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J. Biol. Chem., Vol. 278, Issue 26, 23451-23459, June 27, 2003

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Bcl-2 Protein Is Required for the Adenine/Uridine-rich Element (ARE)-dependent Degradation of Its Own Messenger^*

Annamaria Bevilacqua  , Maria Cristina Ceriani  , Gianfranco Canti , Laura Asnaghi , Roberto Gherzi ¶, Gary Brewer ||, Laura Papucci **, Nicola Schiavone **, Sergio Capaccioli ** and Angelo Nicolin  

From the Department of Pharmacology, University of Milan, 20129 Milan, Italy, the ^¶National Cancer Institute, 16132 Genoa, Italy, the ^||Department of Molecular Genetics and Microbiology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, and the ^**Department of Experimental Pathology and Oncology, University of Florence, 50134 Florence, Italy

We have shown previously that the decay of human bcl-2 mRNA is mediated by an adenine/uridine-rich element (ARE) located in the 3'-untranslated region. Here, we have utilized a non-radioactive cell-free mRNA decay system to investigate the biochemical and functional mechanisms regulating the ARE-dependent degradation of bcl-2 mRNA. Using RNA substrates, mutants, and competitors, we found that decay is specific and ARE-dependent, although maximized by the ARE-flanking regions. In unfractionated extracts from different cell types and in whole cells, the relative enzymatic activity was related to the amount of Bcl-2 protein expressed by the cells at steady state. The degradation activity was lost upon Bcl-2 depletion and was reconstituted by adding recombinant Bcl-2. Ineffective extracts from cells that constitutively do not express Bcl-2 acquire full degradation activity by adding recombinant Bcl-2 protein. We conclude that Bcl-2 is necessary to activate the degradation complex on the relevant RNA target.

Received for publication, October 17, 2002 , and in revised form, March 31, 2003.

^* This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro, Consiglio Nazionale delle Ricerche, Ministero Istruzione, Università e Ricerca, Ministero Sanità. 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Pharmacology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy. Tel.: 39-02-5031-6999; Fax: 39-02-5031-7000; E-mail: angelo.nicolin{at}unimi.it.

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