Activation of PERK kinase in neural cells by proteasome inhibitor treatment.
Inhibition of the proteasome proteolytic pathway occurs as the result of normal aging, as well as in a variety of neurodegenerative conditions, and is believed to promote cellular toxicity in each of these conditions through diverse mechanisms. In the present study, we examined whether proteasome inhibition alters the protein kinase receptor-like endoplasmic reticulum kinase (PERK). Our studies demonstrate that proteasome inhibitors induce the transient activation of PERK in both primary rat neurons as well as the N2a neural cell line. Experiments with siRNA to PERK demonstrated that the modulation of PERK was not significant involved in regulating toxicity, ubiquitinated protein levels, or ribosome perturbations in response to proteasome inhibitor treatment. Surprisingly, PERK was observed to be involved in the up-regulation of p38 kinase following proteasome inhibitor treatment. Taken together, these data demonstrate the ability of proteasome inhibition to activate PERK and demonstrate evidence for novel cross-talk between PERK and the activation of p38 kinase in neural cells following proteasome inhibition. Taken together, these data have implications for understanding the basis by which proteasome inhibition alters neural homeostasis, and the basis by which cell signaling cascades are regulated by proteasome inhibition.
Pennington Biomedical Research Center/Louisiana State University System, Baton Rouge, Louisiana, USA.
Le
L
Zhang
Philip J
PJ
Ebenezer
Kalavathi
K
Dasuri
Annadora J
AJ
Bruce-Keller
Sun Ok
SO
Fernandez-Kim
Ying
Y
Liu
Jeffrey N
JN
Keller
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007976:Leupeptins / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D019892:eIF-2 Kinase / Q000378:metabolism*
D007976:Leupeptins; D011480:Protease Inhibitors; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D019892:eIF-2 Kinase; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde