Apoptosis-inducing factor (AIF): caspase-independent after all

Candé, Céline; Vahsen, Nicola; Garrido, Carmen; Kroemer, Guido

doi:10.1038/sj.cdd.4401400

Cited by 214 publications

(166 citation statements)

References 54 publications

(53 reference statements)

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“…[20][21][22][23] In this study, we found that the nuclear translocation of EndoG was caspase-independent, because its activity was not affected by the pan-caspase inhibitor z-VAD-fmk. Even though nuclear translocation of EndoG occurred at an early time (8 hr) after cisplatin treatment, it did not seem to play an important role in the early apoptosis (8 hr) of cisplatin-treated HN4 cells because siRNA knockdown of EndoG failed to block the early apoptosis (8 hr) of cisplatin-treated HN4 cells.…”

Section: Discussionmentioning

confidence: 62%

“…18 Apoptosis mediated by AIF and/or EndoG has been reported to be caspase-independent 16,17 ; however, there are contradictory reports regarding the release of AIF and EndoG as being caspase-dependent. [19][20][21][22][23] Upon release from mitochondria, AIF and EndoG translocate to the nucleus where they cause DNA fragmentation, 16,17 provoking apoptosis in a caspase-independent manner. 24,25 Cisplatin also has been shown to induce apoptosis through the mitochondrial release of proapoptotic molecules, including cytochrome c, [26][27][28] Omi/HtrA2, 29 Smac/Diablo, 30,31 and AIF.…”

Section: Introductionmentioning

confidence: 99%

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Reactive oxygen species‐dependent EndoG release mediates cisplatin‐induced caspase‐independent apoptosis in human head and neck squamous carcinoma cells

Kim

Lee

Jeong

et al. 2007

Intl Journal of Cancer

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Cisplatin is a chemotherapeutic agent that is widely used to treat cancers such as head and neck squamous cell carcinoma (HNSCC). Previously, we have reported that cisplatin induced an early caspase-dependent apoptosis (8 hr) in a HNSCC cell, HN4. In this study, we examined a late caspase-independent apoptosis as well as an early caspase-dependent apoptosis in cisplatintreated HN4 cells. While z-VAD-fmk, a pan-caspase inhibitor, blocked the caspase activities and protected cells from the early apoptosis, it did not provide protection against delayed apoptosis occurring after extended exposure (16 hr) to cisplatin, suggesting that the delayed apoptotic response in the presence of z-VAD-fmk was caspase-independent. Cisplatin treatment induced reactive oxygen species (ROS) generation, loss of the mitochondrial membrane potential (MMP) and nuclear translocation of endonuclease G (EndoG). Small interfering RNA mediated-knockdown of EndoG significantly protected cells from the delayed apoptosis induced by cisplatin in the presence of z-VAD-fmk. Overexpression of Bcl-2 in HN4 cells prevented loss of MMP, nuclear translocation of EndoG and protected cells from the delayed apoptosis induced by cisplatin in the presence of z-VAD-fmk. Pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger, prevented both ROS generation, loss of the MMP and nuclear translocation of EndoG. Together, our data indicate that cisplatin treatment induced ROS-mediated loss of the MMP, and, then, the nuclear translocation of EndoG, which played a crucial role in caspase-independent apoptosis of HN4 cells in the presence of z-VAD-fmk. This is the first report about the involvement of EndoG in cisplatin-induced caspase-independent apoptosis of cells. ' 2007 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species‐dependent EndoG release mediates cisplatin‐induced caspase‐independent apoptosis in human head and neck squamous carcinoma cells

Kim

Lee

Jeong

et al. 2007

Intl Journal of Cancer

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“…22 Importantly, the various proapoptotic effects of AIF were not inhibited by pharmacological caspase inhibitors such as zVAD or BAF, indicating that AIF can trigger nuclear apoptosis in a caspase-independent manner. 23 Perhaps not surprisingly, the conserved FAD-binding domain of AIF, required for its NADH oxidase activity and for its cytoprotective effects, 15 is dispensable for its proapoptotic function. 13,24 Thus, AIF has a dual mission in the cell: normally, it resides in the mitochondrial membrane, helps maintain optimal mitochondrial respiratory function and protects cells against the undesirable and eventually deadly consequences of oxidative damage.…”

Section: Introductionmentioning

confidence: 99%

Regulation of AIF expression by p53

et al. 2006

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The tumor suppressor p53 plays a pivotal role in suppressing tumorigenesis by inducing genomic stability, cell cycle arrest or apoptosis. AIF is a mitochondrial protein, which, upon translocation to the nucleus, can participate in apoptosis, primarily in a caspase-independent contexts. We now report that AIF gene expression is subject to positive transcriptional regulation by p53. Interestingly, unlike most known p53 target genes, the AIF gene is regulated by basal levels of p53, and activation of p53 by genotoxic stress does not result in a substantial further increase in AIF expression. The AIF gene harbors a p53 responsive element, which is bound by p53 within cells. p53 drives efficient induction of large-scale DNA fragmentation, a hallmark of AIF activity. Importantly, caspase-independent death is compromised in cells lacking functional p53, in line with the known role of AIF in this process. Thus, in addition to its documented effects on caspase-dependent apoptosis, p53 may also sensitize cells to caspase-independent death through positive regulation of AIF expression. Moreover, in the absence of overt apoptotic signals, the constitutive induction of AIF by p53 may underpin a cytoprotective maintenance role, based on the role of AIF in ensuring proper mitochondrial function.

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“…Mitochondrial proteins that induce caspase-dependent apoptosis include cytochrome c and two other proteins, Smac/Diablo and Omi/HtrA2, which antagonize the inhibitors of apoptosis (IAPs). Mitochondria can also release EndoG and apoptosisinducing factor (AIF), one of the major mediators of cell death involved in caspase-independent apoptosis (Joza et al, 2001;Cande et al, 2004;Cregan et al, 2004). Apoptosis-inducing factor is expressed as a precursor of 67 kDa, which is addressed and compartmentalized into mitochondria by two-mitochondrial localization sequences located within the N-terminal prodomain of the protein (Susin et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells

et al. 2006

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Ligation of the cell surface molecule CD44 by anti-CD44 monoclonal antibodies (mAbs) has been shown to induce cell differentiation, cell growth inhibition and in some cases, apoptosis in myeloid leukemic cells. We report, herein, that exposure of human erythroleukemic HEL cells to the anti-CD44 mAb A3D8 resulted in cell growth inhibition followed by caspase-independent apoptosis-like cell death. This process was associated with the disruption of mitochondrial membrane potential (DWm), the mitochondrial release of apoptosis-inducing factor (AIF), but not of cytochrome c, and the nuclear translocation of AIF. All these effects including cell death, loss of mitochondrial DWm and AIF release were blocked by pretreatment with the poly (ADP-ribose) polymerase inhibitor isoquinoline. A significant protection against cell death was also observed by using small interfering RNA for AIF. Moreover, we show that calpain protease was activated before the appearance of apoptosis, and that calpain inhibitors or transfection of calpain-siRNA decrease A3D8-induced cell death, and block AIF release. These data suggest that CD44 ligation triggers a novel caspaseindependent cell death pathway via calpain-dependent AIF release in erythroleukemic HEL cells.

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Apoptosis-inducing factor (AIF): caspase-independent after all

Cited by 214 publications

References 54 publications

Reactive oxygen species‐dependent EndoG release mediates cisplatin‐induced caspase‐independent apoptosis in human head and neck squamous carcinoma cells

Reactive oxygen species‐dependent EndoG release mediates cisplatin‐induced caspase‐independent apoptosis in human head and neck squamous carcinoma cells

Regulation of AIF expression by p53

CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells

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