MicroRNA-29b Regulates Ethanol-induced Neuronal Apoptosis in the Developing Cerebellum through SP1/RAX/PKR Cascade

Qi, Yuanlin; Zhang, Ming Fang; Li, Hui; Frank, Jacqueline A.; Dai, Lu; Liu, Huijuan; Chen, Gang

doi:10.1074/jbc.m113.535195

Cited by 51 publications

(52 citation statements)

References 53 publications

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“…Cerebellar granule neurons (CGNs) were isolated from PD7 pups and cultured as described previously [18, 19]. Briefly, neonatal mice at PD7 were decapitated, and the cerebella were carefully collected.…”

Section: Methodsmentioning

confidence: 99%

“…With this method, ethanol concentrations in the culture medium could be accurately maintained and confirmed by using an ethanol assay kit from Sigma-Aldrich, St. Louis, MO. A series of concentration of 200, 400, and 800 mg/dl was used in this study as described previously [19]. …”

Section: Methodsmentioning

confidence: 99%

“…More importantly, overexpression of wild-type RAX enhanced ethanol-induced RAX/PKR association, PKR activation, and neuronal apoptosis, while mutation of RAX reversed the consequences. Our more recent data further indicated that ethanol regulates RAX/PKR interaction via microRNA-29b/Sp1/RAX cascade [14]. However, the functions of PKR in ethanol neurotoxicity in vivo have not been established.…”

Section: Introductionmentioning

confidence: 99%

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Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum

Chen

et al. 2015

Cerebellum

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Ethanol-induced neuronal loss is closely related to the pathogenesis of fetal alcohol spectrum disorders. The cerebellum is one of the brain areas that are most sensitive to ethanol. The mechanism underlying ethanol neurotoxicity remains unclear. Our previous in vitro studies have shown that the double-stranded RNA (dsRNA)-activated protein kinase (PKR) regulates neuronal apoptosis upon ethanol exposure and ethanol activates PKR through association with its intracellular activator RAX. However, the role of PKR and its interaction with RAX in vivo have not been investigated. In the current study, by utilizing N-PKR−/− mice, C57BL/6J mice with a deficient RAX-binding domain in PKR, we determined the critical role of RAX/PKR association in PKR-regulated ethanol neurotoxicity in the developing cerebellum. Our data indicate that while N-PKR−/− mice have a similar BAC profile as wild-type mice, ethanol induces less brain/body mass reduction as well as cerebellar neuronal loss. In addition, ethanol promotes interleukin-1β (IL-1β) secretion, and IL-1β is a master cytokine regulating inflammatory response. Importantly, ethanol-promoted IL-1β secretion is inhibited in the developing cerebellum of N-PKR−/− mice. Thus, RAX/PKR interaction and PKR activation regulate ethanol neurotoxicity in the developing cerebellum, which may involve ethanol-induced neuroinflammation. Further, PKR could be a possible target for pharmacological intervention to prevent or treat fetal alcohol spectrum disorder (FASD).

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum

Chen

et al. 2015

Cerebellum

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“…These data for the first time showed that miRNAs could mediate and explain the effects of ethanol, albeit in a developmental context. Since then, a growing body of data has shown that alcohol has developmental effects on miRNA expression patterns and that alcohol-sensitive miRNAs in turn may explain fetal alcohol effects (Mantha, Laufer, & Singh, 2014;Pappalardo-Carter et al, 2013;Qi et al, 2014;Tal et al, 2012;Wang, Zhang, et al, 2009). miRNAs have also been associated with alcohol addiction and toxicity.…”

Section: Mirnas As Mediators Of Ethanol Effects In Developing and Adumentioning

confidence: 97%

MicroRNAs and Ethanol Toxicity

Miranda¹

2014

International Review of Neurobiology

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“…Sometimes the drugs targeting DNA methylation could exhibit tissue and gene-specific actions, that is, either the drug may promote DNA methylation or reduce the DNA hypermethylation [92] . DNA methylation is an excellent target for anticancer therapies, as cancer generally associates with highly disrupted methylome.…”

Section: Epigenetic Drug Targeting Dna Methylationmentioning

confidence: 99%

Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets

Jangra¹,

Sriram²,

Pandey³

et al. 2016

Ann Neurosci

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Acute and chronic alcohol exposure evidently influences epigenetic changes, both transiently and permanently, and these changes in turn influence a variety of cells and organ systems throughout the body. Many of the alcohol-induced epigenetic modifications can contribute to cellular adaptations that ultimately lead to behavioral tolerance and alcohol dependence. The persistence of behavioral changes demonstrates that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. The research activities over the past years have demonstrated a crucial role of epigenetic mechanisms in causing long lasting and transient changes in the expression of several genes in diverse tissues, including brain. This has stimulated recent research work that is aimed at characterizing the influence of epigenetic regulatory events in mediating the long lasting and transient effects of alcohol abuse on the brain in humans and animal models of alcohol addiction. In this study, we update our current understanding of the impact of alcohol exposure on epigenetic mechanisms in the brain and refurbish the knowledge of epigenetics in the direction of new drugs development.

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MicroRNA-29b Regulates Ethanol-induced Neuronal Apoptosis in the Developing Cerebellum through SP1/RAX/PKR Cascade

Cited by 51 publications

References 53 publications

Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum

Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum

MicroRNAs and Ethanol Toxicity

Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets

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