Induction of neurite outgrowth in PC12 cells by the bacterial nucleoside N6-methyldeoxyadenosine is mediated through adenosine A2a receptors and via cAMP and MAPK signaling pathways.

Abstract	We have previously shown that N(6)-methyldeoxyadenosine (MDA) is an inducer of differentiation in several tumor cells. Here we show that in addition to its ability to induce neurite-outgrowth in PC12 cells, MDA also significantly enhances the nerve-growth factor-mediated neurite outgrowth of these cells. Thus, MDA acts synergistically with NGF to repress cdc2 and cdk2 synthesis and to enhance tyrosine hydroxylase synthesis. To further elucidate the mechanisms of action of MDA, we investigated the effect of this drug on various signaling pathways. The neuritogenesis observed in PC12 following MDA treatment is mediated through activation of adenylyl cyclase in a PKA independent process and through the recruitment of the p44/p42 MAPK pathway. Furthermore, the adenosine A(2a) receptor antagonist ZM 241385 prevents the MDA-induced neuritogenesis, suggesting that MDA mediates its effect via this adenylyl cyclase-coupled A(2a) receptor. Collectively, these findings suggest that, in PC12 cells, the MDA-induced neuritogenesis requires the recruitment of adenosine A(2a) receptor, the stimulation of adenylate cyclase, and the activation of the p44/42MAP kinase cascade.
Authors	Marie-Pierre Charles, Danièle Adamski, Blandine Kholler, Laurent Pelletier, François Berger, Didier Wion
Journal	Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 304 Issue 4 Pg. 795-800 (May 16 2003) ISSN: 0006-291X [Print] United States
PMID	12727227 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	DNA-Binding Proteins Deoxyadenosines Elk1 protein, rat Enzyme Inhibitors Proto-Oncogene Proteins Receptor, Adenosine A2A Receptors, Purinergic P1 Transcription Factors Triazines Triazoles ZM 241385 ets-Domain Protein Elk-1 CGS 24012 Cyclic AMP Protein Serine-Threonine Kinases CDC2 Protein Kinase CDC2-CDC28 Kinases Cdk2 protein, rat Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases Mitogen-Activated Protein Kinases Adenosine
Topics	Adenosine (analogs & derivatives, pharmacology) Animals CDC2 Protein Kinase (metabolism) CDC2-CDC28 Kinases Cyclic AMP (metabolism) Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases (metabolism) DNA-Binding Proteins Deoxyadenosines (chemistry, metabolism, pharmacology) Enzyme Inhibitors (pharmacology) MAP Kinase Signaling System (physiology) Mitogen-Activated Protein Kinases (metabolism) Neurites (drug effects, metabolism) PC12 Cells Protein Serine-Threonine Kinases (metabolism) Proto-Oncogene Proteins (metabolism) Rats Receptor, Adenosine A2A Receptors, Purinergic P1 (chemistry, metabolism) Second Messenger Systems (physiology) Transcription Factors Triazines (pharmacology) Triazoles (pharmacology) ets-Domain Protein Elk-1

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