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)

In a number of experimental systems, the early stage of the apoptotic process, i.e., the stage that precedes nuclear disintegration, is characterized by the breakdown of the inner mitochondrial transmembrane potential (delta psi(m)). This delta psi(m) disruption may involve mitochondrial permeability transition (PT). Here, we address the question of whether PT transition would suffice to cause apoptosis or, rather, it would constitute a secondary event not causally involved in the apoptotic cascade. Protoporphyrin IX (PPIX), a ligand of the mitochondrial benzodiazepin receptor that is well known for its PT-triggering capacity, induces delta psi(m) disruption, enhanced generation of superoxide anions, as well as signs of nuclear apoptosis in thymocytes and in T cells. The sequence of events triggered by PPIX mimics that observed in natural apoptosis. The PT inhibitory compound bongkrekic acid, a specific ligand of the mitochondrial adenine nucleotide translocator, is an efficient inhibitor of protoporphyrin IX-induced delta psi(m) disruption. Bongkrekic acid prevents all PPIX-induced phenomena, including superoxide anion generation, chromatinolysis, and oligonucleosomal DNA fragmentation. In contrast, inhibitors of mRNA or protein synthesis fail to suppress PPIX-induced delta psi(m) disruption and apoptosis. Transfection-enforced hyperexpression of the apoptosis-inhibitory proto-oncogene bcl-2 also inhibits PPIX-induced delta psi(m) disruption, hyperproduction of reactive oxygen species, and nuclear DNA loss. The delta psi(m)-stabilizing effect of Bcl-2 is observed both in cells and in isolated mitochondria. In conclusion, these data are compatible with the hypotheses that mitochondrial PT is self-sufficient to trigger apoptosis and that Bcl-2 may directly regulate PT.
 ...
PMID:Mitochondrial permeability transition triggers lymphocyte apoptosis. 894 85

In order to determine whether disruption of mitochondrial function could trigger apoptosis in murine haematopoietic cells, we used the potassium ionophore valinomycin. Valinomycin induces apoptosis in the murine pre-B cell line BAF3, which cannot be inhibited by interleukin-3 addition or Bcl-2 over-expression. Valinomycin triggers rapid loss of mitochondrial membrane potential. This precedes cytoplasmic acidification, which leads to cysteine-active-site protease activation, DNA fragmentation and cell death. Bongkrekic acid, an inhibitor of the mitochondrial permeability transition, prevents acidification and subsequent induction of apoptosis by valinomycin.
 ...
PMID:Induction of apoptosis by valinomycin: mitochondrial permeability transition causes intracellular acidification. 1020 Apr 67

Mitochondria play a central role in many apoptotic reactions. Although mitochondrial apoptotic changes and caspase activation have been demonstrated in the apoptotic thymocytes, cell death signal through mitochondria in TCR-stimulated thymocytes has not been fully understood. In this study, we show that TCR stimulation induced disruption of mitochondrial transmembrane potential (Delta Psi(m)), the cytochrome c release from mitochondira, capase-3 activation, and the cell death of thymocytes. Bongkrekic acid, an inhibitor of Delta Psi(m) disruption, blocked the cytochrome c release from mitochondria and the following caspase-3-mediated cell death. Furthermore, a pro-apoptotic Bcl-2 family protein, Bax, but not Bad or Bid, was translocated from cytosol to mitochondria in TCR-stimulated thymocytes. This translocation and the following apoptotic changes were inhibited by SB203580, a p38 kinase inhibitor, in a specific manner. These results suggest that activated p38 kinase pathway by TCR stimulation induces translocation of Bax to mitochondria, causing Delta Psi(m) disruption, and the release of cytochrome c, which finally induces caspase-3-mediated apoptosis in thymocytes.
 ...
PMID:Differential involvement of p38 MAP kinase pathway and Bax translocation in the mitochondria-mediated cell death in TCR- and dexamethasone-stimulated thymocytes. 1153 68

Neuronal apoptosis has been implicated as an important mechanism of cell death in acute and chronic neurodegenerative disorders. Ceramide is a product of sphingolipid metabolism which induces neuronal apoptosis in culture, and ceramide levels increase in neurons during various conditions associated with cell death. In this study we investigate the mechanism of ceramide-induced apoptosis in primary cortical neuronal cells. We show that ceramide treatment initiates a cascade of biochemical alterations associated with cell death: earliest signal transduction changes involve Akt dephosphorylation and inactivation followed by dephosphorylation of proapoptotic regulators such as BAD (proapoptotic Bcl-2 family member), Forkhead family transcription factors, glycogen synthase kinase 3-beta, mitochondrial depolarization and permeabilization, release of cytochrome c into the cytosol, and caspase-3 activation. Bongkrekic acid, an agent that inhibits mitochondrial depolarization, significantly reduces ceramide-induced cell death and correlated caspase-3 activation. Together, these data demonstrate the importance of the mitochondrial-dependent intrinsic pathway of caspase activation for ceramide-induced neuronal apoptosis.
 ...
PMID:Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK-3beta, and induction of the mitochondrial-dependent intrinsic caspase pathway. 1269 38

Neuroblastoma, a pediatric peripheral nervous system tumor, frequently contains alterations in apoptotic pathways, producing chemoresistant disease. Insulin-like growth factor (IGF) system components are highly expressed in neuroblastoma, further protecting these cells from apoptosis. This study investigates IGF-I regulation of apoptosis at the mitochondrial level. Elevated extracellular glucose causes rapid mitochondrial enlargement coupled with an increase in the mitochondrial membrane potential (Delta Psi(M)) followed by mitochondrial membrane depolarization (MMD), uncoupling protein 3 (UCP3) downregulation, caspase-3 activation and decreased Bcl-2. MMD inhibition by Bongkrekic acid prevents high-glucose-induced loss of UCP3 and apoptosis. Glucose exposure induces caspase-9 cleavage within 30 min, and caspase-9 inhibition prevents glucose-mediated apoptosis. IGF-I prevents caspase activation and mitochondrial events leading to apoptosis. These results suggest that elevated glucose produces early initiator caspase activation, followed by Delta Psi(M) changes, in neuroblastoma cells; in turn, IGF-I prevents apoptosis by preventing downstream caspase activation, maintaining Delta Psi(M) and regulating Bcl proteins.
 ...
PMID:Insulin-like growth factor-I regulates glucose-induced mitochondrial depolarization and apoptosis in human neuroblastoma. 1510 34

We previously demonstrated that the combination of paclitaxel and manumycin A, a farnesyltransferase inhibitor, enhanced apoptosis of anaplastic thyroid cancer (ATC) cells. However, the mechanism of the manumycin-induced apoptosis is not fully understood. In this study, we discovered that mitochondrial ultrastructure condensation occurred after treatment with manumycin or manumycin plus paclitaxel. Bongkrekic acid and cyclosporin A, which are known inhibitors of the voltage-dependent anion channel, failed to inhibit cytochrome c release induced by manumycin or manumycin plus paclitaxel, suggesting that mitochondrial permeability transition pores were not involved. We also found that manumycin induced translocation of Bcl-2-associated X protein (Bax), another possible mediator of cytochrome c release, from the cytosol to the mitochondria. Silencing Bax with a specific small interfering RNA blocked manumycin-induced mitochondrial condensation and cytochrome c release, arguing the dependence of manumycin-induced apoptosis on Bax. Using a binary adenoviral vector system, we found that overexpression of Bax enhanced manumycin-induced apoptosis of ATC cells, and the combination of manumycin and overexpression of Bax increased inhibition of ATC xenograft growth in nude mice. Thus, we concluded that manumycin-induced apoptosis in ATC cells was primarily mediated by Bax and that increasing Bax expression may sensitize ATC cells to manumycin.
 ...
PMID:Bcl-2-associated X protein is the main mediator of manumycin a-induced apoptosis in anaplastic thyroid cancer cells. 1576 83