Map kinase and PKC signaling pathways modulate NGF-mediated apoE transcription

• Published in: Neuroscience letters Vol. 595; pp. 54 - 59
• Main Authors: Strachan-Whaley, Megan R, Reilly, Kate, Dobson, James, Kalisch, Bettina E
• Format: Journal Article
• Language: English
• Published: Ireland 19.05.2015
• Subjects: Animals; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Chromones - pharmacology; Estrenes - pharmacology; Indoles - pharmacology; Isothiuronium - analogs & derivatives; Isothiuronium - pharmacology; Maleimides - pharmacology; Mitogen-Activated Protein Kinases - metabolism; Morpholines - pharmacology; Nerve Growth Factor - metabolism; Nerve Growth Factor - pharmacology; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; PC12 Cells; Promoter Regions, Genetic; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Pyrrolidinones - pharmacology; Rats; Signal Transduction; Transcription, Genetic; Type C Phospholipases - antagonists & inhibitors; Nerve growth factor (NGF); Signal transduction; Apolipoprotein E (apoE); Nitric oxide (NO); PC12 cells
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2015.03.032

The present study assessed the mechanisms by which nerve growth factor (NGF) increased the level of apolipoprotein E (apoE) in PC12 cells. NGF (50ng/mL) significantly increased apoE protein levels following 72h of treatment. Similarly NGF increased luciferase activity in cells transfected with a luciferase reporter construct containing a 500bp fragment of the apoE promoter, indicating NGF-induced apoE expression is regulated, at least in part, at the level of transcription. The non-selective nitric oxide synthase (NOS) inhibitor N(ɷ)-nitro-L-arginine methylester (L-NAME; 20mM) did not attenuate the NGF-mediated increase in luciferase activity, while the inducible NOS inhibitor s-methylisothiourea (S-MIU; 2mM) partially attenuated this action of NGF. Inhibition of MAP kinase activation with 50μM U0126 or pre-treatment with the PKC inhibitor bisindolylmaleimide 1 (BIS-1; 10μM) prevented the NGF-mediated activation of the apoE promoter. Pre-treatment with the phospholipase C (PLC) inhibitor U73122 (5μM) partially inhibited the NGF-induced increase in luciferase activity while the Akt inhibitor LY294002 (10μM) had no effect. These data suggest NGF-induced apoE transcription requires MAP kinase and PKC activation and that these TrkA signaling pathways may be modulated by NO.