p38 Mitogen-Activated Protein Kinase Regulates Bax Translocation in Cyanide-Induced Apoptosis

Shou, Yan; Li, L.; Prabhakaran, Krishnan; Borowitz, Joseph L.; Isom, Gary E.

doi:10.1093/toxsci/kfg157

Cited by 46 publications

(26 citation statements)

References 37 publications

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“…25 In a number of different cellular models, inhibition of both JNK and p38 prevented the translocation of Bax. [25][26][27] For peroxynitrite-induced apoptosis to occur, MLK, p38 and JNK had to be simultaneously activated, inducing Bax translocation to the mitochondria. Although it is not possible to causally relate the increased phosphorylation of mitochondrial JNK and the translocation of Bax to mitochondria, it is safe to say that both events are dependent upon the activation of MLK (Figures 2 and 3).…”

Section: Discussionmentioning

confidence: 99%

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

et al. 2006

Cell Death Differ

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The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death. Peroxynitrite-induced death was prevented by overexpression of Bcl-2 and by cyclosporin A, implicating the involvement of the intrinsic apoptotic pathway. Selective inhibition of mixed lineage kinase (MLK), p38 or JNK does not attenuate the decrease in Akt phosphorylation showing that inactivation of the Akt pathway occurs independently of the MLK/MAPK pathway. Together, these results reveal that peroxynitrite-induced activation of the intrinsic apoptotic pathway involves interactions with the MLK/MAPK and Akt signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

et al. 2006

Cell Death Differ

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“…We have shown that the p38 MAPK activation is an upstream initiator of cyanide-induced toxicity in cortical cells [15]. In Mes 23.5 cells, cyanide activated p38 MAPK within 30 min (Fig.…”

Section: Hif-1α Activation Is Mediated By P38 Mapk Pathwaymentioning

confidence: 68%

“…For instance, overexpression of the p38 MAPK kinases can enhance HIF-1α protein levels under either normoxic or hypoxic conditions [14]. In the case of cyanide, we have shown in rat primary cortical cells that p38 MAPK is phosphorylated through a ROS-mediated pathway [15]. Thus, it is possible that the cyanide-induced stimulation of p38 MAPK could lead to activation of the HIF-1 pathway to initiate a cell death cascade.…”

Section: Introductionmentioning

confidence: 99%

HIF-1α activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death

Zhang

Liu

et al. 2007

Free Radical Biology and Medicine

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Cyanide produces degeneration of the nervous system in which different modes of cell death are activated in the vulnerable brain areas. In brain, the mechanism underlying the cell death is not clear. In this study, an immortalized dopaminergic cell line was used to characterize the cell death signaling cascade activated by cyanide. Cyanide-treated cells exhibited a time-and concentration-dependent apoptosis that was caspase-independent. Cyanide induced a rapid surge of intracellular reactive oxygen species (ROS) generation, followed by p38 mitogen-activated protein kinase (MAPK) activation and nuclear accumulation of hypoxia-inducible factor-1α (HIF-1α). Activation of p38 MAPK and HIF-1α accumulation were attenuated by N-acetyl-L-cysteine (antioxidant), catalase (hydrogen peroxide scavenger) or a selective p38 MAPK inhibitor (SB203580). Cyanide activated the hypoxia response element (HRE) promoter, which was also blocked by the antioxidants and SB203580. HRE activation was followed by increased BNIP3 gene transcription, as reflected by elevated BNIP3 mRNA and protein levels. BNIP3 upregulation was reduced by selective RNAi knockdown of HIF-1α. Overexpression of BNIP3 produced mitochondrial dysfunction (reduced membrane potential), caspase-independent apoptosis, and sensitization of the cells to cyanideinduced toxicity. Expression of a dominant negative mutant or RNAi knockdown of BNIP3 protected the cells from cyanide. It was concluded that cyanide activated the HIF-1α-mediated pathway of BNIP3 induction through a redox-sensitive process. Increased BNIP3 expression then served as an initiator of mitochondrial-mediated death.

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“…Since most pro-apoptotic Bcl-2 proteins are localized in the cytosol under normal conditions, cytosol-to-mitochondria translocation of these proteins is an important apoptotic regulatory mechanism. Previous studies have shown that Bax (Bcl-associated X protein) is translocated from cytosol to mitochondria by a p38 MAPK (mitogen-activated protein kinase)-dependent process in cyanide-induced apoptosis [1]. In addition to Bax, another member of the pro-apoptotic Bcl-2 protein family, Bad (Bcl-2/Bcl-X L -antagonist, causing cell death), undergoes translocation in apoptosis induced by various stimuli [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…1 Also at: St. Jude's Children's Research Hospital, Memphis, TN, U.S.A. 2 To whom correspondence should be addressed (e-mail geisom@purdue.edu).…”

Section: Introductionmentioning

confidence: 99%

Calcineurin-mediated Bad translocation regulates cyanide-induced neuronal apoptosis

Shou

Prabhakaran

et al. 2004

Biochemical Journal

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In cyanide-induced apoptosis, an increase in cytosolic free Ca 2+ and generation of reactive oxygen species are initiation stimuli for apoptotic cell death. Previous studies have shown that cyanidestimulated translocation of Bax (Bcl-associated X protein) to mitochondria is linked with release of cytochrome c and subsequent activation of a caspase cascade [Shou, Li, Prabhakaran, Borowitz and Isom (2003) Toxicol. Sci. 75, 99-107]. In the present study, the relationship of the cyanide-induced increase in cytosolic free Ca 2+ to activation of Bad (Bcl-2/Bcl-X L -antagonist, causing cell death) was determined in cortical cells. Bad is a Ca 2+ -sensitive pro-apoptotic Bcl-2 protein, which on activation translocates from cytosol to mitochondria to initiate cytochrome c release. In cultured primary cortical cells, cyanide produced a concentration-and time-dependent translocation of Bad from cytosol to mitochondria. Translocation occurred early in the apoptotic response, since mitochondrial Bad was detected within 1 h of cyanide treatment. Mitochondrial levels of the protein continued to increase up to 12 h post-cyanide exposure. Concurrent with Bad translocation, a Ca 2+ -sensitive increase in cellular calcineurin activity was observed. Increased cytosolic Ca 2+ and calcineurin activation stimulated Bad translocation since BAPTA [bis-(o-aminophenoxy)ethane-N,N,N ,N -tetra-acetic acid], an intracellular Ca 2+ chelator, and cyclosporin A, a calcineurin inhibitor, significantly reduced translocation. BAPTA also blocked release of cytochrome c from mitochondria as well as apoptosis. Furthermore, treatment of cells with the calcineurin inhibitors cyclosporin A or FK506 blocked the apoptotic response, linking calcineurin activation and the subsequent translocation of Bad to cell death. These observations show that by inducing a rapid increase in cytosolic free Ca 2+ , cyanide can partially initiate the apoptotic cascade through a calcineurin-mediated translocation of Bad to mitochondria.

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p38 Mitogen-Activated Protein Kinase Regulates Bax Translocation in Cyanide-Induced Apoptosis

Cited by 46 publications

References 37 publications

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

HIF-1α activation by a redox-sensitive pathway mediates cyanide-induced BNIP3 upregulation and mitochondrial-dependent cell death

Calcineurin-mediated Bad translocation regulates cyanide-induced neuronal apoptosis

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