The involvement of glycogen synthase kinase-3 and protein phosphatase-2A in lactacystin-induced tau accumulation.
Here, we demonstrated that lactacystin inhibited proteasome dose-dependently in HEK293 cells stably expressing tau. Simultaneously, it induces accumulation of both non-phosphorylated and hyperphosphorylated tau and decreases the binding of tau to the taxol-stabilized microtubules. Lactacystin activates glycogen synthase kinsase-3 (GSK-3) and decreases the phosphorylation of GSK-3 at serine-9. LiCl inhibits GSK-3 and thus reverses the lactacystin-induced accumulation of the phosphorylated tau. Lactacystin also inhibits protein phosphase-2A (PP-2A) and it significantly increases the level of inhibitor 1 of PP-2A. These results suggest that inhibition of proteasome by lactacystin induces tau accumulation and activation of GSK-3 and inhibition of PP-2A are involved.
Ren
Qing-Guo
QG
Department of Pathophysiology, Key Laboratory of Neurological Diseases of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
Liao
Xiao-Mei
XM
Wang
Ze-Fen
ZF
Qu
Zhong-Shen
ZS
Wang
Jian-Zhi
JZ
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D061988:Proteasome Inhibitors; D054648:Protein Phosphatase 2; D016875:tau Proteins / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D061988:Proteasome Inhibitors; D016875:tau Proteins; C067713:lactacystin; D038362:Glycogen Synthase Kinase 3; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D000111:Acetylcysteine