Dual inhibitory roles of geldanamycin on the c-Jun NH2-terminal kinase 3 signal pathway through suppressing the expression of mixed-lineage kinase 3 and attenuating the activation of apoptosis signal-regulating kinase 1 via facilitating the activation of Akt in ischemic brain injury

Wen, Xiangru; Li, C.; Zong, Yan-Yan; Yu, Chao; Xu, Jianxiang; Han, Dong; Zhang, G.-Y.

doi:10.1016/j.neuroscience.2008.08.006

Cited by 27 publications

(29 citation statements)

References 48 publications

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“…In contrast to these findings, several groups including ours have found that 17AAG favors cell survival when treated transiently or with lower doses (Koga et al 2006, Kwon et al 2008, Wang et al 2011, Wen et al 2008, Yano et al 2008. Nonetheless, 17AAG's function in stroke has not been studied although its toxic precursor, geldanamycin, exerts beneficial effects in animal stroke models (Kwon et al 2008, Wen, Li, Zong, Yu et al 2013.…”

Section: Introductionmentioning

confidence: 76%

Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death

Bradley

Zhao

Wang

et al. 2014

J. Cell Commun. Signal.

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Stress adaptation effect provides cell protection against ischemia induced apoptosis. Whether this mechanism prevents other types of cell death in stroke is not well studied. This is an important question for regenerative medicine to treat stroke since other types of cell death such as necrosis are also prominent in the stroke brain apart from apoptosis. We report here that treatment with 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), an Hsp90 inhibitor, protected neural progenitor cells (NPCs) against oxygen glucose deprivation (OGD) induced cell death in a dose dependent fashion. Cell death assays indicated that 17AAG not only ameliorated apoptosis, but also necrosis mediated by OGD. This NPC protection was confirmed by exposing cells to oxidative stress, a major stress signal prevalent in the stroke brain. Mechanistic studies demonstrated that 17AAG activated PI3K/Akt and MAPK cell protective pathways. More interestingly, these two pathways were activated in vivo by 17AAG and 17AAG treatment reduced infarct volume in a middle cerebral artery occlusion (MCAO) stroke model. These data suggest that 17AAG protects cells against major cell death pathways and thus might be used as a pharmacological conditioning agent for regenerative medicine for stroke.

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Section: Introductionmentioning

confidence: 76%

Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death

Bradley

Zhao

Wang

et al. 2014

J. Cell Commun. Signal.

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“…It is well known that the PI3K/Akt and ASK1/JNK pathways are related to neuronal survival and apoptosis. Previous papers have shown that cerebral ischemic injury can be regulated by the PI3K/Akt and ASK1/JNK3 signaling cascades [17,19,33]. Recent studies have demonstrated that Akt and ASK1 are physically associated [34].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection of Sevoflurane Against Ischemia/Reperfusion-Induced Brain Injury Through Inhibiting JNK3/Caspase-3 by Enhancing Akt Signaling Pathway

Wen

Liu

et al. 2015

Mol Neurobiol

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In this study, we investigated the neuroprotective effect of sevoflurane against ischemic brain injury and its underlying molecular mechanisms. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with sevoflurane alone or sevoflurane combined with LY294002/wortmannin (selective inhibitor of PI3K) before ischemia. Cresyl violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting and immunoprecipitation were performed to measure the phosphorylation of Akt1, PRAS40, ASK1, and JNK3 and the expression of cleaved-caspase-3. The results demonstrated that a moderate dose of sevoflurane inhalation of 2% for 2 h had significant neuroprotective effects against ischemia/reperfusion induced hippocampal neuron death. Sevoflurane significantly increased Akt and PRAS40 phosphorylation and decreased the phosphorylation of ASK1 at 6 h after reperfusion and the phosphorylation of JNK3 at 3 days after reperfusion following 15 min of transient global brain ischemia. Conversely, LY294002 and wortmannin significantly inhibited the effects of sevoflurane. Taken together, the results suggest that sevoflurane could suppress ischemic brain injury by downregulating the activation of the ASK1/JNK3 cascade via increasing the phosphorylation of Akt1 during ischemia/reperfusion.

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“…In addition, angiopoietin-1-induced Akt activation also phosphorylates MKK4 at Ser80 and suppress apoptosis and oxidative stress-induced JNK activation in vascular endothelial cells (80). Furthermore, Akt interacts with and phosphorylate MLK3 on Ser674 to inhibit its kinase activity (81,82). Insulin-induced phosphorylation of Akt concomitant with reduced kinase activities of MLK3, MKK7 and JNK is observed in human hepatoma HepG2 cells, indicating that activation of Akt antagonizes MLK3-MKK7-JNK signaling (81).…”

Section: Pi3k/akt Antagonizes Stress-and Cytokine-induced Jnk Signalimentioning

confidence: 99%

The phosphatidylinositol 3-kinase/Akt and c-Jun N-terminal kinase signaling in cancer: Alliance or contradiction? (Review)

Zhao

Wang

2015

International Journal of Oncology

102

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Abstract. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and c-Jun N-terminal kinase (JNK) pathway are responsible for regulating a variety of cellular processes including cell growth, migration, invasion and apoptosis. These two pathways are essential to the development and progression of tumors. The dual roles of JNK signaling in apoptosis and tumor development determine the different interactions between the PI3K/Akt and JNK pathways. Activation of PI3K/ Akt signaling can inhibit stress-and cytokine-induced JNK activation through Akt antagonizing and the formation of the JIP1-JNK module, as well as the activities of upstream kinases ASK1, MKK4/7 and MLK. On the other hand, hyperactivation of Akt and JNK is also found in cancers that harbor EGFR overexpression or loss of PTEN. Understanding the activation mechanism of PI3K/Akt and JNK pathways, as well as the interplays between these two pathways in cancer may contribute to the identification of novel therapeutic targets. In the present report, we summarized the current understanding of the PI3K/Akt and JNK signaling networks, as well as their biological roles in cancers. In addition, the interactions and regulatory network between PI3K/Akt and JNK pathways in cancer were discussed.

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Dual inhibitory roles of geldanamycin on the c-Jun NH2-terminal kinase 3 signal pathway through suppressing the expression of mixed-lineage kinase 3 and attenuating the activation of apoptosis signal-regulating kinase 1 via facilitating the activation of Akt in ischemic brain injury

Cited by 27 publications

References 48 publications

Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death

Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death

Neuroprotection of Sevoflurane Against Ischemia/Reperfusion-Induced Brain Injury Through Inhibiting JNK3/Caspase-3 by Enhancing Akt Signaling Pathway

The phosphatidylinositol 3-kinase/Akt and c-Jun N-terminal kinase signaling in cancer: Alliance or contradiction? (Review)

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