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J. Biol. Chem., Vol. 280, Issue 27, 25802-25810, July 8, 2005

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Regulation of the Proapoptotic ARTS Protein by Ubiquitin-mediated Degradation^*

Rona Lotan, Asaf Rotem, Hedva Gonen¶, John P. M. Finberg||, Stav Kemeny, Hermann Steller**, Aaron Ciechanover¶, and Sarit Larisch

From the Apoptosis and Cancer Research Laboratory, Pathology Department, Rambam Medical Center, Bat-Galim, Haifa 31096, Israel,^|| Pharmacology Unit, Rappaport Faculty of Medicine, Technion, P.O.B. 9649, Haifa 31096, Israel,^¶ Department of Biochemistry and the Rappaport Institute for Research in the Medical Sciences, The Bruce Rappaport Faculty of Medicine, Haifa 31096, Israel, and the ^**Howard Hughes Medical Institute, Strang Laboratory of Cancer Research, The Rockefeller University, New York, New York 10021

ARTS is a mitochondrial protein that promotes apoptosis induced by a variety of proapoptotic stimulators. ARTS induces apoptosis, at least in part, through binding to and antagonizing IAPs (inhibitors of apoptosis proteins). As a result of ARTS binding to IAPs, caspase inhibition is removed and apoptosis can be executed. Here we show that high cellular levels of ARTS protein sensitize cells toward apoptosis. Accordingly, in healthy cells ARTS levels are kept low through constant ubiquitin-mediated degradation. Upon proapoptotic stimuli, the ubiquitination process is inhibited, resulting in increased levels of ARTS. Increased ARTS in turn leads to a decrease of Bcl-2 and Bcl-x_L protein levels, cytochrome c release from mitochondria and apoptosis.

Received for publication, February 22, 2005 , and in revised form, April 11, 2005.

^* This work was supported in part by a Fogarty International Research Collaboration Award (FIRCA) from the National Institutes of Health (to H. S. and S. L.), Grant 486-02 from the Israel Science Foundation (to S. L.), and the Chutick Fund (to Technion, S. L., and J. P. M. F.). 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.

These authors contributed equally to this work.

An Investigator with the Howard Hughes Medical Institute.

To whom correspondence should be addressed: Apoptosis and Cancer Research Laboratory, Pathology Dept., Rambam Medical Center, Haifa 31096, Israel. Tel.: 972-4-8543464; Fax: 972-4-8542877; E-mail: s_larisch{at}rambam.health.gov.il.

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