title: PI3 k/akt inhibition induces apoptosis through p38 activation in neurons.
abstract: Accumulating evidence suggests that the PI3K/AKT pathway is a pro-survival signalling system in neurons. Therefore, the inhibition of this pathway may be implicated in the degeneration of neurons in Parkinson's disease (PD), Alzheimer's disease (AD), and other neurological disorders. Here we study the participation of the mitogen-activated protein kinase (MAPK) pathway on apoptosis induced by PI3K/AKT inhibition in cultured cerebellar granule cells (CGCs). LY294002, a specific PI3K/AKT inhibitor, selectively activated the p38 MAPK kinase pathway and enhanced c-Jun phosphorylation, but did not activate JNK. The pharmacological inhibitors SB203580 (p38 inhibitor) and SP600125 (a JNK inhibitor) protected primary cultures of rat CGCs from LY294002-induced apoptosis. Furthermore, both compounds decreased the phosphorylation of c-Jun and lowered mRNA levels of the pro-apoptotic gene dp5, a direct target of c-Jun. Taken together, our data demonstrate that PI3K/AKT inhibition induces neuronal apoptosis, a process that is mediated by the activation of p38 MAPK/c-Jun/dp5.
authors: Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Centros de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Institut de Biomedicina (IBUB), Universitat de Barcelona,. Nucli Universitari de Pedralbes,. 08028 Barcelona, Spain.
authors: Aurelio
authors: A
authors: Vázquez de la Torre
authors: Felix
authors: F
authors: Junyent
authors: Jaume
authors: J
authors: Folch
authors: Carme
authors: C
authors: Pelegrí
authors: Jordi
authors: J
authors: Vilaplana
authors: Carme
authors: C
authors: Auladell
authors: Carlos
authors: C
authors: Beas-Zarate
authors: Mercè
authors: M
authors: Pallàs
authors: Ester
authors: E
authors: Verdaguer
authors: Antoni
authors: A
authors: Camins
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008858:Microscopy, Phase-Contrast; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt