Induction of Krox-24 by endogenous cannabinoid type 1 receptors in Neuro2A cells is mediated by the MEK-ERK MAPK pathway and is suppressed by the phosphatidylinositol 3-kinase pathway.
Neuro2a cells endogenously express cannabinoid type 1 (CB1) receptors. CB1 stimulation with HU210 activated ERK and induced the transcription factor Krox-24. A functional MEK-ERK pathway is an important requirement for CB1-mediated Krox-24 induction as blockade of MEK signaling by UO126 reduces both basal and CB1-mediated activation of Krox-24. CB1 receptor stimulation did not activate either JNK or p38 MAPK pathways or the pro-proliferation phosphatidylinositol 3-kinase (PI3K)-Akt pathway. However, serum removal or blockade of PI3K signaling by LY294002 transiently stimulated basal Krox-24 expression and increased CB1-mediated induction of Krox-24. This was consistent with a transient increase in pMEK, pERK, and pCREB levels following PI3K blockade. These data demonstrate that CB1-mediated activation of the Krox-24 transcription factor is negatively regulated through the PI3K-Akt pathway and reveals several points of signaling cross-talk between these two important kinase pathways.
Graham
E Scott
ES
Department of Pharmacology, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Ball
Nicola
N
Scotter
Emma L
EL
Narayan
Pritika
P
Dragunow
Mike
M
Glass
Michelle
M
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D015398:Signal Transduction
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D004791:Enzyme Inhibitors; D043882:Receptors, Cannabinoid; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases