PI3 k/akt inhibition induces apoptosis through p38 activation in neurons.
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.
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GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N CHEMICAL GENE-Y GENE-N GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-N GENE-N GENE-N CHEMICAL GENE-N GENE-N CHEMICAL CHEMICAL GENE-N GENE-N GENE-Y GENE-Y GENE-N
MAPK PI3K AKT PI3K AKT PI3K AKT p38 MAPK kinase LY294002 c-Jun JNK p38 JNK c-Jun dp5 c-Jun PI3K AKT PI3 k SB203580 p38 akt SP600125 LY294002 p38 MAPK c-Jun dp5 mitogen-activated protein kinase