TY - JOUR
T1 - Differential regulation of AKT, MAPK and GSK3β during C2-ceramide-induced neuronal death
AU - Arboleda, Gonzalo
AU - Cárdenas, Yolanda
AU - Rodríguez, Yeldy
AU - Morales, Luis Carlos
AU - Matheus, Luisa
AU - Arboleda, Humberto
N1 - Funding Information:
CAD cells were a kind gift from Dr. Dona M. Chikaraishi, Department of Neurobiology, Duke University Medical Center, Durham, NC, USA. This work was supported by grants from COLCIENCIAS ( 1222-408-20401 ), DIB-Universidad Nacional de Colombia ( 20101007590, 20201009689, 201010010493 and 20101009684 ) and fundación para la Promoción de la Investigación y la Tecnología-Banco de la República (Grant 1935).
Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2010/12
Y1 - 2010/12
N2 - Evidence has implicated apoptosis as a mechanism underlying cell demise in diverse neurodegenerative diseases including Parkinson's disease (PD). Endogenous toxins and other stress signals activate the sphingomyelin pathway increasing the levels of ceramide, an important regulator of cell death.In the present paper we have analysed the contribution of PI3K/AKT-GSK3β and MAPK (ERK and JNK) pathways to cell death in a catecholaminergic cell line following exposure to C2-ceramide. We also explored the potential neuroprotective action of insulin-like growth factor-1 (IGF-1) and neurotrophin-3 (NT3).We demonstrated that C2-ceramide-induced cell death is associated to an early decrease in phosphorylation (inhibition) of PI3K/AKT and ERK, followed by phosphorylation (activation) of JNK and de-phosphorylation (activation) of glycogen synthase kinase-3 beta (GSK3β). NT3 and IGF-1 increased survival at early time points, but only IGF-1 is capable to attenuate C2-ceramide-mediated neuronal death, and this neuroprotection is associated to strong and permanent activation of AKT and inhibition of GSK3β. In conclusion, C2-ceramide initiates a series of events including an early inactivation of PI3K/AKT and ERK pathways followed by activation of JNK and activation of GSK3β and neuronal death, changes that are counteracted by IGF-1.
AB - Evidence has implicated apoptosis as a mechanism underlying cell demise in diverse neurodegenerative diseases including Parkinson's disease (PD). Endogenous toxins and other stress signals activate the sphingomyelin pathway increasing the levels of ceramide, an important regulator of cell death.In the present paper we have analysed the contribution of PI3K/AKT-GSK3β and MAPK (ERK and JNK) pathways to cell death in a catecholaminergic cell line following exposure to C2-ceramide. We also explored the potential neuroprotective action of insulin-like growth factor-1 (IGF-1) and neurotrophin-3 (NT3).We demonstrated that C2-ceramide-induced cell death is associated to an early decrease in phosphorylation (inhibition) of PI3K/AKT and ERK, followed by phosphorylation (activation) of JNK and de-phosphorylation (activation) of glycogen synthase kinase-3 beta (GSK3β). NT3 and IGF-1 increased survival at early time points, but only IGF-1 is capable to attenuate C2-ceramide-mediated neuronal death, and this neuroprotection is associated to strong and permanent activation of AKT and inhibition of GSK3β. In conclusion, C2-ceramide initiates a series of events including an early inactivation of PI3K/AKT and ERK pathways followed by activation of JNK and activation of GSK3β and neuronal death, changes that are counteracted by IGF-1.
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U2 - 10.1016/j.neuro.2010.08.001
DO - 10.1016/j.neuro.2010.08.001
M3 - Research Article
C2 - 20696185
AN - SCOPUS:78049457564
SN - 0161-813X
VL - 31
SP - 687
EP - 693
JO - NeuroToxicology
JF - NeuroToxicology
IS - 6
ER -