex vivo. Most importantly, Smac peptides strongly enhanced the antitumor activity of Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in an intracranial malignant glioma xenograft model in vivo. Complete eradication of established tumors and survival of mice was only achieved upon combined treatment with Smac peptides and Apo2L/TRAIL without detectable toxicity to normal brain tissue. Thus, Smac agonists are promising candidates for cancer therapy by potentiating cytotoxic therapies.
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PMID:Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. 1211 45

During apoptosis, Smac (second mitochondria-derived activator of caspases)/DIABLO, an IAP (inhibitor of apoptosis protein)-binding protein, is released from mitochondria and potentiates apoptosis by relieving IAP inhibition of caspases. We demonstrate that exposure of MCF-7 cells to the death-inducing ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), results in rapid Smac release from mitochondria, which occurs before or in parallel with loss of cytochrome c. Smac release is inhibited by Bcl-2/Bcl-xL or by a pan-caspase inhibitor demonstrating that this event is caspase-dependent and modulated by Bcl-2 family members. Following release, Smac is rapidly degraded by the proteasome, an effect suppressed by co-treatment with a proteasome inhibitor. As the RING finger domain of XIAP possesses ubiquitin-protein ligase activity and XIAP binds tightly to mature Smac, an in vitro ubiquitination assay was performed which revealed that XIAP functions as a ubiquitin-protein ligase (E3) in the ubiquitination of Smac. Both the association of XIAP with Smac and the RING finger domain of XIAP are essential for ubiquitination, suggesting that the ubiquitin-protein ligase activity of XIAP may promote the rapid degradation of mitochondrial-released Smac. Thus, in addition to its well characterized role in inhibiting caspase activity, XIAP may also protect cells from inadvertent mitochondrial damage by targeting pro-apoptotic molecules for proteasomal degradation.
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PMID:Proteasome-mediated degradation of Smac during apoptosis: XIAP promotes Smac ubiquitination in vitro. 1212 69

Mitochondria are 'life-essential' organelles for the production of metabolic energy in the form of ATP. Paradoxically mitochondria also play a key role in controlling the pathways that lead to cell death. This latter role of mitochondria is more than just a 'loss of function' resulting in an energy deficit but is an active process involving different mitochondrial proteins. Cytochrome c was the first characterised mitochondrial factor shown to be released from the mitochondrial intermembrane space and to be actively implicated in apoptotic cell death. Since then, other mitochondrial proteins, such as AIF, Smac/DIABLO, endonuclease G and Omi/HtrA2, were found to undergo release during apoptosis and have been implicated in various aspects of the cell death process. Members of the Bcl-2 protein family control the integrity and response of mitochondria to apoptotic signals. The molecular mechanism by which mitochondrial intermembrane space proteins are released and the regulation of mitochondrial homeostasis by Bcl-2 proteins is still elusive. This review summarises and evaluates the current knowledge concerning the complex role of released mitochondrial proteins in the apoptotic process.
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PMID:The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet. 1223 90

Many viruses belonging to diverse viral families with differing structure and replication strategies induce apoptosis both in cultured cells in vitro and in tissues in vivo. Despite this fact, little is known about the specific cellular apoptotic pathways induced during viral infection. We have previously shown that reovirus-induced apoptosis of HEK cells is initiated by death receptor activation but requires augmentation by mitochondrial apoptotic pathways for its maximal expression. We now show that reovirus infection of HEK cells is associated with selective cytosolic release of the mitochondrial proapoptotic factors cytochrome c and Smac/DIABLO, but not the release of apoptosis-inducing factor. Release of these factors is not associated with loss of mitochondrial transmembrane potential and is blocked by overexpression of Bcl-2. Stable expression of caspase-9b, a dominant-negative form of caspase-9, blocks reovirus-induced caspase-9 activation but fails to significantly reduce activation of the key effector caspase, caspase-3. Smac/DIABLO enhances apoptosis through its action on cellular inhibitor of apoptosis proteins (IAPs). Reovirus infection is associated with selective down-regulation of cellular IAPs, including c-IAP1, XIAP, and survivin, effects that are blocked by Bcl-2 expression, establishing the dependence of IAP down-regulation on mitochondrial events. Taken together, these results are consistent with a model in which Smac/DIABLO-mediated inhibition of IAPs, rather than cytochrome c-mediated activation of caspase-9, is the key event responsible for mitochondrial augmentation of reovirus-induced apoptosis. These studies provide the first evidence for the association of Smac/DIABLO with virus-induced apoptosis.
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PMID:Reovirus-induced apoptosis requires mitochondrial release of Smac/DIABLO and involves reduction of cellular inhibitor of apoptosis protein levels. 1238 2

We have examined the effects of the CDK1 inhibitor CGP74514A on cell cycle- and apoptosis-related events in human leukemia cells. An 18-hr exposure to 5 microM CGP74514A induced mitochondrial damage (i.e., loss of Delta psi(m)) and apoptosis in multiple human leukemia cell lines (e.g., U937, HL-60, KG-1, CCRF-CEM, Raji, and THP; range 30-95%). In U937 cells, CGP74514A- induced apoptosis (5 microM) became apparent within 4 hr and approached 100% by 24 hr. The pan- caspase inhibitor Boc-fmk and the caspase-8 inhibitor lETD-fmk opposed CGP74514A-induced caspase-9 activation and PARP degradation, but not cytochrome c or Smac/DIABLO release. CGP74514A-mediated apoptosis was substantially blocked by ectopic expression of full-length Bel- 2, a loop-deleted mutant Bcl-2, and Bcl-x(L). CGP74514A treatment (5 microM; 18 hr) resulted in increased p21(CIP1) expression, p27(KIP1) degradation, diminished E2F1 expression, and dephosphorylation of p34(CDC2). It also induced early (i.e., within 2 hr) inhibition of CDK1 activity and dephosphorylation of pRb, followed by pRb degradation, but did not block pRb phosphorylation at CDK2- and CDK4- specific sites. These findings indicate that the selective CDK1 inhibitor, CGP74514A, induces complex changes in cell cycle-related proteins in human leukemia cells accompanied by extensive mitochondrial damage, caspase activation, and apoptosis.
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PMID:Induction of apoptosis in human leukemia cells by the CDK1 inhibitor CGP74514A. 1242 20

Apoptosis is a genetically regulated biological process that plays a major role in chemotherapy-induced tumor cell killing. It may be triggered by two major intracellular signaling cascades, the mitochondrial pathway and the death receptor pathway, both leading to caspase activation and cleavage of specific cellular substrates. The p53 gene is involved in the regulation of apoptosis. Caspase activation following wild-type p53 induction is associated with the release of the apoptogenic factors cytochrome c and Smac/DIABLO from the mitochondria, that is in turn controlled by the pro-apoptotic and anti-apoptotic Bcl-2 family proteins. In ovarian cancer p53 status is a strong predictor of response to platinum-based chemotherapy. Patients whose tumors have p53 mutations experience a lower chance of achieving a complete response following platinum-based regimens when compared to patients without p53 mutations. Conversely, experimental and clinical data seem to show that paclitaxel enhances apoptosis through a p53-independent pathway, that probably involves the Bax gene. Whereas patients with wild-type p53 tumors have a good chance to respond to platinum, patients with mutant p53 tumors may have a clinical benefit from the addition of paclitaxel to platinum-based chemotherapy. Therefore determining p53 status can be useful in predicting therapeutic response to specific drugs. Moreover the understanding of cellular mechanisms regulating apoptosis might offer a strong rationale for the combination of chemotherapy with other biological treatments.
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PMID:Molecular mechanisms of apoptosis and chemosensitivity to platinum and paclitaxel in ovarian cancer: biological data and clinical implications. 1244 Aug 9

The effects of the PKC activator and down-regulator bryostatin 1 and the PKC and Chk1 inhibitor 7-hydroxystaurosporine (UCN-01) were compared with respect to potentiation of 1-beta-D-arabinofuranosylcytosine (ara-C)-induced apoptosis in human myelomonocytic leukemia cells (U937). Whereas bryostatin 1 and UCN-01 both markedly enhanced ara-C-induced mitochondrial injury (e.g., cytochrome c and Smac/DIABLO release, loss of mitochondrial membrane potential), caspase activation, and apoptosis, ectopic expression of an N-terminal loop-deleted Bcl-2 mutant protein protected cells from ara-C/UCN-01- but not ara-C/bryostatin 1-mediated lethality. Conversely, ectopic expression of CrmA or dominant-negative caspase-8 abrogated potentiation of ara-C-mediated apoptosis by bryostatin 1 but not by UCN-01. Exposure of cells to ara-C and bryostatin 1 (but not UCN-01) resulted in sustained release of tumor necrosis factor (TNF) alpha; moreover, potentiation of ara-C lethality by bryostatin 1 (but not by UCN-01) was reversed by coadministration of TNF soluble receptors or the selective PKC inhibitor bisindolylmaleimide (1 microM). Finally, similar events were observed in the human promyelocytic leukemia cell line HL-60. Together, these findings suggest that potentiation of ara-C lethality in human myeloid leukemia cells by bryostatin 1 but not UCN-01 involves activation of the extrinsic, receptor-mediated apoptotic pathway, and represents a consequence of bryostatin 1-mediated release of TNF-alpha. They also argue that the mechanism by which bryostatin 1 promotes ara-C-induced mitochondrial injury, caspase activation, and apoptosis involves factors other than or in addition to PKC down-regulation or modulation of Bcl-2 phosphorylation status.
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PMID:Bryostatin 1 and UCN-01 potentiate 1-beta-D-arabinofuranosylcytosine-induced apoptosis in human myeloid leukemia cells through disparate mechanisms. 1248 56

Interactions between the protein kinase C (PKC) activator/down-regulator bryostatin 1 and paclitaxel have been examined in human myeloid leukemia cells (U937) and in highly paclitaxel-resistant cells ectopically expressing a Bcl-2 phosphorylation loop-deleted protein (Delta Bcl-2). Treatment (24 hours) of wild-type cells with paclitaxel (eg, 5 to 20 nM) in combination with 10 nM bryostatin 1 induced a marked increase in mitochondrial damage (eg, cytochrome c and Smac/DIABLO [second mitochondria-derived activator of caspases/direct IAP binding protein with low pI] release), caspase activation, Bid cleavage, and apoptosis; moreover, bryostatin 1 circumvented the block to paclitaxel-induced mitochondrial injury and apoptosis conferred by ectopic expression of the loop-deleted protein. Coadministration of tumor necrosis factor (TNF) soluble receptors, or ectopic expression of CrmA or dominant-negative caspase-8, abrogated potentiation of paclitaxel-induced mitochondrial injury and apoptosis by bryostatin 1, implicating the extrinsic apoptotic pathway in this process. Similar events occurred in HL-60 leukemia cells. Potentiation of paclitaxel-induced apoptosis in wild-type and mutant cells by bryostatin 1 was associated with increases in TNF-alpha mRNA and protein and was mimicked by exogenous TNF-alpha. Coadministration of the selective PKC inhibitor GFX (1 microM) blocked the increase in TNF-alpha mRNA levels and apoptosis in bryostatin 1/paclitaxel-treated cells. Lastly, synchronization of cells in G(2)M increased their sensitivity to TNF-alpha-associated lethality. Collectively, these findings indicate that in U937 cells, bryostatin 1 promotes paclitaxel-mediated mitochondrial injury and apoptosis, and circumvents resistance to cell death conferred by loss of the Bcl-2 phosphorylation domain, through the PKC-dependent induction of TNF-alpha. They further suggest that this process is amplified by paclitaxel-mediated arrest of cells in G(2)M, where they are more susceptible to TNF-alpha-induced lethality.
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PMID:Induction of tumor necrosis factor by bryostatin 1 is involved in synergistic interactions with paclitaxel in human myeloid leukemia cells. 1252 1

The Bcl-2 family member Mcl-1 is essential for macrophage survival. However, the mechanisms that contribute to the expression of Mcl-1 in these cells have not been fully characterized. The present study focused on the role of signal transducer and activator of transcription 3 (STAT3) in regulation of Mcl-1 in macrophages. Sodium salicylate (NaSal) treatment induced apoptotic cell death in primary human macrophages in a dose- and time-dependent fashion. Incubation with NaSal resulted in the loss of mitochondrial transmembrane potential, the release of cytochrome c and second mitochondria-derived activator of caspase/direct IAP binding protein with low pH of isoelectric point (pI) from the mitochondria, and the activation of caspases 9 and 3. Western blot analysis and reverse transcription-polymerase chain reaction demonstrated that NaSal down-regulated the expression of Mcl-1. Electrophoretic mobility shift assay and Western blot analysis for phosphorylated STAT3 demonstrated that STAT3 was constitutively activated in macrophages and that this STAT3 activation was suppressed by NaSal. The activation of STAT3 in macrophages was dependent on Ser727 phosphorylation, in the absence of detectable Tyr705 phosphorylation. Ectopic expression of STAT3 in murine RAW264.7 macrophages rescued the inhibition of Mcl-1 promoter-reporter gene activation and the cell death induced by NaSal treatment, while a dominant-negative STAT3 resulted in cell death. To confirm its role in primary macrophages, STAT3 antisense (AS) oligodeoxynucleotides (ODNs) were employed. STAT3 AS, but not control, ODNs decreased STAT3 and Mcl-1 expression and resulted in macrophage apoptosis. These observations demonstrate that the STAT3-mediated expression of Mcl-1 is essential for the survival of primary human in vitro differentiated macrophages.
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PMID:Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival. 1263 18

Cytotoxic lymphocytes employ Granzyme B as a potent initiator of apoptosis to cleave and activate effector caspases. Unexpectedly, cells transfected with Bcl-2 were resistant to granzyme B-induced killing, suggesting that a mitochondrial pathway was critical. Utilizing cells expressing a dominant-negative caspase 9, the current study demonstrated that caspase activation via the apoptosome was not required. Indeed, cleavage of caspase 3 to p20 still occurred in Bcl-2-transfectants but processing to p17 was blocked. This blockade was recapitulated by the Inhibitor-of-Apoptosis-Protein XIAP and relieved by Smac/DIABLO. Thus granzyme B mediates direct cleavage of caspase 3 and also activates mitochondrial disruption, resulting in the release of proapoptotic proteins that suppress caspase inhibition. Engagement of both pathways is critical for granzyme-induced killing.
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PMID:Granzyme B-induced apoptosis requires both direct caspase activation and relief of caspase inhibition. 1264 53


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