Glycogen synthase kinase-3β activity plays very important roles in determining the fate of oxidative stress-inflicted neuronal cells

Lee, Kyu Yong; Koh, Seong Ho; Noh, Min Young; Park, Kun Woo; Lee, Young Joo; Kim, Seung Hyun

doi:10.1016/j.brainres.2006.10.055

Cited by 82 publications

(65 citation statements)

References 42 publications

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“…Oxidative Stress Causes, and Ropinirole Prevents, Dephosphorylation of Akt/GSK-3␤-It has previously been reported that activated (dephosphorylated) GSK-3␤ promotes cell death, whereas N-terminal serine phosphorylation deactivates GSK-3␤ and promotes cell survival (33)(34)(35)(36). We examined the phosphorylation states of Akt and GSK-3␤ after exposure to H 2 O 2 .…”

Section: Effects Of Ropinirole On Downstream Effectors Of Pi-3k/aktmentioning

confidence: 99%

“…It is known that phosphorylation of ␤-catenin by GSK-3␤ causes its degradation by the ubiquitin proteasome system; therefore, we examined the activity of GSK-3␤ in cells treated with H 2 O 2 with or without ropinirole or GSK-3␤ inhibitor VIII pretreatment. GSK-3␤ has been shown to phosphorylate at Ser 33 , Ser 37 , and Thr 41 of ␤-catenin in vivo and in vitro (37). Thus, we used GST-tagged ␤-catenin protein as a substrate to measure the kinase activity of GSK-3␤.…”

Section: Effects Of Ropinirole On Downstream Effectors Of Pi-3k/aktmentioning

confidence: 99%

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Differential Modulation of Akt/Glycogen Synthase Kinase-3β Pathway Regulates Apoptotic and Cytoprotective Signaling Responses

Nair

Olanow

2008

Journal of Biological Chemistry

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We have previously reported that specific dopamine agonists mediate protection against apoptosis induced by oxidative stress by activating the D 2 receptor-coupled phosphoinositide 3-kinase (PI-3K)/Akt pathway. In the present study we examined the downstream effectors of PI-3K/Akt signaling and their role in cell death after oxidative stress and protection provided by ropinirole, a D 2 receptor agonist in PC12 cells and primary cultures of dopamine neurons. Ropinirole treatment was associated with rapid translocation and phosphorylation of the PI-3K substrate Akt and phosphorylation of Akt substrates. One of these Akt downstream substrates was identified as the proapoptotic factor glycogen synthase kinase-3␤ (GSK-3␤). Ropinirole-induced protection was associated with phosphorylation of GSK-3␤ (inactivation). In contrast, inhibition of PI-3K blocked the phosphorylation of Akt and GSK-3␤ (activation) and prevented the protection mediated by ropinirole. Suppression of Akt with specific short hairpin RNA in normal PC12 cells caused cell death, which was associated with reduced phosphorylation of GSK-3␤ and reduced levels of ␤-catenin, a transcriptional activator that is regulated by GSK-3␤. Knock-out of GSK-3␤ expression with a short hairpin RNA alone was itself sufficient to cause cell death. We further demonstrated that oxidative stress induced by hydrogen peroxide (H 2 O 2 ) dephosphorylates Akt and GSK-3␤, increases GSK-3␤ activity, and promotes an interaction with ␤-catenin and its degradation. Inhibition of GSK-3␤ activity by inhibitor VIII protects cells from H 2 O 2 similar to ropinirole. These results indicate that GSK-3␤ downstream of Akt plays a critical role in cell death and survival in these models.The characteristic pathology of Parkinson disease (PD) 2 is degeneration of dopaminergic neurons coupled with Lewy body inclusions in the substantia nigra pars compacta (1). The mechanism underlying dopaminergic cell death in PD has not been elucidated. A variety of cellular and molecular changes indicative of mitochondrial dysfunction, oxidative stress, proteasomal dysfunction, and apoptosis have been identified in the parkinsonian brain (for review, see Refs. 2 and 3). Specifically, a large body of evidence suggests that oxidative stress or reactive oxygen species-mediated apoptosis may contribute to the progressive and selective neuronal degeneration observed in PD (4). Brains of PD patients have increased iron, which promotes free radical formation, decreased levels of reduced glutathione, which is the major anti-oxidant in the brain, and evidence of oxidative damage to DNA, lipids, and proteins (5). Furthermore, in the substantia nigra pars compacta of PD patients there are increased levels of cyclooxygenase, which contribute to formation of the oxidant species dopamine-quinone (5), and reduced mitochondrial complex I activity, which promotes free radical formation (6 -8).Current therapies for PD are primarily based on a dopamine replacement strategy. Although they provide effective anti-parkinsonian ef...

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Section: Effects Of Ropinirole On Downstream Effectors Of Pi-3k/aktmentioning

confidence: 99%

Section: Effects Of Ropinirole On Downstream Effectors Of Pi-3k/aktmentioning

confidence: 99%

Differential Modulation of Akt/Glycogen Synthase Kinase-3β Pathway Regulates Apoptotic and Cytoprotective Signaling Responses

Nair

Olanow

2008

Journal of Biological Chemistry

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“…Although the detailed mechanisms underlying oxidative stress-induced neuronal death remain unknown, drugs with antioxidant properties have therapeutic significance in preventing AD (Pratico, 2008). H 2 O 2 is widely used as a toxicant to establish in vitro models of oxidative stress-induced neuronal apoptosis as it is an uncharged and freely diffusible molecule (Lee et al, 2007).…”

Section: Prevention Of Ros-induced Neuronal Toxicity Via Regulating Tmentioning

confidence: 99%

Bis(12)-Hupyridone, a Promising Multi-Functional Anti-Alzheimer’s Dimer Derived from Chinese Medicine

Han¹,

Cui²,

Choi³

et al. 2012

When Things Go Wrong - Diseases and Disorders of the Human Brain

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“…[19][20][21][22][23] Although donepezil has neuroprotective effects attributed to its up-regulation of the anti-apoptotic protein Bcl-2, the stimulation of nicotinic acetylcholine receptors (nAChRs) and the activation of the phosphoinositide 3 kinase (PI3K)/ Akt pathway, 9,[24][25][26][27] no report has been issued on its anti-proliferative effects, and furthermore, the molecular mechanism involved in donepezil-induced apoptosis is poorly understood. In the present study, we tested the cytotoxic effects of donepezil on different cancer cells, and found that leukemia cells HL-60 and U937, were most vulnerable to this drug.…”

Section: )mentioning

confidence: 99%

Donepezil, a Potent Acetylcholinesterase Inhibitor, Induces Caspase-Dependent Apoptosis in Human Promyelocytic Leukemia HL-60 Cells

Park

Lee

et al. 2010

Biological & Pharmaceutical Bulletin

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Apoptosis is a process of active cell death characterized by cell surface blebbing, changes in membrane permeability, nuclear DNA condensation, and internucleosomal fragmentation.1) Several apoptotic pathways exist in cells responsive to apoptotic stimuli, and although each pathway is initiated by different mechanisms, they share a common final phase of apoptosis, which involves the activation of executioner caspases and the dismantling of substrates critical for cell survival.2) Classical apoptosis can be initiated via two distinct biochemical mechanisms, both of which result in caspase activation: (i) the extrinsic pathway that involves ligation of cell surface death receptors by their respective ligands, and (ii) the intrinsic mitochondrial pathway, which is largely controlled by the Bcl-2 family of pro-and anti-apoptotic proteins. It has been well established that the expressions of many gene products, such as Bid, Bax and Bcl-2, are critical for programmed cell death. Bcl-2 and Bcl-xl have anti-apoptotic functions, whereas Bid, Bax, Bim and Bcl-xs promote apoptosis. The balance between these two groups of genes determines the fate of cells in many systems, 3) and in particular, determines the depolarization of the mitochondrial membrane and the release of cytochrome c from mitochondria into the cytosol.4) This released cytochrome c then binds to apoptotic protease activating factor-1 (Apaf-1), which causes its oligomerization. 5) Procaspase-9 then binds to Apaf-1 oligomers to form a high-molecular-mass complex called apoptosome.6) In addition, this interaction activates caspase-9, which activates caspase-3 and thus triggers the irreversible apoptotic program. 7)Donepezil (R,S-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride) is prescribed for the treatment of cognitive dysfunction in Alzheimer's disease (AD).8) It prevents the hydrolysis of acetylcholine (ACh) and elevates ACh concentrations in the synaptic cleft, which increases cholinergic transmission.9) Previous studies haveshown that donepezil has neuroprotective effects in addition to its AChE-inhibiting action, and that these effects are due to the stimulation of nicotinic acetylcholine receptors, the activation of the phosphoinositide-3 kinase/Akt pathway, and the up-regulation of the anti-apoptotic protein Bcl-2. 10,11) However, no report has been issued on the molecular mechanism underlying the anti-proliferative effects of donepezil.In the present study, we demonstrate that donepezilinduced apoptosis involves the mitochondrial pathway via loss of mitochondrial membrane potential, a hallmark of permeability transition, and that this causes the release of cytochrome c to cytosol, and the sequential activations of caspases-8, -9, and -3 via the modulation of Bcl-2 in human promyelocytic leukemia HL-60 cells. Furthermore, this is the first report to show that donepezil induces apoptosis through a mitochondria-mediated caspase-dependent pathway. Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea: and d Eisai Korea ...

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Glycogen synthase kinase-3β activity plays very important roles in determining the fate of oxidative stress-inflicted neuronal cells

Cited by 82 publications

References 42 publications

Differential Modulation of Akt/Glycogen Synthase Kinase-3β Pathway Regulates Apoptotic and Cytoprotective Signaling Responses

Differential Modulation of Akt/Glycogen Synthase Kinase-3β Pathway Regulates Apoptotic and Cytoprotective Signaling Responses

Bis(12)-Hupyridone, a Promising Multi-Functional Anti-Alzheimer’s Dimer Derived from Chinese Medicine

Donepezil, a Potent Acetylcholinesterase Inhibitor, Induces Caspase-Dependent Apoptosis in Human Promyelocytic Leukemia HL-60 Cells

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