Does apoptosis‐inducing factor (AIF) have both life and death functions in cells?

Porter, Alan G.; Urbano, Alexander

doi:10.1002/bies.20444

Cited by 58 publications

(38 citation statements)

References 72 publications

(207 reference statements)

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“…Moreover, AIF translocation was also observed in mice in the absence of caspase activation [13], and the biochemical changes were consistent with those described in many caspase-dependent cell death models [14]. Contrasting with its death-inducing properties after nuclear translocation, mitochondria-located AIF has been shown to have a protective role in healthy and in tumour cells [11,15]. Mitochondrial AIF is even thought to contribute to cell survival by protecting cells against harmful oxidative damage in the absence of deleterious stress while predisposing them to a more efficient killing in response to severe stress.…”

Section: Introductionsupporting

confidence: 80%

“…In healthy cells, AIF is required for efficient oxidative phosphorylation. Upon apoptotic insult, it translocates to the cytosol and subsequently into the nucleus where it eventually binds to DNA and induces caspase-independent cell death [10][11][12]. The concept that AIF is able to induce apoptotic cell death independent of caspases is supported by a series of experiments where programmed cell death was executed even in presence of chemical caspase inhibitors such as Z-VAD-Fmk (zVAD) or BAF.…”

Section: Introductionmentioning

confidence: 99%

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Promotion of cell death or neurite outgrowth in PC-12 and N2a cells by the fungal alkaloid militarinone A depends on basal expression of p53

et al. 2008

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The fungal alkaloid militarinone A (MiliA) was recently found to stimulate neuronal outgrowth in PC-12 cells by persistant activation of pathways that are also involved in NGF-mediated differentiation, namely the PI3-K/PKB and the MEK/ERK pathways. Application of equal concentrations of MiliA to other cells such as the murine neuroblastoma cell line N2a resulted in immediate onset of apoptosis by nuclear translocation of apoptosis inducing factor (AIF), activation of caspases and c-Jun/AP-1 transcription factor without an intermediate differentiated phenotype, although minor transient phosphorylation of PKB and MAPK as well as activation of NF-jB were also observed. Translocation of AIF was preceded by p53 phosphorylation at Ser15 and blocked by pifithrin a, a known inhibitor of p53-transcriptional activity. We here show that both cell types activate the same pathways albeit in different time scales. This is mainly due to contrasting basal expression levels of p53, which in turn regulates expression of AIF. In PC-12 cells, continuous activation of these pathways after prolonged treatment with 40 lM MiliA first led to up-regulation of p53, phosphorylation of p53, release of AIF from mitochondria and its translocation into the nucleus. Additionally, also activation of the c-Jun/ AP-1 transcription factor was observed, and PC-12 cells subsequently underwent apoptosis 48-72 h post-treatment. We report that similar pathways working on different levels are able to initially shape very divergent cellular responses.

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Section: Introductionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Promotion of cell death or neurite outgrowth in PC-12 and N2a cells by the fungal alkaloid militarinone A depends on basal expression of p53

et al. 2008

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“…Decreased AIF protein expression leads to resistance to temozolomide-induced cell death AIF plays an important role in caspaseindependent cell death in many cancer cell types when treated with different chemotherapeutic agents (Porter and Urbano, 2006). To establish the functional consequences in glioma cells with altered AIF levels as a result of nuclear BNIP3, we treated the U251 and U87 stable cell lines that have different nuclear BNIP3 levels with TMZ, an oral chemotherapeutic agent approved for the treatment of newly diagnosed and recurrent GBM (Fig.…”

Section: Bnip3 Is Bound To the Aif Promoter And Represses Its Expressmentioning

confidence: 99%

“…When cells are exposed to stress, AIF is released from the mitochondria, translocates to the nucleus and mediates caspase independent cell death (Susin et al, 1999). Increasing total AIF expression in cells leads to increased sensitivity to cell death whereas knockdown of AIF levels leads to protection from apoptosis in many different cell types (Joza et al, 2001;Porter and Urbano, 2006). During apoptotic signaling, AIF is cleaved removing its transmembrane domain (Porter and Urbano, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Increasing total AIF expression in cells leads to increased sensitivity to cell death whereas knockdown of AIF levels leads to protection from apoptosis in many different cell types (Joza et al, 2001;Porter and Urbano, 2006). During apoptotic signaling, AIF is cleaved removing its transmembrane domain (Porter and Urbano, 2006). Cleaved AIF leaves the mitochondria when permeabilization of the mitochondrial membrane occurs, and it then translocates to the nucleus.…”

Section: Introductionmentioning

confidence: 99%

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BNIP3 (Bcl-2 19 kDa Interacting Protein) Acts as Transcriptional Repressor of Apoptosis-Inducing Factor Expression Preventing Cell Death in Human Malignant Gliomas

Burton¹,

Eisenstat²,

Gibson³

2009

J. Neurosci.

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The Bcl-2 19 kDa interacting protein (BNIP3) is a pro-cell-death BH3-only member of the Bcl-2 family. We previously found that BNIP3 is localized to the nucleus in the majority of glioblastoma multiforme (GBM) tumors and fails to induce cell death. Herein, we have discovered that nuclear BNIP3 binds to the promoter of the apoptosis-inducing factor (AIF) gene and represses its expression. BNIP3 associates with PTB-associating splicing factor (PSF) and HDAC1 (histone deacetylase 1) contributing to transcriptional repression of the AIF gene. This BNIP3-mediated reduction in AIF expression leads to decreased temozolomide-induced apoptosis in glioma cells. Furthermore, nuclear BNIP3 expression in GBMs correlates with decreased AIF expression. Together, we have discovered a novel transcriptional repression function for BNIP3 causing reduced AIF expression and increased resistance to apoptosis. Thus, nuclear BNIP3 may confer a survival advantage to glioma cells and explain, in part, why BNIP3 is expressed at high levels in solid tumors, especially GBM.

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Shedding of Syndecan–1 From Human Hepatocytes Alters Very Low Density Lipoprotein Clearance

et al. 2012

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We recently showed that the heparan sulfate proteoglycan syndecan-1 mediates hepatic clearance of triglyceride-rich lipoproteins in mice based on systemic deletion of syndecan-1 and hepatocyte-specific inactivation of sulfotransferases involved in heparan sulfate biosynthesis (MacArthur et al. (2007) J. Clin. Invest. 117:153–164; Stanford et al. (2009) J. Clin. Invest. 119:3236–3245; Stanford et al. (2010) J. Biol. Chem. 285:286–294). In this report we show that syndecan-1 expressed on primary human hepatocytes and Hep3B human hepatoma cells can mediate binding and uptake of VLDL. Syndecan-1 also undergoes spontaneous shedding from primary human and murine hepatocytes and Hep3B cells. In human cells, phorbol myristic acid (PMA) induces syndecan-1 shedding, resulting in accumulation of syndecan-1 ectodomains in the medium. Shedding occurs through a protein kinase C-dependent activation of A Disintegrin and Metalloproteinase-17. PMA-stimulation significantly decreases DiD-VLDL binding to cells, and shed syndecan-1 ectodomains bind to VLDL. Although mouse hepatocytes appear resistant to induced-shedding in vitro, injection of lipopolysaccharide into mice results in loss of hepatic syndecan-1, accumulation of ectodomains in the plasma, impaired VLDL catabolism, and hypertriglyceridemia. Conclusion These findings suggest that syndecan-1 mediates hepatic VLDL turnover in humans as well as in mice and that shedding might contribute to hypertriglyceridemia in patients with sepsis.

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Does apoptosis‐inducing factor (AIF) have both life and death functions in cells?

Cited by 58 publications

References 72 publications

Promotion of cell death or neurite outgrowth in PC-12 and N2a cells by the fungal alkaloid militarinone A depends on basal expression of p53

Promotion of cell death or neurite outgrowth in PC-12 and N2a cells by the fungal alkaloid militarinone A depends on basal expression of p53

BNIP3 (Bcl-2 19 kDa Interacting Protein) Acts as Transcriptional Repressor of Apoptosis-Inducing Factor Expression Preventing Cell Death in Human Malignant Gliomas

Shedding of Syndecan–1 From Human Hepatocytes Alters Very Low Density Lipoprotein Clearance

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