Mechanism of zinc-induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3beta in SH-SY5Y neuroblastoma cells

• Published in: Journal of neurochemistry Vol. 92; no. 5; p. 1104
• Main Authors: An, Wen-Lin, Bjorkdahl, Cecilia, Liu, Rong, Cowburn, Richard F, Winblad, Bengt, Pei, Jin-Jing
• Format: Journal Article
• Language: English
• Published: England 01.03.2005
• Subjects: Analysis of Variance; Animals; Antibiotics, Antineoplastic - pharmacology; Blotting, Western - methods; Brain - drug effects; Brain - metabolism; Brain - ultrastructure; Cell Line, Tumor - drug effects; Cell Survival - drug effects; Culture Media, Serum-Free - pharmacology; Cytoplasm - drug effects; Cytoplasm - metabolism; Cytoplasm - ultrastructure; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors - pharmacology; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Humans; Immunohistochemistry - methods; In Vitro Techniques; Medicin och hälsovetenskap; Microscopy, Immunoelectron - methods; Models, Biological; Neuroblastoma; Phosphorylation - drug effects; rab5 GTP-Binding Proteins - metabolism; Rats; Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Sirolimus - pharmacology; tau Proteins - metabolism; Tetrazolium Salts; Thiazoles; Time Factors; Zinc - pharmacology; Zinc Sulfate - pharmacology
• ISSN: 0022-3042
• DOI: 10.1111/j.1471-4159.2004.02948.x

We have previously reported an aberrant accumulation of activated protein kinase B (PKB), glycogen synthase kinase (GSK)-3beta, extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38 and p70 S6 kinase (p70S6K) in neurons bearing neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). However, the mechanism by which these tau candidate kinases are involved in the regulation of p70S6K and GSK-3beta phosphorylation is unknown. In the current study, 100 microM zinc sulfate was used, and influences of various components of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on p70S6K and GSK-3beta phosphorylation have been investigated in serum-deprived SH-SY5Y neuroblastoma cells. We found that zinc could induce an increase of phosphorylated (p) p70S6K, p-PKB, p-GSK-3beta, p-ERK1/2, p-JNK and p-p38, especially in long-term treatment (4-8 h). Treatment with different inhibitors including rapamycin, wortmannin, LY294002, and U0126, and their combinations, indicated that phosphorylation of p70S6K and GSK-3beta is regulated by rapamycin-dependent, PI3K and MAPK pathways. Furthermore, phosphorylation of p70S6K and GSK-3beta affected levels of tau unphosphorylated at the Tau-1 site and phosphorylated at the PHF-1 site, and p70S6K phosphorylation affected the total tau level. Thus, 100 microM zinc might activate PKB, GSK-3beta, ERK1/2, JNK, p38 and p70S6K, that are consequently involved in tau changes in SH-SY5Y cells.