Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death

Yu, Seong‐Woon; Andrabi, Shaida A.; Wang, Hongmin; Kim, No Soo; Poirier, Guy G.; Dawson, Ted M.; Dawson, Valina L.

doi:10.1073/pnas.0606528103

Cited by 664 publications

(592 citation statements)

References 31 publications

(62 reference statements)

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“…To that end, we used synthetic PAR polymer throughout this study with a specific interest on the effects of PAR polymer on mitochondria. A lipid-based BioPORTER system was used for intracellular delivery of PAR polymer, as reported previously Yu et al, 2006). We also adopted a cell-free in vitro system to assess the outcomes of direct, physical interaction of PAR polymer with isolated brain mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Induction of Mitochondrial Dysfunction by Poly(ADP-Ribose) Polymer: Implication for Neuronal Cell Death

Baek

Bae

Kim

et al. 2013

Molecules and Cells

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Poly(ADP-ribose) polymerase-1 (PARP-1) mediates neuronal cell death in a variety of pathological conditions involving severe DNA damage. Poly(ADP-ribose) (PAR) polymer is a product synthesized by PARP-1. Previous studies suggest that PAR polymer heralds mitochondrial apoptosis-inducing factor (AIF) release and thereby, signals neuronal cell death. However, the details of the effects of PAR polymer on mitochondria remain to be elucidated. Here we report the effects of PAR polymer on mitochondria in cells in situ and isolated brain mitochondria in vitro. We found that PAR polymer causes depolarization of mitochondrial membrane potential and opening of the mitochondrial permeability transition pore early after injury. Furthermore, PAR polymer specifically induces AIF release, but not cytochrome c from isolated brain mitochondria. These data suggest PAR polymer as an endogenous mitochondrial toxin and will further our understanding of the PARP-1-dependent neuronal cell death paradigm.

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Section: Discussionmentioning

confidence: 99%

Induction of Mitochondrial Dysfunction by Poly(ADP-Ribose) Polymer: Implication for Neuronal Cell Death

Baek

Bae

Kim

et al. 2013

Molecules and Cells

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“…The discovery of a PARG protein capable of regulating PAR accumulation in close proximity to, or possibly within mitochondria may be of relevance for the model that overactivation of PARP-1 leads to the breakdown of the mitochondrial membrane potential and subsequent release of apoptosis inducing factor (AIF). In this model, AIF released from the mitochondria rapidly translocates to the nucleus and activates an endonuclease facilitating chromatinolysis and cell death in a caspase-independent manner [61][62][63]. While it is possible that NAD+ depletion as a result of PAR formation may affect the mitochondrial membrane potential ( [64,65] ), there also is accumulating evidence that PAR itself may be acting as a cell death signaling molecule triggering the formation of a mitochondrial pore transition (MPT) in a yet unknown way [66].…”

Section: Discussionmentioning

confidence: 99%

Two small enzyme isoforms mediate mammalian mitochondrial poly(ADP-ribose) glycohydrolase (PARG) activity

Meyer

Meyer-Ficca

Whatcott

et al. 2007

Experimental Cell Research

101

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Poly(ADP-ribose)glycohydrolase (PARG) is the major enzyme capable of rapidly hydrolyzing poly (ADP-ribose)(PAR) formed by the diverse members of the PARP enzyme family. This study presents an alternative splice mechanism by which two novel PARG protein isoforms of 60 kDa and 55 kDa are expressed from the human PARG gene, termed hPARG60 and hPARG55, respectively. Homologous forms were found in the mouse (mPARG63 and mPARG58) supporting the hypothesis that expression of small PARG isoforms is conserved among mammals. A PARG protein of ∼60kDa has been described for decades but with its genetic basis unknown, it was hypothesized to be a product of posttranslational cleavage of larger PARG isoforms. While this is not excluded entirely, isolation and expression of cDNA clones from different sources of RNA indicate that alternative splicing leads to expression of a catalytically active hPARG60 in multiple cell compartments. A second enzyme, hPARG55 that can be expressed through alternative translation initiation from hPARG60 transcripts is strictly targeted to the mitochondria. Functional studies of a mitochondrial targeting signal (MTS) in PARG exon IV suggest that hPARG60 may be capable of shuttling between nucleus and mitochondria, which would be in line with a proposed function of PAR in genotoxic stress-dependent, nuclear-mitochondrial crosstalk.

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“…The effect of AZD2281 was not a result of restoration of cellular NAD þ level (Figure 9b), and is thus distinct from nicotinic acid rescue shown in Figure 2. PARP1-mediated synthesis of poly ADPribose in response to DNA damage can trigger release of apoptosis inducing factor from mitochondria to induce apoptosis, and PAPR1 inhibition may block apoptosis in certain cells (Yu et al, 2006). However, the antagonizing effect of AZD2281 occurs without PARP1 activation and there is insufficient cellular NAD þ for poly ADP-ribose reaction, suggesting the likely involvement of additional mechanisms for cell survival.…”

Section: Nampt Is Overexpressed In Human Prostate Cancermentioning

confidence: 99%

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

et al. 2010

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Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in regenerating nicotinamide adenine dinucleotide (NAD þ ) from nicotinamide in mammals. NAMPT has crucial roles for many cellular functions by regulating NAD þ -dependent SIRT1 deacetylase. However, roles of NAMPT in cancer are poorly defined. In this study, we show that NAMPT is prominently overexpressed in human prostate cancer cells along with SIRT1. Elevation of NAMPT expression occurs early for the prostate neoplasia. Inhibition of NAMPT significantly suppresses cell growth in culture, soft agar colony formation, cell invasion and growth of xenografted prostate cancer cells in mice. NAMPT knockdown sensitizes prostate cancer cells to oxidative stress caused by H 2 O 2 or chemotherapeutic treatment. Overexpression of NAMPT increases prostate cancer cell resistance to oxidative stress, which is partially blocked by SIRT1 knockdown. We demonstrate that in addition to modulating SIRT1 functions, the NAMPT inhibition reduces forkhead box, class 'O' (FOXO)3a protein expression and its downstream anti-oxidant genes catalase and manganese superoxide dismutase. Our results suggest important roles of concomitant upregulation of NAMPT and SIRT1 along with increased FOXO3a protein level for prostate carcinogenesis and their contribution to oxidative stress resistance of prostate cancer cells. These findings may have implications for exploring the NAMPT pathway for prostate cancer prevention and treatment.

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Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death

Cited by 664 publications

References 31 publications

Induction of Mitochondrial Dysfunction by Poly(ADP-Ribose) Polymer: Implication for Neuronal Cell Death

Induction of Mitochondrial Dysfunction by Poly(ADP-Ribose) Polymer: Implication for Neuronal Cell Death

Two small enzyme isoforms mediate mammalian mitochondrial poly(ADP-ribose) glycohydrolase (PARG) activity

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

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