Alcohol and gene expression in nerve cells with emphasis on transcription factor AP-1

Detta är en avhandling från Medical Neurochemistry, Lund University Hospital, 221 85 Lund, Sweden

Sammanfattning: Alcohol induces profound effects on the function of the nerve cells in the nervous system. Alterations in gene expression is an important way by which these effects could be induced and sustained. Activating Protein-1 (AP-1) is a dimeric transcription factor constituted of proteins from the fos and jun immediate-early gene families. AP-1 induces gene expression of genes having a functional AP-1 binding site in their promoter. Alcohol has previously been demonstrated to modulate the expression of individual fos and jun genes and to alter the AP-1 binding activity in neuronal cells. The present study investigated the effects of alcohol on jun gene expression and AP-1 transcriptional activity and the signalling pathways involved in these processes in a human neuroblastoma SH-SY5Y cell line. Furthermore, experiments were conducted to screen for ethanol sensitive genes. The main findings of this study were that acute ethanol attenuated basal and TPA-induced junD mRNA expression without affecting the expression of the other jun genes, c-jun and junB. Acute ethanol exposure also attenuated muscarinic receptor-induced activation of the MAP kinases, p38 and JNK. The p38 MAPK was shown to be involved in muscarinic receptor-induced activation of junB and junD mRNA expression. Long-term ethanol exposure enhanced AP-1 transcriptional activity. This enhancement was blocked by inhibitors of PKC and MAPKs. Cellular retinoic acid-binding protein-I (CRABP-I) was identified as an ethanol sensitive gene. The CRABP-I gene expression was up-regulated by ethanol in a time- and dose-dependent manner. This findings support the idea that immediate-early genes and AP-1 are involved in the alcohol-induced changes in the function of nerve cells and that alcohol alters the expression of particular genes.

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