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RISS 인기검색어
- 검색키워드
- 저자 : Sobey, Christopher G. (검색결과 3 건)
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Interplay between Notch and p53 promotes neuronal cell death in ischemic stroke
Balaganapathy, Priyanka,Baik, Sang-Ha,Mallilankaraman, Karthik,Sobey, Christopher G,Jo, Dong-Gyu,Arumugam, Thiruma V SAGE Publications 2018 Journal of cerebral blood flow and metabolism Vol.38 No.10
<P> Stroke is the world's second leading cause of mortality, with a high incidence of morbidity. Numerous neuronal membrane receptors are activated by endogenous ligands and may contribute to infarct development. Notch is a well-characterized membrane receptor involved in cell differentiation and proliferation, and now shown to play a pivotal role in cell death during ischemic stroke. Blockade of Notch signaling by inhibition of γ-secretase, an enzyme that generates the active form of Notch, is neuroprotective following stroke. We have also identified that Pin1, a peptidyl-prolyl isomerase that regulates p53 transactivation under stress, promotes the pathogenesis of ischemic stroke via Notch signaling. Moreover, Notch can also mediate cell death through a p53-dependent pathway, resulting in apoptosis of neural progenitor cells. The current study has investigated the interplay between Notch and p53 under ischemic stroke conditions. Using pharmacological inhibitors, we have demonstrated that a Notch intracellular domain (NICD)/p53 interaction is involved in transcriptional regulation of genes downstream of p53 and NICD to modify stroke severity. Furthermore, the NICD/p53 interaction confers stability to p53 by rescuing it from ubiquitination. Together, these results indicate that Notch contributes to the pathogenesis of ischemic stroke by promoting p53 stability and signaling. </P>
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Notch signaling and neuronal death in stroke
Arumugam, Thiruma V.,Baik, Sang-Ha,Balaganapathy, Priyanka,Sobey, Christopher G.,Mattson, Mark P.,Jo, Dong-Gyu Elsevier 2018 Progress in neurobiology Vol.165 No.-
<P><B>Abstract</B></P> <P>Ischemic stroke is a leading cause of morbidity and death, with the outcome largely determined by the amount of hypoxia-related neuronal death in the affected brain regions. Cerebral ischemia and hypoxia activate the Notch1 signaling pathway and four prominent interacting pathways (NF-κB, p53, HIF-1α and Pin1) that converge on a conserved DNA-associated nuclear multi-protein complex, which controls the expression of genes that can determine the fate of neurons. When neurons experience a moderate level of ischemic insult, the nuclear multi-protein complex up-regulates adaptive stress response genes encoding proteins that promote neuronal survival, but when ischemia is more severe the nuclear multi-protein complex induces genes encoding proteins that trigger and execute a neuronal death program. We propose that the nuclear multi-protein transcriptional complex is a molecular mediator of neuronal hormesis and a target for therapeutic intervention in stroke.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We review the roles of Notch in the neuropathology of ischemic stroke. </LI> <LI> We discuss the mechanisms for how Notch interacts with other gene transcription regulators such as HIF-1α, NF-κB, p53 and Pin1 following a stroke. </LI> <LI> We introduce a novel concept of a multi-protein complex which controls the expression of genes that determine the fate of neurons in stroke. </LI> <LI> We discuss if and how the multi-protein complex may regulate neuronal plasticity and resilience during the remodeling phase following stroke. </LI> <LI> We conclude with a perspective on how this research may lead to novel approaches for clinical intervention in ischemic stroke. </LI> </UL> </P>
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Cheng, Y.L.,Park, J.S.,Manzanero, S.,Choi, Y.,Baik, S.H.,Okun, E.,Gelderblom, M.,Fann, D.Y.W.,Magnus, T.,Launikonis, B.S.,Mattson, M.P.,Sobey, C.G.,Jo, D.G.,Arumugam, T.V. Blackwell Science ; Academic Press 2014 Neurobiology of disease Vol.62 No.-
Recent findings suggest that Notch-1 signaling contributes to neuronal death in ischemic stroke, but the underlying mechanisms are unknown. Hypoxia inducible factor-1α (HIF-1α), a global regulator of cellular responses to hypoxia, can interact with Notch and modulate its signaling during hypoxic stress. Here we show that Notch signaling interacts with the HIF-1α pathway in the process of ischemic neuronal death. We found that a chemical inhibitor of the Notch-activating enzyme, γ-secretase, and a HIF-1α inhibitor, protect cultured cortical neurons against ischemic stress, and combined inhibition of Notch-1 and HIF-1α further decreased neuronal death. HIF-1α and Notch intracellular domain (NICD) are co-expressed in the neuronal nucleus, and co-immunoprecipitated in cultured neurons and in brain tissue from mice subjected to focal ischemic stroke. Overexpression of NICD and HIF-1α in cultured human neural cells enhanced cell death under ischemia-like conditions, and a HIF-1α inhibitor rescued the cells. RNA interference-mediated depletion of endogenous NICD and HIF-1α also decreased cell death under ischemia-like conditions. Finally, mice treated with inhibitors of γ-secretase and HIF-1α exhibited improved outcome after focal ischemic stroke, with combined treatment being superior to individual treatments. Additional findings suggest that the NICD and HIF-1α collaborate to engage pro-inflammatory and apoptotic signaling pathways in stroke.
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