Journal article
Interaction between RAX and PKR Modulates the Effect of Ethanol on Protein Synthesis and Survival of Neurons
The Journal of biological chemistry, Vol.281(23), pp.15909-15915
06/09/2006
DOI: 10.1074/jbc.M600612200
PMID: 16574643
Abstract
Ethanol exposure inhibits protein synthesis and causes cell death in the developing central nervous system. The double-stranded RNA (dsRNA)-activated protein kinase (PKR), a serine/threonine protein kinase, plays an important role in translational regulation and cell survival. PKR has been well known for its anti-viral response. Upon activation by viral infection or dsRNA, PKR phosphorylates its substrate, theα-subunit of eukaryotic translation initiation factor-2 (eIF2α) leading to inhibition of translation initiation. It has recently been shown that, in the absence of a virus or dsRNA, PKR can be activated by direct interactions with its protein activators, PACT, or its mouse homologue, RAX. We have demonstrated that exposure to ethanol increased the phosphorylation of PKR and eIF2α in the developing cerebellum. The effect of ethanol on PKR/eIF2α phosphorylation positively correlated to the expression of PACT/RAX in cultured neuronal cells. Using PKR inhibitors and PKR null mouse fibroblasts, we verified that ethanol-induced eIF2α phosphorylation was mediated by PKR. Overexpression of a wild-type RAX dramatically enhanced sensitivity to ethanol-induced PKR/eIF2α phosphorylation, as well as translational inhibition and cell death. In contrast, overexpression of a mutant (S18A) RAX inhibited ethanol-mediated PKR/eIF2α activation. Ethanol promoted PKR and RAX association in cells expressing wild-type RAX but not in cells expressing S18A RAX. S18A RAX functioned as a dominant negative protein and blocked ethanol-induced inhibition of protein synthesis and cell death. Our results suggest that the interactions between PKR and PACT/RAX modulate the effect of ethanol on protein synthesis and cell survival in the central nervous system.
Details
- Title: Subtitle
- Interaction between RAX and PKR Modulates the Effect of Ethanol on Protein Synthesis and Survival of Neurons
- Creators
- Gang Chen - West Virginia UniversityCuiling Ma - West Virginia UniversityKimberly A Bower - West Virginia UniversityZunji Ke - Chinese Academy of SciencesJia Luo - West Virginia University
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.281(23), pp.15909-15915
- DOI
- 10.1074/jbc.M600612200
- PMID
- 16574643
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 06/09/2006
- Academic Unit
- Pathology
- Record Identifier
- 9984186575902771
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