HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 23, 15909-15915, June 9, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/23/15909    most recent M600612200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, G. Articles by Luo, J. Search for Related Content PubMed PubMed Citation Articles by Chen, G. Articles by Luo, J. Social Bookmarking                      What's this?

Interaction between RAX and PKR Modulates the Effect of Ethanol on Protein Synthesis and Survival of Neurons^*

Gang Chen, Cuiling Ma, Kimberly A. Bower, Zunji Ke, and Jia Luo¹

From the Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, Morgantown, West Virginia 26506 and Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

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, the-subunit of eukaryotic translation initiation factor-2 (eIF2) 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 eIF2 in the developing cerebellum. The effect of ethanol on PKR/eIF2 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 eIF2 phosphorylation was mediated by PKR. Overexpression of a wild-type RAX dramatically enhanced sensitivity to ethanol-induced PKR/eIF2 phosphorylation, as well as translational inhibition and cell death. In contrast, overexpression of a mutant (S18A) RAX inhibited ethanol-mediated PKR/eIF2 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.

Received for publication, January 20, 2006 , and in revised form, March 24, 2006.

^* This research was supported by Grants AA015407 and AA013984 from the National Institutes of Health and a grant from the Nature and Sciences Foundation of the Chinese Academy of Sciences (30470544). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506. Tel.: 304-293-7208; Fax: 304-293-7823, E-mail: jluo{at}hsc.wvu.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				G. A. Peters, D. D. Seachrist, R. A. Keri, and G. C. Sen The double-stranded RNA-binding protein, PACT, is required for postnatal anterior pituitary proliferation PNAS, June 30, 2009; 106(26): 10696 - 10701. [Abstract] [Full Text] [PDF]

				C. Ma, K. A. Bower, G. Chen, X. Shi, Z.-J. Ke, and J. Luo Interaction between ERK and GSK3{beta} Mediates Basic Fibroblast Growth Factor-induced Apoptosis in SK-N-MC Neuroblastoma Cells J. Biol. Chem., April 4, 2008; 283(14): 9248 - 9256. [Abstract] [Full Text] [PDF]

				C. Ma, J. Wang, Y. Gao, T.-W. Gao, G. Chen, K. A. Bower, M. Odetallah, M. Ding, Z. Ke, and J. Luo The Role of Glycogen Synthase Kinase 3{beta} in the Transformation of Epidermal Cells Cancer Res., August 15, 2007; 67(16): 7756 - 7764. [Abstract] [Full Text] [PDF]

				K. H. Kok, M.-H. J. Ng, Y.-P. Ching, and D.-Y. Jin Human TRBP and PACT Directly Interact with Each Other and Associate with Dicer to Facilitate the Production of Small Interfering RNA J. Biol. Chem., June 15, 2007; 282(24): 17649 - 17657. [Abstract] [Full Text] [PDF]