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

J. Biol. Chem., Vol. 282, Issue 36, 26202-26209, September 7, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/36/26202    most recent M700776200v1 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 Arora, V. Articles by Korneluk, R. G. Search for Related Content PubMed PubMed Citation Articles by Arora, V. Articles by Korneluk, R. G. Social Bookmarking                      What's this?

Degradation of Survivin by the X-linked Inhibitor of Apoptosis (XIAP)-XAF1 Complex^*

From the Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario K1H 8L1, Canada

X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a putative tumor suppressor in which expression is significantly reduced in human cancer cell lines and primary tumors. The proapoptotic effects of XAF1 have been attributed to both caspase-dependent and -independent means. In particular, XAF1 reverses the anti-caspase activity of XIAP, a physiological inhibitor of apoptosis. We further investigated the function of XAF1 by examining its relationship with other IAPs. Immunoprecipitation studies indicate that XAF1 binds to XIAP, cIAP1, cIAP2, Livin, TsIAP, and NAIP but not Survivin, an IAP that prevents mitotic catastrophe and in which antiapoptotic activity is exerted through direct XIAP interaction and stabilization. We found that overexpressed XAF1 down-regulates the protein expression of Survivin. Under these conditions, Survivin expression was restored in the presence of the proteasome inhibitor MG132 or a XIAP RING mutant that is defective in ubiquitin-protein isopeptide ligase (E3) activity, suggesting that XAF1 interaction activates E3 activity of XIAP and targets Survivin by direct ubiquitination. In addition, RNA interference targeting endogenous XIAP protected Survivin degradation by XAF1. Furthermore, interferon--mediated XAF1 induction promoted formation of an endogenous XIAP-XAF1-Survivin complex. This complex facilitated Survivin degradation, which was prevented in XAF1^-/- stable clones. Altogether, our study demonstrates that XAF1 mediates Survivin down-regulation through a complex containing XIAP, supporting dual roles for XAF1 in apoptosis and mitotic catastrophe.

Received for publication, January 26, 2007 , and in revised form, June 22, 2007.

^* This work was supported by funds from the Canadian Institutes of Health Research (CIHR) and the Howard Hughes Medical Institute (HHMI) (to R. G. K.). 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 These two authors contributed equally to this work.

² Recipient of a Michael Cuccione Foundation and CIHR Institute of Cancer Research postdoctoral fellowship.

³ Recipient of a National Sciences and Engineering Research Council of Canada postdoctoral fellowship.

⁴ To whom correspondence should be addressed: Apoptosis Research Centre, Children's Hospital of Eastern Ontario, Research Inst., 401 Smyth Rd., Ottawa, Ontario K1H 8L1, Canada. Tel.: 613-738-3281; Fax: 613-738-4833; E-mail: bob{at}mgcheo.med.uottawa.ca.

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

This article has been cited by other articles:

				M. D. Siegelin, D. E. Reuss, A. Habel, A. Rami, and A. von Deimling Quercetin promotes degradation of survivin and thereby enhances death-receptor-mediated apoptosis in glioma cells Neuro-oncol, January 1, 2009; 11(2): 122 - 131. [Abstract] [Full Text] [PDF]

				M. D. Siegelin, D. E. Reuss, A. Habel, C. Herold-Mende, and A. von Deimling The flavonoid kaempferol sensitizes human glioma cells to TRAIL-mediated apoptosis by proteasomal degradation of survivin Mol. Cancer Ther., November 1, 2008; 7(11): 3566 - 3574. [Abstract] [Full Text] [PDF]

				H. H. Cheung, S. Plenchette, C. J. Kern, D. J. Mahoney, and R. G. Korneluk The RING Domain of cIAP1 Mediates the Degradation of RING-bearing Inhibitor of Apoptosis Proteins by Distinct Pathways Mol. Biol. Cell, July 1, 2008; 19(7): 2729 - 2740. [Abstract] [Full Text] [PDF]

				C. M. Connell, R. Colnaghi, and S. P. Wheatley Nuclear Survivin Has Reduced Stability and Is Not Cytoprotective J. Biol. Chem., February 8, 2008; 283(6): 3289 - 3296. [Abstract] [Full Text] [PDF]