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Proteasome inhibition modulates kinase activation in neural cells: Relevence to ubiquitination, ribosomes, and survival
Author(s) -
Zhang Le,
Ebenezer Philip J.,
Dasuri Kalavathi,
BruceKeller Annadora J.,
Liu Ying,
Keller Jeffrey N.
Publication year - 2009
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22147
Subject(s) - proteasome , mg132 , proteasome inhibitor , kinase , microbiology and biotechnology , signal transduction , mapk/erk pathway , neurotoxicity , protein kinase a , biology , lactacystin , mitogen activated protein kinase , ubiquitin , p38 mitogen activated protein kinases , chemistry , biochemistry , toxicity , organic chemistry , gene
In this study we examined whether established signal transduction cascades, p44/42 mitogen‐activated protein kinase (ERK1/2) and Jun N‐terminal kinases (JNK) pathways, are altered in N2a neural cells in response to proteasome inhibition. Additionally, we sought to elucidate the relative contribution of these signal transduction pathways to the multiple downstream effects of proteasome inhibition. Our data indicate that ERK1/2 and JNK are activated in response to proteasome inhibition. Washout of proteasome inhibitor (MG132) results in an enhancement of ERK1/2 activation and amelioration of JNK activation. Treatment with an established MAPK inhibitor resulted in an increase in proteasome inhibitor toxicity, and incubation with JNK inhibitor was observed to attenuate proteasome inhibitor toxicity significantly. Subsequent studies demonstrated that inhibition of ERK1/2 and JNK activity does not alter the gross increase in ubiquitinated protein following proteasome inhibitor administration. Similarly, ERK1/2 and JNK activity do not appear to play a role in the disruption of polysomes following proteasome inhibitor administration in neural cells. Together these data indicate that ERK1/2 and JNK activation may play differential roles in modulating neurochemical disturbances and neurotoxicity induced by proteasome inhibition. © 2009 Wiley‐Liss, Inc.