Effects of alcohol on gene expression in neural cells.

Our studies in the NG108-15 neuroblastoma x glioma cell line previously showed that the molecular chaperonin, Hsc70, is an ethanol-responsive gene (EtRG) regulated at the level of transcription by ethanol. We recently identified two related molecular chaperonins, GRP94 and GRP78, as EtRGs with GRP94 mRNA abundance being induced by ethanol more than three-fold vs. control. Stable transfection studies show that GRP78 transcription is also regulated by ethanol and that ethanol also potentiates GRP78 induction by classical inducing agents such as tunicamycin. Recently, we have found that ethanol induction of Hsc70 may require cis-acting promoter sequences recognized by the DNA-binding protein Sp1. Chronic ethanol exposure does not alter Sp1 DNA-binding activity, thus suggesting a possible ethanol-induced post-translational modification that activates Sp1 function. We predict that the molecular mechanisms underlying ethanol regulation of Hsc70, GRP94 and GRP78 may be similar since they have related functions. GRP94 and GRP78 (GRP94/78) are known to be induced by agents which inhibit glycoprotein processing or deplete endoplasmic reticulum stores of calcium. In turn, induction of GRP78 expression is known to selectively alter the transport of glycoproteins and produce "tolerance" to depletion of sequestered intracellular calcium. The regulation of these genes by ethanol could thus relate to the known effects of ethanol on calcium homeostasis and protein trafficking. The actions of ethanol on chaperonin gene expression may have important mechanistic implications for CNS adaptation to ethanol, particularly if other EtRGs share the same regulatory mechanisms.