Relative timing of redistribution of cytochrome c and Smac/DIABLO from mitochondria during apoptosis assessed by double immunocytochemistry on mammalian cells

Lim, Maria L. R.; Chen, Baohong; Beart, Philip M; Nagley, Phillip

doi:10.1016/j.yexcr.2006.01.026

Cited by 19 publications

(38 citation statements)

References 29 publications

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“…These results also provide an explanation for the reported contradictory results showing either a concurrent (Zhou et al, 2005) or independent (Lim et al, 2006) release of cytochrome c and Smac/DIABLO during apoptosis. Stimuli that induce an upregulation of survivin should block or delay the release of Smac/ DIABLO, even in the presence of an outer membrane permeability transition that would otherwise allow its release.…”

Section: Discussionsupporting

confidence: 57%

Regulation of mitochondrial Smac/DIABLO-selective release by survivin

et al. 2007

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The intrinsic apoptotic pathway is characterized by the release of several mitochondrial intermembrane proteins into the cytosol of dying cells. It is unclear whether the release of these proteins follows a common or specific pathway. In the present report we show that survivin and, to a lesser extent, the survivin splice variant survivin DeltaEx3 regulate the specific liberation of second mitochondria-derived activator of caspase/direct IAP binding protein with low pI (Smac/DIABLO), an inhibitor of apoptosis proteins binding protein, during apoptosis induced by etoposide, a DNA damaging agent. This antineoplastic drug induced posttranscriptional upregulation of survivin and survivin DeltaEx3. In turn, mitochondrial survivin associated with Smac/DIABLO, delaying its release. In addition, cytosolic survivin also stabilized the cytosolic levels of released Smac/DIABLO. These results provide an explanation for the observed differences in the release of mitochondrial intermembrane proteins in various apoptotic models and present a new mechanism for the anti-apoptotic effects of survivin in cancer cells.

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Section: Discussionsupporting

confidence: 57%

Regulation of mitochondrial Smac/DIABLO-selective release by survivin

et al. 2007

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“…A study by Pardo et al [34] found that cyt c was released earlier than Smac was. To some extent, the release of Smac was partially dependent on cyt c. Some research revealed that the time order for releasing Smac and cyt c was not identical in different cell lines, and mechanisms for their release were different under the same or different induction conditions [35,36,37]. Since mitochondria played an essential role in the apoptosis of SMMC-7721 induced by CdCl 2 , a possible mechanism for a further increase in the 3 protein expressions was that the mitochondria were targeted and damaged when cells were cotreated with CdCl 2 and hSmac leading to permeability, and the membrane potential changed resulting in more Smac and cyt c released into the cytosol.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Antiproliferative and Proapoptotic Effects of Cadmium Chloride Combined with hSmac in Hepatocellular Carcinoma Cells

Guo

Li²,

Zhang³

et al. 2011

Chemotherapy

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Background: To study the effects of cadmium chloride (CdCl₂) combined with hSmac on the proliferation and apoptosis of hepatocellular carcinoma cells, i.e. SMMC-7721. Methods: SMMC-7721 cells were transfected with pcDNA3.1⁺-hSmac using a lipofectamine-mediated method, and then cell viability was detected by MTT assay after exposure to 10, 20, and 30 µmol/l CdCl₂. Apoptosis was determined by both acridine orange-ethidium bromide staining and flow cytometry, and expressions of caspase-3, caspase-9, and cytochrome c by Western blot. Results: CdCl₂ had cytotoxicity to SMMC-7721 cells, and it could inhibit proliferation in a dose-dependent manner and induce apoptosis; hSmac could inhibit proliferation and induce apoptosis independently in SMMC-7721 cells. Furthermore, cotreatment with CdCl₂ and hSmac could enhance antiproliferative and proapoptotic effects in SMMC-7721 cells. Conclusions: hSmac could enhance the cytotoxicity of CdCl₂.

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“…While treatment of HeLa cells with STS leads to more or less coincident release of cyt c and Smac, HeLa cells treated with other apoptotic stimuli induce preferential release of Smac over cyt c (Ng et al, unpublished data). On the other hand, cyt c release occurs prior to Smac in human 143B TK 2 cells treated with STS (28). Timing of release of AIF also differs with apoptotic stimuli.…”

Section: Redistribution Of Ims Proteinsmentioning

confidence: 99%

The mitochondrial gateway to cell death

Smith

Kluck

et al. 2008

IUBMB Life

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Mitochondria play a key role in death signaling. The intermembrane space of these organelles contains a number of proteins which promote cell death once they are redistributed to the cytosol. The formation of pores in the outer membrane of mitochondria defines a gateway through which the apoptogenic proteins pass during death signaling. Interactions between pro‐apoptotic and pro‐survival members of the Bcl‐2 family of proteins are decisive in the initiation of pore opening. While the specific composition of the pore in molecular terms is still subject to debate and continuing investigation, it is recognized functionally as a passive channel which not only allows egress of proteins to cytosol but also entry in the reverse direction. A variety of constraints may restrict the release of proteins from the intermembrane space to the cytosol. These include trapping in the intercristal spaces formed by the convoluted invaginations of the inner membrane, binding of proteins to the inner membrane or to other soluble proteins of the intermembrane space, or insertion of proteins into the inner membrane. There is a corresponding variety of mechanisms that facilitate release of apoptogenic proteins from such entrapment. Morphological changes that expand the inner membrane enable proteins to be released from enclosure in intercristal spaces, allowing these proteins access to the mitochondrial gateway. Specific cases include cytochrome c molecules bound to inner membrane cardiolipin and released upon oxidation of that lipid component. Further, AIF that is embedded in the inner membrane is released by proteases (caspases or calpains), which enter from the cytosol once the outer membrane pore has opened. The facilitation (or restriction) of apoptogenic protein release through the mitochondrial gateway may provide new opportunities for regulating cell death. © 2008 IUBMB IUBMB Life, 60(6): 383–389, 2008.

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Relative timing of redistribution of cytochrome c and Smac/DIABLO from mitochondria during apoptosis assessed by double immunocytochemistry on mammalian cells

Cited by 19 publications

References 29 publications

Regulation of mitochondrial Smac/DIABLO-selective release by survivin

Regulation of mitochondrial Smac/DIABLO-selective release by survivin

Enhancement of Antiproliferative and Proapoptotic Effects of Cadmium Chloride Combined with hSmac in Hepatocellular Carcinoma Cells

The mitochondrial gateway to cell death

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