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

J. Biol. Chem., Vol. 276, Issue 2, 1185-1194, January 12, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/2/1185    most recent M006647200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Li, M. Articles by Beg, A. A. Search for Related Content PubMed PubMed Citation Articles by Li, M. Articles by Beg, A. A. Social Bookmarking                      What's this?

The RelA(p65) Subunit of NF-B Is Essential for Inhibiting Double-stranded RNA-induced Cytotoxicity^*

Ming Li, Wendy Shillinglaw^§, William J. Henzel^§, and Amer A. Beg^¶

From the  Department of Biological Sciences, Columbia University, New York, New York 10027 and ^§ Protein Chemistry Department, Genentech Incorporated, South San Francisco, California 94080

Double-stranded RNA (dsRNA) molecules generated during virus infection can initiate a host antiviral response to limit further infection. Such a response involves induction of antiviral gene expression by the dsRNA-activated protein kinase (PKR) and the NF-B transcription factor. In addition, dsRNA can also induce apoptosis by an incompletely understood mechanism that may serve to further limit viral replication. Here we demonstrate a novel role for the RelA subunit of NF-B in inhibiting dsRNA-induced cell death. dsRNA treatment resulted in caspase 3 activation and apoptotic morphological transformations in mouse embryonic fibroblasts (MEFs) derived from RelA/ mice but not from RelA+/+ mice. Such dsRNA-induced killing could be inhibited by expression of either a dominant-negative mutant of PKR or wild-type RelA. Interestingly, caspase 3 activated following dsRNA treatment of RelA/ MEFs was essential for apoptotic nuclear changes but dispensable for cytotoxicity. A broader specificity caspase inhibitor was also unable to inhibit dsRNA-induced cytotoxicity, suggesting that caspase activation is not essential for the induction of cell death by dsRNA in MEFs. However, combined inhibition of caspase 3 and reactive oxygen species production resulted in complete inhibition of dsRNA-induced cytotoxicity. These results demonstrate an essential role for NF-B in protecting cells from dsRNA-induced apoptosis and suggest that NF-B may inhibit both caspase-dependent and reactive oxygen species-dependent cytotoxic pathways.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati