| Title | Retinoic Acid Induced nNOS Expression Depends on a Novel PI3K/AKT/DAX1 Pathway in Human TGW-nu-I Neuroblastoma Cells. | | Author(s) | Nagl F, Schönhofer K, Seidler B, Mages J, Allescher HD, Schmid RM, Schneider G, Saur D | | Institution | Technical University of Munich. | | Source | Am J Physiol Cell Physiol 2009 Sep 2. | | Abstract | Neuronal nitric oxide synthase (nNOS) derived nitric oxide (NO) acts as a neurotransmitter and intracellular signaling molecule in the central and peripheral nervous system. NO regulates multiple processes like neuronal development, plasticity and differentiation and is a mediator of neurotoxicity. The nNOS gene is highly complex with twelve alternative first exons, exon 1a-1l, transcribed from distinct promoters, leading to nNOS variants with different 5; untranslated regions. Transcriptional control of the nNOS gene is not understood in detail. To investigate regulation of nNOS gene expression by retinoic acid (RA) we used the human neuroblastoma cell line TGW-nu-I as a model system. We show that RA induces nNOS transcription in a protein synthesis-dependent fashion. We identify the PI3K/AKT signaling pathway and the atypical orphan nuclear receptor DAX1 (NR0B1) as critical mediators involved in RA induced nNOS gene transcription. RA treatment increases DAX1 expression via PI3K/AKT signaling. Upregulation of DAX1 expression in turn induces nNOS transcription in response to RA. These results identify nNOS as a target gene of a novel RA-PI3K-AKT-DAX1 dependent pathway in human neuroblastoma cells and stress the functional importance of the transcriptional regulator DAX1 for nNOS gene expression in response to RA treatment. Key words: neuronal nitric oxide synthase, phosphatidylinositol 3 kinase (PI3K)/AKT signaling, DAX1, retinoic acid, transcriptional regulation. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19726747 |
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