Effects of alcohol on gene expression in neural cells

Wilke, Norbert; Sganga, Michael W.; Barhite, Steven; Miles, Michael F.

doi:10.1007/978-3-0348-7330-7_6

Cited by 21 publications

(14 citation statements)

References 16 publications

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“…A preliminary study shows that ethanol does not enhance the expression of TGF-b1 in RKO cells (data not shown), suggesting that the overexpression of p21 WAF1/ CIP1 by ethanol is not via the induction of TGF-b1. It has been reported that ethanol can also increase the transcription of several stress responsive genes such as GRP78, GRP90 and Hsc70 in neuronal cells (Miles et al, 1991;Wilke et al, 1994;Hsieh et al, 1996). The GRP78 gene is up-regulated by ethanol through the SP1 site.…”

Section: Discussionmentioning

confidence: 99%

Ethanol upregulates the expression of p21WAF1/CIP1 and prolongs G1 transition via a p53-independent pathway in human epithelial cells

1997

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The control of cell cycle progression is necessary for accuracy in the replication of DNA and the distribution of genetic information to daughter cells. Disturbances in progression of the cell cycle may result in the loss of genomic integrity, a`hallmark' of cancer cells. Extensive consumption of alcoholic beverages is a risk factor associated with the development of various human epidermoid cancer including oral and pharyngeal squamous cell carcinomas. However, e ects of ethanol on cell cycle progression and on the expression of genes associated with the cell cycle have not been studied. We report here that exposure of human epithelial cells to ethanol, at concentrations (100 ± 200 mM) that do not cause cell death, (a) does not a ect or only reduces slightly the cellular level of p53 protein, (b) upregulates the transcription of the WAF1/CIP1 gene, (c) inhibits the Cdk2 activity, and (d) reduces the rate of cellular proliferation by inducing a delay in G 1 phase transition. The results also indicate that, at these non-cytotoxic concentrations, ethanol exhibits its e ects through a p53-independent mechanism.

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Section: Discussionmentioning

confidence: 99%

Ethanol upregulates the expression of p21WAF1/CIP1 and prolongs G1 transition via a p53-independent pathway in human epithelial cells

1997

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“…A number of excellent studies using gene arrays have identified a variety of genes that are upregulated or downregulated by short-or long-term exposure to alcohol in experimental animals and man (Lewohl et al, 2000;Dodd et al, 2006;Mulligan et al, 2006). Despite these investigations, little is known of the molecular mechanisms by which alcohol might alter transcriptional efficiency (Wilke et al, 1994;Hassan et al, 2003). One gene reported to be especially sensitive to alcohol is Gabra4, which is expressed at high levels in the CNS, in neurons of the thalamus, striatum, dentate gyrus, and cerebral cortex (Pirker et al, 2000;Roberts et al, 2005Roberts et al, , 2006.…”

Section: Introductionmentioning

confidence: 99%

Alcohol Regulates Gene Expression in Neurons via Activation of Heat Shock Factor 1

Pignataro

Miller²,

Ma³

et al. 2007

J. Neurosci.

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Drinking alcohol causes widespread alterations in gene expression that can result in long-term physiological changes. Although many alcohol-responsive genes (ARGs) have been identified, the mechanisms by which alcohol alters transcription are not well understood. To elucidate these mechanisms, we investigated Gabra4, a neuron-specific gene that is rapidly and robustly activated by alcohol (10 -60 mM), both in vitro and in vivo. Here we show that alcohol can activate elements of the heat shock pathway in mouse cortical neurons to enhance the expression of Gabra4 and other ARGs. The activation of Gabra4 by alcohol or high temperature is dependent on the binding of heat shock factor 1 (HSF1) to a short downstream DNA sequence, the alcohol response element (ARE). Alcohol and heat stimulate the translocation of HSF1 from the cytoplasm to the nucleus and the induction of HSF1-dependent genes, Hsp70 and Hsp90, in cultured neurons and in the mouse cerebral cortex in vivo. The reduction of HSF1 levels using small interfering RNA prevented the stimulation of Gabra4 and Hsp70 by alcohol and heat shock. Microarray analysis showed that many ARGs contain ARE-like sequences and that some of these genes are also activated by heat shock. We suggest that alcohol activates phylogenetically conserved pathways that involve intermediates in the heat shock cascade and that sequence elements similar to the ARE may mediate some of the changes in gene expression triggered by alcohol intake, which could be important in a variety of pathophysiological responses to alcohol.

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“…If Ca in the nucleus is active, it should phosphorylate and activate the transcription factor, cAMP-response element binding protein (CREB), and other nuclear proteins (42) and contribute to ethanol-induced changes in gene expression (43)(44)(45)(46). Nuclear sequestration of Ca would also be expected to reduce phosphorylation of plasma membrane and cytosolic proteins.…”

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confidence: 99%

Ethanol causes translocation of cAMP-dependent protein kinase catalytic subunit to the nucleus.

Dohrman

Diamond

Gordon

1996

Proc. Natl. Acad. Sci. U.S.A.

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Short-and long-term ethanol exposures have been shown to alter cellular levels of cAMP, but little is known about the effects of ethanol on cAMP-dependent protein kinase (PKA). When cAMP levels increase, the catalytic subunit of PKA (Ca) is released from the regulatory subunit, phosphorylates nearby proteins, and then translocates to the nucleus, where it regulates gene expression. Altered localization of Cai would have profound effects on multiple cellular functions. Therefore, we investigated whether ethanol alters intracellular localization of Ca. NG108-15 cells were incubated in the presence or absence of ethanol for as long as 48 h, and localization of PKA subunits was determined by immunocytochemistry. We found that ethanol exposure produced a significant translocation of Ca from the Golgi area to the nucleus. Cai remained in the nucleus as long as ethanol was present. There was no effect of ethanol on localization of the type I regulatory subunit of PKA. Ethanol also caused a 43% decrease in the amount of type I regulatory subunit but had no effect on the amount of Ca as determined by Western blot. These data suggest that ethanol-induced translocation of Ca to the nucleus may account, in part, for diverse changes in cellular function and gene expression produced by alcohol.

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Effects of alcohol on gene expression in neural cells

Cited by 21 publications

References 16 publications

Ethanol upregulates the expression of p21WAF1/CIP1 and prolongs G1 transition via a p53-independent pathway in human epithelial cells

Ethanol upregulates the expression of p21WAF1/CIP1 and prolongs G1 transition via a p53-independent pathway in human epithelial cells

Alcohol Regulates Gene Expression in Neurons via Activation of Heat Shock Factor 1

Ethanol causes translocation of cAMP-dependent protein kinase catalytic subunit to the nucleus.

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