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)

The serine/threonine kinase Akt/PKB is a major downstream effector of growth factor-mediated cell survival. Activated Akt, like Bcl-2 and Bcl-xL, prevents closure of a PT pore component, the voltage-dependent anion channel (VDAC); intracellular acidification; mitochondrial hyperpolarization; and the decline in oxidative phosphorylation that precedes cytochrome c release. However, unlike Bcl-2 and Bcl-xL, the ability of activated Akt to preserve mitochondrial integrity, and thereby inhibit apoptosis, requires glucose availability and is coupled to its metabolism. Hexokinases are known to bind to VDAC and directly couple intramitochondrial ATP synthesis to glucose metabolism. We provide evidence that such coupling serves as a downstream effector function for Akt. First, Akt increases mitochondria-associated hexokinase activity. Second, the antiapoptotic activity of Akt requires only the first committed step of glucose metabolism catalyzed by hexokinase. Finally, ectopic hexokinase expression mimics the ability of Akt to inhibit cytochrome c release and apoptosis. We therefore propose that Akt increases coupling of glucose metabolism to oxidative phosphorylation and regulates PT pore opening via the promotion of hexokinase-VDAC interaction at the outer mitochondrial membrane.
 ...
PMID:Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. 1139 Mar 60

Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug. In controlled monotherapy and as adjunct to L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and anti-apoptotic activity against several neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N-methyl-(R)-salsolinol) and ischemia. In vivo, it reduces the sequelae of traumatic brain injury in mice and speeds their recovery. The neuroprotective activity of rasagaline does not result from MAO B inhibition, since its S-enantiomer, TVP1022, which has 1000-fold weaker MAO inhibitory activity, exhibits similar neuroprotective properties. Introduction of a carbamate moiety into the rasagiline molecule to confer cholinesterase inhibitory activity for the treatment of Alzheimer's disease, resulted in compounds TV3326 [(N-Propargyl-(3R)Aminoindan-5-YL)-Ethyl Methyl Carbamate] and its S-enantiomer TV3279 [(N-Propargyl-(3S)Aminoindan-5-YL)-Ethyl Methyl Carbamate], which retain the neuroprotective activities of rasagiline and TVP1022. They also antagonize scopolamine-induced impairments in spatial memory. In addition, TV3326 exhibits brain-selective MAO A and B inhibitory activity after chronic administration and has antidepressant-like activity in the forced swim test. This is associated with an increase in brain levels of serotonin. The anti-apoptotic activity of these propargylamine-containing derivatives may be related to their ability to delay the opening of voltage-dependent anion channels (VDAC), which are part of the mitochondrial permeability transition pore. The propargylamine moiety is responsible for the increase in the mitochondrial family of Bcl-2 proteins, prevention in the fall in mitochondrial membrane potential, prevention of the activation of caspase 3, and of translocation of glyceraldehyde-3-phosphate dehydrogenase from the cytoplasm to the nucleus. The latter processes are closely associated with neurotoxin-induced apoptosis. Rasagiline interacts with and prevents the binding of PKI 1195 to the pro-apoptotic peripheral benzodiazepine receptor, which together with Bcl-2, hexokinase, porin, and adenine nucleotide translocator constitutes part of the VDAC. Furthermore, rasagiline, TV3326 and TV3279 are able to influence the processing of amyloid precursor protein by activation of alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus. This process has been shown to involve the upregulation of PKC and MAP kinase. It is quite likely that the induction of Bcl-2 and activation of PKC by rasagiline and TV3326 is closely linked to the anti-apoptotic action of these drugs and their ability to process APP by activation of alpha-secretase.
 ...
PMID:Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. 1204 33

The serine/threonine kinase Akt/protein kinase B inhibits apoptosis induced by a variety of stimuli, including overexpression or activation of proapoptotic Bcl-2 family members. The precise mechanisms by which Akt prevents apoptosis are not completely understood, but Akt may function to maintain mitochondrial integrity, thereby preventing cytochrome c release following an apoptotic insult. This effect may be mediated, in part, via promotion of physical and functional interactions between mitochondria and hexokinases. Here we show that growth factor deprivation induced proteolytic cleavage of the proapoptotic Bcl-2 family member BID to yield its active truncated form, tBID. Activated Akt inhibited mitochondrial cytochrome c release and apoptosis following BID cleavage. Akt also antagonized tBID-mediated BAX activation and mitochondrial BAK oligomerization, two downstream events thought to be critical for tBID-induced apoptosis. Glucose deprivation, which impaired the ability of Akt to maintain mitochondrion-hexokinase association, prevented Akt from inhibiting BID-mediated apoptosis. Interestingly, tBID independently elicited dissociation of hexokinases from mitochondria, an effect that was antagonized by activated Akt. Ectopic expression of the amino-terminal half of hexokinase II, which is catalytically active and contains the mitochondrion-binding domain, consistently antagonized tBID-induced apoptosis. These results suggest that Akt inhibits BID-mediated apoptosis downstream of BID cleavage via promotion of mitochondrial hexokinase association and antagonism of tBID-mediated BAX and BAK activation at the mitochondria.
 ...
PMID:Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. 1470 45

In thymocytes, dexamethasone initiates cytochrome c-dependent processing of caspase-9 and the activation of caspase-3 to trigger apoptotic damage. Using murine thymocytes or a thymocyte cell line WEHI 7.1, we show that this pathway is inhibited by dominant-negative caspase-9, the anti-apoptotic protein Bcl-2, or by blocking components of the mitochondrial permeability transition pore complex (PTPC). We use DIDS (dithiocyanatostilbene-2,2-disulfonic acid), a pharmacological modifier of VDAC (voltage-dependent anion channel) function or ectopic expression of hexokinase-II, to examine the role of the VDAC--a mitochondrial outer membrane protein--in this apoptotic pathway. This approach implicated the VDAC in dexamethasone-mediated cytochrome c release, processing of caspase-9 and caspase-3, the loss of mitochondrial transmembrane potential (Deltapsim), nuclear damage and cell lysis. Inhibiting the adenine nucleotide transporter (ANT), a protein on the mitochondrial inner membrane, also blocks dexamethasone-induced apoptosis, but the ANT regulates caspase-3 processing and nuclear damage but not the mitochondrial efflux of cytochrome c. Collectively, the data identify two separable, but connected events in dexamethasone-induced mitochondrial damage in thymocytes. The first event is an increase in permeability of the mitochondrial outer membrane leading to VDAC-regulated efflux of cytochrome c and initial processing of caspase-9 followed by ANT-dependent caspase-3 processing and apoptotic damage to cells.
 ...
PMID:The mitochondrial phase of the glucocorticoid-induced apoptotic response in thymocytes comprises sequential activation of adenine nucleotide transporter (ANT)-independent and ANT-dependent events. 1497 Oct 37

Glucocorticoids induce apoptosis in lymphocytes by causing the release of cytochrome c into the cytosol; however, the events in the signaling phase between translocation of the steroid-receptor complex to the nucleus and the release of cytochrome c have not been elucidated. Previously, we found that, in response to steroid treatment, WEHI7.2 mouse thymic lymphoma cells overexpressing catalase (CAT38) show delayed apoptosis (delayed cytochrome c release) compared to the parental cells, while Bcl-2 overexpressing cells (Hb12) are protected from steroid-induced apoptosis. In lymphocytes, glucocorticoid treatment decreases glucose uptake. Both glucose deprivation and the attendant ATP drop are known inducers of apoptosis. Therefore, we used (31)P and (1)H NMR spectroscopy to compare metabolic profiles of WEHI7.2, CAT38 and Hb12 cells in the presence and absence of dexamethasone to determine: (1) whether glucocorticoid effects on glucose metabolism contribute to the mechanism of steroid-induced apoptosis; and (2) whether catalase or Bcl-2 overexpression altered metabolism thereby providing a mechanism of steroid resistance. Loss of mitochondrial hexokinase activity was correlated to the induction of apoptosis in WEHI7.2 and CAT38 cells. CAT38 and Hb12 cells have an altered basal metabolism which includes increases in hexokinase activity, lactate production when subcultured into new medium, use of mitochondria for ATP production and potentially increased glutaminolysis. These data suggest that: (1) glucocorticoid effects on glucose metabolism may contribute to the mechanism of steroid-induced lymphocyte apoptosis; and (2) the altered metabolism seen in catalase and Bcl-2 overexpressing cells may contribute to both the steroid resistance and increased tumorigenicity of these variants.
 ...
PMID:Overexpression of catalase or Bcl-2 alters glucose and energy metabolism concomitant with dexamethasone resistance. 1527 25

The serine/threonine kinase Akt inhibits mitochondrial cytochrome c release and apoptosis induced by a variety of proapoptotic stimuli. The antiapoptotic activity of Akt is coupled, at least in part, to its effects on cellular metabolism. Here, we provide genetic evidence that Akt is required to maintain hexokinase association with mitochondria. Targeted disruption of this association impairs the ability of growth factors and Akt to inhibit cytochrome c release and apoptosis. Targeted disruption of mitochondria-hexokinase (HK) interaction or exposure to proapoptotic stimuli that promote rapid dissociation of hexokinase from mitochondria potently induce cytochrome c release and apoptosis, even in the absence of Bax and Bak. These effects are inhibited by activated Akt, but not by Bcl-2, implying that changes in outer mitochondrial membrane (OMM) permeability leading to apoptosis can occur in the absence of Bax and Bak and that Akt inhibits these changes through maintenance of hexokinase association with mitochondria.
 ...
PMID:Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. 1557 36

Depletion of mitochondrial DNA (mtDNA) or treatment with mitochondrial poison CCCP initiates mitochondrial stress signaling, which operates through altered Ca2+ homeostasis. In C2C12 rhabdomyoblasts and A549 human lung carcinoma cells mitochondrial stress signaling activates calcineurin and a number of Ca2+ responsive factors including ATF, NFAT, CEBP/delta and CREB. Additionally, PKC and MAP kinase are also activated. A number of nuclear gene targets including those involved in Ca2+ storage/release (RyR1, calreticulin, calsequestrin), glucose metabolism (hexokinase, pyruvate kinase, Glut4), oncogenesis (TGFbeta1, cathepsin L, IGFR1, melanoma antigen) and apoptosis (Bcl-2, Bid, Bad, p53) are upregulated. Mitochondrial stress in both C2C12 myoblasts and A549 cells induced morphological changes and invasive phenotypes. These cells also showed markedly increased resistance to etoposide-induced apoptosis that is a hallmark of highly invasive tumors. Our results describe a new mechanism of altered nuclear gene expression and phenotypic changes triggered by mitochondrial dysfunction and mtDNA damage.
 ...
PMID:Mitochondria-to-nucleus stress signaling in mammalian cells: nature of nuclear gene targets, transcription regulation, and induced resistance to apoptosis. 1597 49

Mitochondria fulfill a wide array of functions dedicated to the energetic metabolism as well as the control of cell death. These functions imply that mitochondria can be activated by a variety of signals and can integrate them to trigger a process called mitochondrial membrane permeabilization (MMP), which induces the ultimate events of apoptosis. MMP consists in a sudden increase in the permeability of mitochondrial membrane that results in the release of critical proapoptotic intermembrane space effectors into the cytosol such as cytochrome c, apoptosis-inducing factor (AIF), Smac/Diablo, Endo G, and pro-caspases. In many models of apoptosis, mitochondrial translocation of proteins and/or lipids concomitantly with alterations of the intracellular milieu has been shown to activate MMP. This applies to tumor suppressors of the Bax/Bcl-2 family (Bax, Bad, Bid, Bim), several protein kinases (Akt, ASK1, hexokinase), p53, NF-kappaB, and nuclear orphan receptors such as TR3/Nur77. After mitochondrial membrane association, these proteins target constitutive mitochondrial proteins including the permeability transition pore complex (PTPC), Bcl-X(L), HSP70, and/or the lipid interphase. Subsequently, they switch their vital function into a lethal function to promote membrane permeabilization and protein release. In this review, we will describe some general rules of inter-organelle cross-talk activating MMP and will review selected examples of pro-apoptotic protein translocation. Finally, we will propose new pharmacological strategies to modulate this process in a therapeutic perspective.
 ...
PMID:The modulation of inter-organelle cross-talk to control apoptosis. 1678 50

Mitochondria are proving to be worthy targets for activating specific killing of cancer cells in tumors and a diverse range of mitochondrial targeted drugs are currently in clinical trial to determine their effectiveness as anti-cancer therapies. The mechanism of action of mitochondrial targeted anti-cancer drugs relies on their ability to disrupt the energy producing systems of cancer cell mitochondria, leading to increased reactive oxygen species and activation of the mitochondrial dependent cell death signaling pathways inside cancer cells. We propose that this emerging class of drugs be called "mitocans", a term that reflects their mitochondrial targeting and anti-cancer roles. They are discussed in this review in the context of their mode of action whereby they target the functional differences and altered properties of the mitochondria inside cancerous but not normal cells. Hence, mitocans include drugs affecting the following mitochondrial associated activities: hexokinase inhibitors; electron transport/respiratory chain blockers; activators of the mitochondrial membrane permeability transition pore targeting constituent protein subunits, either the voltage dependent anion-selective channel (VDAC) or adenine nucleotide transporter (ANT); inhibitors of Bcl-2 anti-apoptotic family proteins and Bax/Bid pro-apoptotic mimetics. In particular, a recent surge has occurred in the number of patent documents describing small molecule inhibitors and BH3 mimetic blockers of Bcl-2/Bcl-x(L) function as obvious and important targets for promoting mitochondrial induced cancer cell death and for enhancing the actions of other chemotherapeutic agents. One of the other highly significant results to emerge from clinical applications of mitochondrial targeted drugs as cancer therapies to date is that they have shown limited side-effects on the normal "healthy" cell populations in vivo. It is still too early to judge the clinical impact that mitocans will make in treating cancer. Further clinical studies will be required before these novel drugs become established as single modality anti-cancer therapies or are used in conjunction with existing chemotherapies. However, it is clear from the present studies that mitocans offer great potential as effective and exciting new developments in cancer therapy, providing direct activation of cancer cell death by mitochondrial mediated apoptosis and that this complements the other pathways by which existing treatments kill cancer cells. Undoubtedly, mitocans will become an integral part of modern weaponry in the fight to eliminate cancer.
 ...
PMID:Mitocans: mitochondrial targeted anti-cancer drugs as improved therapies and related patent documents. 1822 Oct 44

Previously we demonstrated that insulin protects against neuronal oxidative stress by restoring antioxidants and energy metabolism. In this study, we analysed how insulin influences insulin-(IR) and insulin growth factor-1 receptor (IGF-1R) intracellular signaling pathways after oxidative stress caused by ascorbate/Fe2+ in rat cortical neurons. Insulin prevented oxidative stress-induced decrease in tyrosine phosphorylation of IR and IGF-1R and Akt inactivation. Insulin also decreased the active form of glycogen synthase kinase-3beta (GSK-3beta) upon oxidation. Since phosphatidylinositol 3-kinase (PI-3K)/Akt-mediated inhibition of GSK-3beta may stimulate protein synthesis and decrease apoptosis, we analysed mRNA and protein expression of "candidate" proteins involved in antioxidant defense, glucose metabolism and apoptosis. Insulin prevented oxidative stress-induced increase in glutathione peroxidase-1 and decrease in hexokinase-II expression, supporting previous findings of changes in glutathione redox cycle and glycolysis. Moreover, insulin precluded Bcl-2 decrease and caspase-3 increased expression. Concordantly, insulin abolished caspase-3 activity and DNA fragmentation caused by oxidative stress. Thus, insulin-mediated activation of IR/IGF-1R stimulates PI-3K/Akt and inhibits GSK-3beta signaling pathways, modifying neuronal antioxidant defense-, glucose metabolism- and anti-apoptotic-associated protein synthesis. These and previous data implicate insulin as a promising neuroprotective agent against oxidative stress associated with neurodegenerative diseases.
 ...
PMID:Insulin neuroprotection against oxidative stress is mediated by Akt and GSK-3beta signaling pathways and changes in protein expression. 1834 71


1 2 3 4 Next >>