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標題: Involvement of cAMP in nerve growth factor-triggered p35/Cdk5 activation and differentiation in PC12 cells
作者: Chen, M.C.
赫, 林
Lin, H.
Hsu, F.N.
Huang, P.H.
Lee, G.S.
Wang, P.S.
關鍵字: adenosine 3 ',5 '-cyclic monophosphate;nerve growth factor;cyclin-dependent kinase 5;cyclin-dependent kinase-5;signal-regulated kinase;neuronal;differentiation;protein-kinase;adenosine-monophosphate;pheochromocytoma cells;transcription factor;neurite outgrowth;induced;apoptosis;pathway
Project: American Journal of Physiology-Cell Physiology
期刊/報告no:: American Journal of Physiology-Cell Physiology, Volume 299, Issue 2, Page(s) C516-C527.
Chen MC, Lin H, Hsu FN, Huang PH, Lee GS, Wang PS. Involvement of cAMP in nerve growth factor-triggered p35/Cdk5 activation and differentiation in PC12 cells. Am J Physiol Cell Physiol 299: C516-C527, 2010. First published May 12, 2010; doi: 10.1152/ajpcell.00534.2009.-The signaling mechanisms underlying cell differentiation have been extensively studied with the use of rat PC12 cells as a model system. Nerve growth factor (NGF) is a trophic factor inducing PC12 cell differentiation through the activation of the p35/cyclin-dependent kinase 5 (Cdk5) complex. It has been reported that adenylyl cyclase activation and cAMP production may be involved in NGF-dependent actions. Our previous results indicate that cAMP activates the p35/Cdk5 complex in reproductive cells. Therefore, the role of cAMP in NGF-triggered p35/Cdk5 activation and PC12 differentiation was interesting to explore. Our results indicate that roscovitine, a molecular inhibitor of Cdk5, blocks cAMP-triggered PC12 differentiation, which was evaluated by neurite initiation, a decrease in proliferation, and cell cycle G(1) arrest. The following data show that cAMP treatment increased Cdk5 activity through p35 upregulation. cAMP downstream components, protein kinase A (PKA) and phosphorylated cAMP response element binding protein (CREB), are involved in this regulation. The immunocytochemical results indicate that PKA inhibition disrupted cAMP-triggered p35/Cdk5 localization in PC12 cells. In addition, adenylyl cyclase inhibition was found to diminish NGF-induced intracellular cAMP production, CREB phosphorylation, and p35 expression. The cAMP antagonist and the PKA inhibitors reduced NGF-induced p35 expression. Finally, NGF-triggered PC12 differentiation was partially decreased by adenylyl cyclase or PKA inhibitors. In conclusion, these results demonstrate that cAMP may play a role in NGF-p35/Cdk5-dependent PC12 differentiation.
ISSN: 0363-6143
DOI: 10.1152/ajpcell.00534.2009
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