bcl-X(S)-induced cell death in 3T3 cells does not require or induce caspase activation (original) (raw)
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Modulation of cell death by Bcl-XL through caspase interaction
Proceedings of the …, 1998
The caspases are cysteine proteases that have been implicated in the execution of programmed cell death in organisms ranging from nematodes to humans. Many members of the Bcl-2 family, including Bcl-x L , are potent inhibitors of programmed cell death and inhibit activation of caspases in cells.
Caspase9-induced Mitochondrial Disruption through Cleavage of Anti-apoptotic BCL2 Family Members
Journal of Biological Chemistry, 2007
Mitochondrial disruption during apoptosis results in the release of cytochrome c that forms apoptosomes with Apaf-1 and caspase-9. Activation of caspase-9 by dimerization in apoptosomes then triggers a caspase signaling cascade. In addition, other apoptosis signaling molecules released from the mitochondrion, such as apoptosis-inducing factor and endonuclease G, may induce caspase-9-independent apoptosis. To determine the signaling events induced by caspase-9, we used chemically induced dimerization for specific activation of caspase-9. We observed that caspase-9 dimerization resulted in the loss of mitochondrial membrane potential and the cleavage of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1. Moreover, cleavage-resistant Bcl-2, Bcl-xL, or Mcl-1 potently inhibited caspase-9-dependent loss of mitochondrial membrane potential and the release of cytochrome c. Our data suggest that a caspase-9 signaling cascade induces feedback disruption of the mitochondrion through cleavage of anti-apop...
Journal of Biological Chemistry, 1999
A growing body of evidence supports a role for mitochondria and mitochondria-derived factors in the cell death process. In particular, much attention has focused on cytochrome c, a key component of the electron transport chain, that has been reported to translocate from the mitochondria to the cytosol in cells undergoing apoptosis. The mechanism for this release is, as yet, unknown. Here we report that ectopic expression of Bax induces apoptosis with an early release of cytochrome c preceding many apoptosis-associated morphological alterations as well as caspase activation and subsequent substrate proteolysis. A loss of mitochondrial transmembrane potential was detected in vivo, although no mitochondrial swelling or loss of transmembrane potential was observed in isolated mitochondria treated with Bax in vitro. Caspase inhibitors, such as endogenous XIAP and synthetic peptide benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk), although capable of altering the kinetics and perhaps mode of cell death, had no influence on this release, suggesting that if cytochrome c plays a role in caspase activation it must precede this step in the apoptotic process. Mitochondrial permeability transition was also shown to be significantly prevented by caspase inhibition, indicating that the translocation of cytochrome c from mitochondria to cytosol is not a consequence of events requiring mitochondrial membrane depolarization. In contrast, Bcl-xL was capable of preventing cytochrome c release while also significantly inhibiting cell death. It would therefore appear that the mitochondrial release of factors such as cytochrome c represents a critical step in committing a cell to death, and this release is independent of permeability transition and caspase activation but is inhibited by Bcl-xL.
Necrosis-like death can engage multiple pro-apoptotic Bcl-2 protein family members
Apoptosis, 2012
Necroptosis is a physiologically relevant mode of cell death with some well-described initiating events, but largely unknown executioners. Here we investigated necrostatin-1 (Nec-1) sensitive death elicited by different necroptosis stimuli in L929 mouse fibrosarcoma cells, mouse embryonic fibroblasts (MEF) and bone marrow-derived macrophages. We found that TNFαor zVAD-induced necroptosis occurs independently of the recently implicated executioners Bmf or PARP-2, but can involve the Bcl-2 family proteins Bid and Bak.
Functions of BCL-X L at the Interface between Cell Death and Metabolism
International Journal of Cell Biology, 2013
The BCL-2 homolog BCL-XL, one of the two protein products ofBCL2L1, has originally been characterized for its prominent prosurvival functions. Similar to BCL-2, BCL-XLbinds to its multidomain proapoptotic counterparts BAX and BAK, hence preventing the formation of lethal pores in the mitochondrial outer membrane, as well as to multiple BH3-only proteins, thus interrupting apical proapoptotic signals. In addition, BCL-XLhas been suggested to exert cytoprotective functions by sequestering a cytosolic pool of the pro-apoptotic transcription factor p53 and by binding to the voltage-dependent anion channel 1 (VDAC1), thereby inhibiting the so-called mitochondrial permeability transition (MPT). Thus, BCL-XLappears to play a prominent role in the regulation of multiple distinct types of cell death, including apoptosis and regulated necrosis. More recently, great attention has been given to the cell death-unrelated functions of BCL-2-like proteins. In particular, BCL-XLhas been shown to mod...
Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies
Nature Cell Biology, 2006
Apoptosis, or programmed cell death, results from the activation of an evolutionarily conserved genetic pathway 1 . Apoptosis manifests in irreversible damage to cellular constituents through caspase activation and mitochondrial dysfunction 2,3 . Mammals evolved a more complex regulation of caspase activation with the involvement of mitochondria, namely the requirement for cytochrome c 4,5 . The BCL-2 family members are major regulators of mitochondrial integrity and mitochondrion-initiated caspase activation 2,6 .
Different forms of cell death induced by putative BCL2 inhibitors
Cell Death and Differentiation, 2009
Several inhibitors of BCL2 proteins have been identified that induce apoptosis in a variety of tumor cells, indicating their potential in cancer therapy. We investigated the specificity of six putative BCL2 inhibitors (obatoclax, gossypol, apogossypol, EM20-25, chelerythrine and ABT-737). Using cells deficient either for Bax/Bak or caspase-9, we found that only ABT-737 specifically targeted BCL2 proteins and induced apoptosis by activation of caspase-9, as only ABT-737 induced apoptosis was completely inhibited in cells deficient for Bax/Bak or caspase-9. Our data show that only ABT-737 is a specific BCL2 inhibitor and all other compounds investigated were not specific for BCL2 proteins. Furthermore, investigations of the effects of these compounds in primary chronic lymphocytic leukemic cells showed that all compounds induced certain biochemical hallmarks of apoptosis, such as release of cytochrome c and caspase cleavage. However, they all caused strikingly different ultrastructural changes. ABT-737 induced all the characteristic ultrastructural changes of apoptosis together with early rupture of the outer mitochondrial membrane, whereas obatoclax, chlelerythrine and gossypol induced pronounced mitochondrial swelling with formation of phospholipid inclusions. Therefore, we conclude that biochemical measurements used earlier to define apoptosis like mitochondrial release of cytochrome c and caspase cleavage, are insufficient to distinguish between classic apoptosis and other forms of cell death.
The various components of multicellular organisms involve large-scale reshaping facilitated by well-coordinated cell growth and cell death. Multicellular organisms have an evolved controlled mechanism for cell death, which is known as apoptosis or programmed cell death (PCD). Apoptosis is characterized by a series of biochemical and morphological changes like blebbing, loss of asymmetry and attachment of cell membrane, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. Apoptosis is an integral part of the mul-ticellular organism, having its presence right from developmental stages to adult life. Apoptosis is initiated by a variety of external or internal stimuli and happens by a well-controlled mechanism. The controlled and coordinated steps involved in apoptotic cell death make it different from other types of cell death, like necro-sis, which involves uncontrolled cell death resulting in lysis of cells, and invoking inflammatory respo...