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J. Biol. Chem. 279 (40): 41504-41511

© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

Antizyme Targets Cyclin D1 for Degradation

A NOVEL MECHANISM FOR CELL GROWTH REPRESSION*

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Ruchi M. Newman{ddagger}§¶, Arian Mobascher¶||**, Ursula Mangold{ddagger}, Chieko Koike{ddagger}{ddagger}{ddagger}, Sri Diah{ddagger}§§, Marion Schmidt||¶¶, Daniel Finley||, , and Bruce R. Zetter{ddagger}||||||

{ddagger}Program in Vascular Biology and Department of Surgery, Children's Hospital, and the ||Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

Abstract: Overproduction of the ornithine decarboxylase (ODC) regulatory protein ODC-antizyme has been shown to correlate with cell growth inhibition in a variety of different cell types. Although the exact mechanism of this growth inhibition is not known, it has been attributed to the effect of antizyme on polyamine metabolism. Antizyme binds directly to ODC, targeting ODC for ubiquitin-independent degradation by the 26 S proteasome. We now show that antizyme induction also leads to degradation of the cell cycle regulatory protein cyclin D1. We demonstrate that antizyme is capable of specific, noncovalent association with cyclin D1 and that this interaction accelerates cyclin D1 degradation in vitro in the presence of only antizyme, cyclin D1, purified 26 S proteasomes, and ATP. In vivo, antizyme up-regulation induced either by the polyamine spermine or by antizyme overexpression causes reduction of intracellular cyclin D1 levels. The antizyme-mediated pathway for cyclin D1 degradation is independent of the previously characterized phosphorylation- and ubiquitination-dependent pathway, because antizyme up-regulation induces the degradation of a cyclin D1 mutant (T286A) that abrogates its ubiquitination. We propose that antizyme-mediated degradation of cyclin D1 by the proteasome may provide an explanation for the repression of cell growth following antizyme up-regulation.

Received for publication June 30, 2004. Revision received July 20, 2004.

* This work was supported by United States Public Health Service Grant CA37393 (to B. R. Z.) and by a grant from Aventis (to B. R. Z. and D. 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.


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

§ Present address: The Burnham Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037.

These authors contributed equally to this work.

** Present address: Rheinische Kliniken Duesseldorf, Dept. of Psychiatry, Duesseldorf University, Bergische Landstr. 2, 40629 Duesseldorf, Germany. Supported by a fellowship from Dr. Mildred Scheel-Stiftung fuer Krebsforschung.

{ddagger}{ddagger} Present address: The 4th Department, Osaka Bioscience Institute, 6-2-4 Furue-dai, Suita, Osaka 562-0874, Japan.

§§ Present address: NIEHS, Maildrop F3-04, Rm. F312, 111 Alexander Dr., Research Triangle Park, NC 27709.

¶¶ Supported by a fellowship from the Deutsche Forschungsgemeinschaft.

|||| To whom correspondence should be addressed: Karp Bldg., Rm. 11.125, Children's Hospital, 300 Longwood Ave., Boston, MA 02115. Tel.: 617-919-2320; Fax: 617-730-0268; E-mail: Bruce.Zetter{at}childrens.harvard.edu.

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