Apoptosis‐associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl‐2
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It is reported that Smac/DIABLO export from mitochondria into the cytosol is provoked by cytotoxic drugs and DNA damage, as well as by ligation of the CD95 death receptor.Abstract:
Smac/DIABLO is a mitochondrial protein that potentiates some forms of apoptosis, possibly by neutralizing one or more members of the IAP family of apoptosis inhibitory proteins. Smac has been shown to exit mitochondria and enter the cytosol during apoptosis triggered by UV- or γ-irradiation. Here, we report that Smac/DIABLO export from mitochondria into the cytosol is provoked by cytotoxic drugs and DNA damage, as well as by ligation of the CD95 death receptor. Mitochondrial efflux of Smac/DIABLO, in response to a variety of pro-apoptotic agents, was profoundly inhibited in Bcl-2-overexpressing cells. Thus, in addition to modulating apoptosis-associated mitochondrial cytochrome c release, Bcl-2 also regulates Smac release, suggesting that both molecules may escape via the same route. However, whereas cell stress-associated mitochondrial cytochrome c release was largely caspase independent, release of Smac/DIABLO in response to the same stimuli was blocked by a broad-spectrum caspase inhibitor. This suggests that apoptosis-associated cytochrome c and Smac/DIABLO release from mitochondria do not occur via the same mechanism. Rather, Smac/DIABLO efflux from mitochondria is a caspase-catalysed event that occurs downstream of cytochrome c release.read more
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References
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Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.
TL;DR: Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development, and participates in at least some types of therapeutically induced tumour regression.
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Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade
Peng Li,Deepak Nijhawan,Imawati Budihardjo,Srinivasa M. Srinivasula,Manzoor Ahmad,Emad S. Alnemri,Xiaodong Wang +6 more
TL;DR: Mutation of the active site of caspase-9 attenuated the activation of cazase-3 and cellular apoptotic response in vivo, indicating that casp enzyme-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP.
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Induction of apoptotic program in cell-free extracts : requirement for datp and cytochrome c
TL;DR: Cells undergoing apoptosis in vivo showed increased release of cy tochrome c to their cytosol, suggesting that mitochondria may function in apoptosis by releasing cytochrome c.
Journal ArticleDOI
Prevention of Apoptosis by Bcl-2: Release of Cytochrome c from Mitochondria Blocked
Jie Yang,Xuesong Liu,Xuesong Liu,Kapil N. Bhalla,Caryn Naekyung Kim,Ana Maria Ibrado,Jiyang Cai,Tsung I. Peng,Dean P. Jones,Xiaodong Wang,Xiaodong Wang +10 more
TL;DR: One possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria, which is normally located in the mitochondrial intermembrane space.
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The Release of Cytochrome c from Mitochondria: A Primary Site for Bcl-2 Regulation of Apoptosis
TL;DR: In a cell-free apoptosis system, mitochondria spontaneously released cytochrome c, which activated DEVD-specific caspases, leading to fodrin cleavage and apoptotic nuclear morphology, and Bcl-2 acts to inhibit cy tochrome c translocation, thereby blocking caspase activation and the apoptotic process.