Beta-amyloid-activated cell cycle in SH-SY5Y neuroblastoma cells: correlation with the MAP kinase pathway.
Primary cultures of rat cortical neurons exposed to toxic concentrations of beta-amyloid peptide (betaAP) begin an unscheduled mitotic cell cycle that does not progress beyond the S phase. To analyze possible signal transduction pathways involved in this effect, the action of betaAP has been studied in SH-SY5Y neuroblastoma cells differentiated by a 7-d exposure to 10 microM retinoic acid. Treatment with the betaAP fragment, betaAP(25-35), (25 microM) for 24, 48, or 72 h caused apoptotic cell death, detected by flow cytometry as a prediploid cell population. Cell cycle analysis showed that betaAP(25-35) modified cell cycle profiles by markedly increasing the number of cells in the S phase and reducing the population of the G2/M area. These effects seem to involve activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK1/2). Inhibition of this pathway by the specific inhibitor PD98059 (2 microM) completely prevented changes of cell cycle distribution induced by betaAP and significantly reduced neuronal death. The data suggest that MAPK cascade can mediate the induction of cell cycle induced by betaAP, thus contributing to the toxicity of the peptide.
Frasca
Giuseppina
G
Departments of Experimental and Clinical Pharmacology, University of Catania, 95125 Catania, Italy.
Chiechio
Santina
S
Vancheri
Carlo
C
Nicoletti
Ferdinan
F
Copani
Agata
A
Angela Sortino
Maria
M
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000633:toxicity; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D014212:Tretinoin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one