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)

Calpain has been implicated in excitotoxic neurode-generation, but its mechanism of action particularly in adult brains remains unclear. We generated mutant mice lacking or overexpressing calpastatin, the only solely calpain-specific inhibitor ever identified or synthesized. Modulation of calpastatin expression caused no defect in the mice under normal conditions, indicating that calpastatin functions as a negative regulator of calpain only under pathological conditions. Kainate-evoked excitotoxicity in hippocampus resulted in proteolytic activation of a proapoptotic Bcl-2 subfamily member (Bid), nuclear translocation of mitochondria-derived DNA fragmentation factors (apoptosis-inducing factor and endonuclease G), DNA fragmentation, and nuclear condensation in pyramidal neurons. These apoptotic responses were significantly augmented by calpastatin deficiency. Consistently calpastatin overexpression suppressed them. No evidence of caspase-3 activation was detected. Our results demonstrated that calpain mediates excitotoxic signals through mobilization of proapoptotic factors in a caspase-independent manner. These mutant mice will serve as useful tools for investigating calpain involvement in various diseases.
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PMID:Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways in adult brains: evidence from calpastatin mutant mice. 1569 48

Apoptosis is known to be an important phenomenon in exerting antitumor response to cancer therapy, which is regulated by Bcl-2 family proteins through mitochondrial permeability transition (MPT). Insertion by the activated Bax/Bak in response to DNA damage induces mitochondrial membrane permeabilization (MMP) via an anion channel, VDAC in mitochondrial outer membrane that plays a crucial role in releasing small molecules such as cytochrome c, Smac/DIABLO, Omi/HtrA2, AIF, and endonuclease G leading to cell death. The released small molecules are involved in caspase-dependent and -independent cell death pathway that is inhibited by Bcl-2/xL. Despite the fact that the pancaspase inhibitor, zVAD-fmk inhibited the caspase cascade, cell death mediated by caspase-independent pathway was not blocked. Similarly, although etoposide induced-apoptosis was inhibited in Bax(-/-)/Bak(-/-)mouse embryonic fibroblasts, autophagy was not inhibited, which was regulated by Bcl-xL. It appears that the cross-talk between caspase-dependent and -independent apoptotic cell death including autophagic cell death that was mediated by MPT affects overall tumor response to anticancer treatment. In this review, to assist a comprehensive understanding of MPT-mediated cell death pathway for exploring appropriate targets in cancer therapy, role of the caspase-dependent and -independent cell death pathway in the interaction of these pathways is discussed.
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PMID:Caspase-dependent and -independent cell death pathways after DNA damage (Review). 1607 61

Acetaminophen hepatotoxicity is the leading cause of drug-induced liver failure. Despite substantial efforts in the past, the mechanisms of acetaminophen-induced liver cell injury are still incompletely understood. Recent advances suggest that reactive metabolite formation, glutathione depletion, and alkylation of proteins, especially mitochondrial proteins, are critical initiating events for the toxicity. Bcl-2 family members Bax and Bid then form pores in the outer mitochondrial membrane and release intermembrane proteins, e.g., apoptosis-inducing factor (AIF) and endonuclease G, which then translocate to the nucleus and initiate chromatin condensation and DNA fragmentation, respectively. Mitochondrial dysfunction, due to covalent binding, leads to formation of reactive oxygen and peroxynitrite, which trigger the membrane permeability transition and the collapse of the mitochondrial membrane potential. In addition to the diminishing capacity to synthesize ATP, endonuclease G and AIF are further released. Endonuclease G, together with an activated nuclear Ca2+,Mg2+-dependent endonuclease, cause DNA degradation, thereby preventing cell recovery and regeneration. Disruption of the Ca2+ homeostasis also leads to activation of intracellular proteases, e.g., calpains, which can proteolytically cleave structural proteins. Thus, multiple events including massive mitochondrial dysfunction and ATP depletion, extensive DNA fragmentation, and modification of intracellular proteins contribute to the development of oncotic necrotic cell death in the liver after acetaminophen overdose. Based on the recognition of the temporal sequence and interdependency of these mechanisms, it appears most promising to therapeutically target either the initiating event (metabolic activation) or the central propagating event (mitochondrial dysfunction and peroxynitrite formation) to prevent acetaminophen-induced liver cell death.
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PMID:Intracellular signaling mechanisms of acetaminophen-induced liver cell death. 1617 35

Neuronal cells injured by ischemia and reperfusion to a certain extent are committed to death in necrotic or apoptotic form. Necrosis is induced by gross ATP depletion or 'energy crisis' of the cell, whereas apoptosis is induced by a mechanism still to be defined in detail. Here, we investigated this mechanism by focusing on a DNA damage-sensor, poly(ADP-ribose) polymerase-1 (PARP-1). A 2-h oxygen and glucose deprivation (OGD) followed by reoxygenation (Reox) induced apoptosis, rather than necrosis, in rat cortical neurons. During the Reox, PARP-1 was much activated and autopoly(ADP-ribosyl)ated, consuming the substrate, NAD+. Induction of apoptosis by OGD/Reox was suppressed by overexpression of Bcl-2, indicating mitochondrial impairment in this induction process. Mitochondrial permeability transition (MPT), or membrane depolarization, and a release of proapoptotic proteins, i.e. cytochrome c, apoptosis-inducing factor and endonuclease G, from mitochondria were observed during the Reox. These apoptotic changes of mitochondria and the nucleus were attenuated by PARP-1 inhibitors, 1,5-dihydroxyisoquinoline and benzamide, and also by small interfering RNA specific for PARP-1. These results indicated that PARP-1 plays a principal role in inducing mitochondrial impairment that ultimately leads to apoptosis of neurons after cerebral ischemia.
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PMID:Mitochondrial impairment induced by poly(ADP-ribose) polymerase-1 activation in cortical neurons after oxygen and glucose deprivation. 1618 22

Status epilepticus (SE)-induced neuronal death is morphologically necrotic and is initiated by excessive glutamate release, which activates postsynaptic N-methyl-D-aspartate (NMDA) receptors and triggers receptor-mediated calcium influx (excitotoxicity). This results in activation of intracellular proteases and neuronal nitric oxide synthase, with generation of free radicals, and damage to cellular membranes, structural proteins, and essential enzymes. Programmed cell death mechanisms, such as p53 activation, activation of cell death-promoting Bcl-2 family members, and endonuclease-induced DNA laddering, occur in SE-induced neuronal death. Caspase-independent excitotoxic mechanisms, such as NMDA-induced calpain I activation, with activation and translocation of the cell death-promoting Bcl-2 family member Bid from cytoplasm to mitochondria, and subsequent translocation of apoptosis-inducing factor and endonuclease G to nuclei (which cause large-scale and internucleosomal DNA cleavage, respectively), may be triggered by SE. Poly(ADP-ribose) polymerase-1 (PARP-1) activation and cysteinyl cathepsin and DNase II release from lysosomes may occur following SE as well, but these events await future investigation. In the future, rational combinations of central nervous system-penetrable neuroprotective agents, based on our knowledge of excitotoxic mechanisms, may be useful in refractory human SE.
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PMID:Prolonged seizures and cellular injury: understanding the connection. 1627 99

Apoptosis or programmed cell death (PCD) is a physiological process that constitutes the natural fate of end-stage differentiated cells. It is essential for tissue patterning during embryonic development and for maintenance of tissue homeostasis of the adult organism. The execution of the death programme is characterized by a sequence of morphological and biochemical changes. These include early mitochondrial alterations, cell shrinkage, chromatin condensation and nuclear fragmentation, membrane blebbing, caspase activation, the presentation of phosphatidylserine at the cell surface, and the formation of membrane bound vesicles termed apoptotic bodies . The apoptosis is evolutionary conserved. The main regulatory proteins involved include caspases and bcl-2 family proteins. Three groups of the Bcl-2 family proteins can be distinguished: the antiapoptotic proteins, like Bcl-2 and Bcl-x L, the pro-apoptotic members e.g., Bax, Bak and the BH3-only proteins. In apoptosis mitochondria have two essential functions. First, provide energy, in the form of ATP, which is required for cells to die by the apoptosis pathway. Second, to release pro-apoptotic proteins normally sequestered in the intermembrane space into the cytosol where they trigger downstream apoptotic signaling pathways. Mitochondrial dysfunction in apoptosis is related with specific permeabilization of the outer mitochondrial membrane to large molecules. They can be divided into two groups. First, cytochrome c, Smac/DIABLO and HtrA2/Omi, activates the caspase dependent mitochondrial pathway. The second group, endonuclease G and AIF translocate to the nucleus and induce DNA degradation in a caspase independent manner. Mitochondrial membrane potential (MMP), delta(phi)m, may control the permeability of the outer membrane and regulate cytochrome c release. When the mitochondria loss their delta(phi) undergo swelling, and release IMs proteins.
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PMID:[Understanding cell death: a challenge for biomedicine]. 1677 20

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.
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PMID:The modulation of inter-organelle cross-talk to control apoptosis. 1678 50

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. CTX III-induced K562 cell apoptosis was confirmed by DNA fragmentation (DNA ladder, sub-G1 formation) and phosphatidylserine (PS) externalization with an IC(50) value of 1.7 microg/ml at 48 h. A mechanistic analysis demonstrated that CTX III-induced apoptotic cell death was accompanied by up-regulation of both Bax and endonuclease G (Endo G), and downregulation of Bcl-X(L). CTX III had no effect on the levels of Bcl-2, Bid, XIAP survivin, and AIF proteins. CTX III treatment caused loss of the mitochondrial membrane potential (DeltaPsim), release of mitochondrial cytochrome c to the cytosol, and activation of both caspase-9 and -3. CTX III-induced apoptosis was significantly blocked by the broad-spectrum caspase inhibitor Z-VAD-FMK. However, CTX III did not generate reactive oxygen species (ROS) and antioxidants, including N-acetylcysteine and catalase, did not block CTX III-induced apoptosis in K562 cells. Modulation of Bax, Bcl-XL, and the Endo G proteins, release of mitochondrial cytochome c, and activation of caspase-3 and -9 all are involved in the CTX III-triggered apoptotic process in human leukemia K562 cells.
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PMID:Up-regulation of Bax and endonuclease G, and down-modulation of Bcl-XL involved in cardiotoxin III-induced apoptosis in K562 cells. 1695 23

The Bcl-2 family of proteins regulates mitochondrial functions during cell death by modulating the efflux of death-promoting proteins such as cytochrome c and endonuclease G. Upon the binding of death ligands to their receptors, caspase-8 cleaves Bid, a BH3-only protein, into tBid that causes the mitochondrial damages resulting in the release of cytochrome c and endonuclease G. Also, another BH3-only protein, hNoxa, has been shown to induce the efflux of cytochrome c from the mitochondria. Whether the efflux proteins from the mitochondria in response to tBid or hNoxa are the same or different, however, has not been addressed. We have demonstrated that endonuclease G activities are not detectable among the proteins released from isolated mitochondria by hNoxa but are detectable in that by tBid. These results suggest that the efflux of proteins from the mitochondria are differentially modulated by tBid and hNoxa.
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PMID:Differential efflux of mitochondrial endonuclease G by hNoxa and tBid. 1700 76

In living cells, apoptosis is effected through many different pathways. Programmed cell death (PCD) may proceed with the involvement of membrane receptors, mitochondria, granzyme B, or the endoplasmic reticulum. The mitochondrial pathway is initiated from within the cell as a consequence of changes in reductive potential. It may also be caused by DNA mutation or various disturbances in the cell's metabolism. In some cases, the intrinsic pathway is connected with the extrinsic one, generated by the cell's environment. The central organelle which initiates the intrinsic pathway is the mitochondrion. Changes in the permeability of the mitochondrial outer membrane cause an outflow of cytochrom c, which interacts with cytoplasmic factor Apaf-1 and procaspase 9, in the presence of ATP, and thus triggers the caspase cascade. Apart from cytochrom c, more than 40 regular or executor particles involved in apoptosis might be released from the mitochondrion. These include Smac/DIABLO, Omi/HTR A2, endonuclease G, AIF, and IAP. Moreover, regulatory functions are performed by Bcl-2 family proteins present in the cytoplasm that affect mitochondrial membrane permeability and by heat shock proteins (HSPs), both of these regulating caspase function. The phenomenon of programmed cell death is the main subject of research for many groups of scientists. There are still many aspects which need to be elucidated.
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PMID:[Mitochondria and cell death]. 1701 63


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