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

J. Biol. Chem., Vol. 279, Issue 50, 52106-52116, December 10, 2004

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 279/50/52106    most recent M408678200v1 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 Li, Q. Articles by Chui, Y.-L. Search for Related Content PubMed PubMed Citation Articles by Li, Q. Articles by Chui, Y.-L. Social Bookmarking                      What's this?

A Death Receptor-associated Anti-apoptotic Protein, BRE, Inhibits Mitochondrial Apoptotic Pathway^*

Qing Li¶, Arthur Kar-Keung Ching, Ben Chung-Lap Chan||, Stephanie Ka-Yee Chow, Pak-Leong Lim, Tony Cheong-Yip Ho**, Wai-Ki Ip**, Chun-Kwok Wong**, Christopher Wai-Kei Lam**, Kenneth Ka-Ho Lee, John Yeuk-Hon Chan¶¶, and Yiu-Loon Chui||||

From the Clinical Immunology Unit and Sir Y. K. Pao Centre for Cancer, the ^**Department of Chemical Pathology, and the Department of Anatomy, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territory, Hong Kong Special Administrative Region, China, and the ^¶¶Department of Molecular Pathology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030

BRE, brain and reproductive organ-expressed protein, was found previously to bind the intracellular juxtamembrane domain of a ubiquitous death receptor, tumor necrosis factor receptor 1 (TNF-R1), and to down-regulate TNF--induced activation of NF-B. Here we show that BRE also binds to another death receptor, Fas, and upon overexpression conferred resistance to apoptosis induced by TNF-, anti-Fas agonist antibody, cycloheximide, and a variety of stress-related stimuli. However, down-regulation of the endogenous BRE by small interfering RNA increased apoptosis to TNF-, but nottoetoposide, indicating that the physiological antiapoptotic role of this protein is specific to death receptor-mediated apoptosis. We further demonstrate that BRE mediates antiapoptosis by inhibiting the mitochondrial apoptotic machinery but without translocation to the mitochondria or nucleus or down-regulation of the cellular level of truncated Bid. Dissociation of BRE rapidly from TNF-R1, but not from Fas, upon receptor ligation suggests that this protein interacts with the death inducing signaling complex during apoptotic induction. Increased association of BREwith phosphorylated, sumoylated, and ubiquitinated proteins after death receptor stimulation was also detected. We conclude that in contrast to the truncated Bid that integrates mitochondrial apoptosis to death receptor-triggered apoptotic cascade, BRE inhibits the integration. We propose that BRE inhibits, by ubiquitination-like activity, components in or proximal to the death-inducing signaling complexes that are necessary for activation of the mitochondria.

Received for publication, July 30, 2004 , and in revised form, September 8, 2004.

^* This work was supported in part by Grant CUHK 4090/02M from Research Grant Committee of Hong Kong. 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.

The on-line version of this article (available at http://www.jbc.org) contains Fig. S1.

Both authors contributed equally to this work.

^¶ Supported by a postgraduate studentship awarded by The Chinese University of Hong Kong.

^|| Supported by a postdoctoral fellowship awarded by The Chinese University of Hong Kong.

Present address: Dept. of Pharmacy, The Chinese University of Hong Kong, Shatin, New Territory, Hong Kong Special Administrative Region, China.

^|||| To whom correspondence should be addressed: Clinical Immunology Unit, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territory, Hong Kong. Tel.: 852-2632-2588; Fax: 852-2645-0856; E-mail: yiuloonchui{at}cuhk.edu.hk.

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

This article has been cited by other articles:

				B. Schiedlmeier, A. C. Santos, A. Ribeiro, N. Moncaut, D. Lesinski, H. Auer, K. Kornacker, W. Ostertag, C. Baum, M. Mallo, et al. HOXB4's road map to stem cell expansion PNAS, October 23, 2007; 104(43): 16952 - 16957. [Abstract] [Full Text] [PDF]