The c-Abl-MST1 Signaling Pathway Mediates Oxidative Stress-Induced Neuronal Cell Death
ABSTRACT Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. The protein kinase MST1 (mammalian Ste20-like kinase 1) plays a major role in oxidative stress-induced cell death in primary mammalian neurons. However, the mechanisms that regulate MST1 in oxidative stress responses remain largely unknown. In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1. Inhibition of c-Abl promotes the degradation of MST1 through C terminus of Hsc70-interacting protein (CHIP)-mediated ubiquitination, and thereby attenuates cell death. Oxidative stress induces the c-Abl-dependent tyrosine phosphorylation of MST1 and increases the interaction between MST1 and FOXO3 (Forkhead box O3), thereby activating the MST1-FOXO signaling pathway, leading to cell death in both primary culture neurons and rat hippocampal neurons. The identification of the c-Abl tyrosine kinase as a novel upstream activator of MST1 suggests that the c-Abl-MST1 signaling cascade plays an important role in cellular responses to oxidative stress.
- SourceAvailable from: Judith Hagenbuchner
Neuroblastoma - Present and Future, 02/2012; , ISBN: 978-953-307-016-2
- "This induces the nuclear accumulation and activation of FOXO3 even in presence of inhibitory PKB signals. Increased interaction of MST1 and FOXO3 activates the MST1-FOXO3 signaling pathway finally leading to cell death in both primary cultured neurons and rat hippocampal neurons (Xiao et al, 2011). Interestingly, in Drosophila the activation of the JNK/FOXO signaling pathway leads to neuronal resistance to oxidative stress via the expression of Jafrac1 the fly homologue of peroxiredoxin II. "
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ABSTRACT: Alzheimer’s disease (AD), the most common form of neuropsychiatric disorder, is characterized by neuronal degeneration and inexorably progressing dementia, especially in the elderly population. With a rapidly aging population in both developed and developing countries, AD has emerged as one of the largest growing problems worldwide. Current drugs improve the symptoms of AD, but do not have any profound intervention to delay its onset. Thus, understanding the molecular mechanisms underlying the genes tied to AD will be crucial to the development of therapeutic targets. This review will summarize the aetiology, pathology, and the evidence for the genetic components in AD, discuss the proposed amyloid cascade and the following tau hyperphosphorylation hypothesises, oxidative stress mediated neuronal cell death, as well as the function of Retromer complex during the developing of AD. Our laboratory’s current research progress and the challenges that still remained will be also highlighted.Chinese Science Bulletin 05/2013; 58(15). DOI:10.1007/s11434-013-5673-x · 1.37 Impact Factor
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