p38 Map Kinase Mediates Bax Translocation in Nitric Oxide–Induced Apoptosis in Neurons

Ghatan, Saadi; Larner, Stephen F.; Kinoshita, Yoshito; Hetman, Michał; Patel, Leena; Xia, Zhengui; Youle, Richard J.; Morrison, Richard S.

doi:10.1083/jcb.150.2.335

Cited by 372 publications

(275 citation statements)

References 99 publications

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“…Moreover, experiments using antioxidants indicated that ROS act upstream of Bax relocalization and mitochondrial membrane depolarization (21). In this study, we provided further evidence that increased level of ROS induced by combination treatment with As 2 O 3 and phytosphingosine is essential for the p38 MAPK -mediated mitochondrial relocalization of Bax.…”

Section: Discussionsupporting

confidence: 55%

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

Park¹,

Kang²,

Park

et al. 2007

Molecular Cancer Therapeutics

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Resistance to anticancer drugs can sometimes be overcome by combination treatment with other therapeutic drugs. Here, we showed that phytosphingosine treatment in combination with arsenic trioxide (As 2 O 3 ) enhanced cell death of naturally As 2 O 3 -resistant human myeloid leukemia cells. The combination treatment induced an increase in intracellular reactive oxygen species level, mitochondrial relocalization of Bax, poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cytochrome c release from the mitochondria. N-acetyl-L-cysteine, a thiol-containing antioxidant, completely blocked Bax relocalization, PARP-1 activation, and cytochrome c release. Pretreatment of 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, a PARP-1 inhibitor, or PARP-1/small interfering RNA partially attenuated cytochrome c release, whereas the same treatment did not affect Bax relocalization. The combination treatment induced selective activation of p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK by treatment of SB203580 or expression of dominant-negative forms of p38 MAPK suppressed the combination treatment -induced Bax relocalization but did not affect PARP-1 activation. In addition, antioxidant N-acetyl-L-cysteine completely blocked p38 MAPK activation. These results indicate that phytosphingosine in combination with As 2 O 3 induces synergistic apoptosis in As 2 O 3 -resistant leukemia cells through the p38 MAPKmediated mitochondrial translocation of Bax and the PARP-1 activation, and that p38 MAPK and PARP-1 activations are reactive oxygen species dependent. The molecular mechanism that we elucidated in this study may provide insight into the design of future combination cancer therapies to cells intrinsically less sensitive to As 2 O 3 treatment. [Mol Cancer Ther 2007;6(1):82 -92]

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Section: Discussionsupporting

confidence: 55%

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

Park¹,

Kang²,

Park

et al. 2007

Molecular Cancer Therapeutics

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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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“…24 Stimulated by death signals, the C-terminal domain of Bax changes its conformation and the C-terminal a-helix is removed from the BH3 domain, which allows the BH3 domain to interact with other antiapoptotic Bcl-2 family members. 27,28 Caspase 25 and p38 MAP kinase 29 may stimulate the translocation of Bax upon apoptotic stimulus. After Bax inserts into the mitochondrial membrane, Bax can directly induce the release of cytochrome c 30,31 or form permeability transition pore.…”

Section: Introductionmentioning

confidence: 99%

Human αA- and αB-crystallins bind to Bax and Bcl-XS to sequester their translocation during staurosporine-induced apoptosis

et al. 2004

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aA-and aB-crystallins are distinct antiapoptotic regulators. Regarding the antiapoptotic mechanisms, we have recently demonstrated that aB-crystallin interacts with the procaspase-3 and partially processed procaspase-3 to repress caspase-3 activation. Here, we demonstrate that human aA-and aBcrystallins prevent staurosporine-induced apoptosis through interactions with members of the Bcl-2 family. Using GST pulldown assays and coimmunoprecipitations, we demonstrated that a-crystallins bind to Bax and Bcl-X S both in vitro and in vivo. Human aA-and aB-crystallins display similar affinity to both proapoptotic regulators, and so are true with their antiapoptotic ability tested in human lens epithelial cells, human retina pigment epithelial cells (ARPE-19) and rat embryonic myocardium cells (H9c2) under treatment of staurosporine, etoposide or sorbitol. Two prominent mutants, R116C in aA-crystallin and R120G, in aB-crystallin display much weaker affinity to Bax and Bcl-X S . Through the interaction, a-crystallins prevent the translocation of Bax and Bcl-X S from cytosol into mitochondria during staurosporine-induced apoptosis. As a result, a-crystallins preserve the integrity of mitochondria, restrict release of cytochrome c, repress activation of caspase-3 and block degradation of PARP. Thus, our results demonstrate a novel antiapoptotic mechanism for a-crystallins. Keywords: aA-crystallin; R116C; aB-crystallin; R120G; Bax; Bcl-X S Abbreviations: a-crystallin, alpha-crystallin; GFP, green fluorescence protein; HaA, human aA-crystallin; HaB, human aB-crystallin; GFP-HaA, green fluorescence and human aAcrystallin fusion protein; GFP-HaB, green fluorescence and human aB-crystallin fusion protein; MEM, Eagle's minimal essential medium; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; PMSF, phenylmethylsufonyl fluoride; HLE, human lens epithelial cells; SDS, sodium dodecylsulfate; TBS, tris-buffered saline; TBS-T, tris-buffered saline with tween-20.

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p38 Map Kinase Mediates Bax Translocation in Nitric Oxide–Induced Apoptosis in Neurons

Cited by 372 publications

References 99 publications

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

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

Human αA- and αB-crystallins bind to Bax and Bcl-XS to sequester their translocation during staurosporine-induced apoptosis

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