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J. Biol. Chem., Vol. 279, Issue 19, 20154-20166, May 7, 2004

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Identification of TINO

A NEW EVOLUTIONARILY CONSERVED BCL-2 AU-RICH ELEMENT RNA-BINDING PROTEIN^*

Martino Donnini, Andrea Lapucci¶, Laura Papucci, Ewa Witort, Alain Jacquier||, Gary Brewer**, Angelo Nicolin, Sergio Capaccioli, and Nicola Schiavone¶¶

From the Department of Experimental Pathology and Oncology, School of Medicine, University of Florence, 50134 Florence, Italy, the Department of Pharmacology, School of Medicine, University of Milan, 20129 Milan, Italy, the ^||Unité de Génétique des Interactions Macromoléculaires URA 2171-CNRS Institut Pasteur, F-75724 Paris, France, and the ^**Department of Molecular Genetics, Microbiology and Immunology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

Modulation of mRNA stability by regulatory cis-acting AU-rich elements (AREs) and ARE-binding proteins is an important posttranscriptional mechanism of gene expression control. We previously demonstrated that the 3'-untranslated region of BCL-2 mRNA contains an ARE that accounts for rapid BCL-2 down-regulation in response to apoptotic stimuli. We also demonstrated that the BCL-2 ARE core interacts with a number of ARE-binding proteins, one of which is AU-rich factor 1/heterogeneous nuclear ribonucleoprotein D, known for its interaction with mRNA elements of others genes. In an attempt to search for other BCL-2 mRNA-binding proteins, we used the yeast RNA three-hybrid system assay and identified a novel human protein that interacts with BCL-2 ARE. We refer to it as TINO. The predicted protein sequence of TINO reveals two amino-terminal heterogeneous nuclear ribonucleoprotein K homology motifs for nucleic acid binding and a carboxyl-terminal RING domain, endowed with a putative E3 ubiquitin-protein ligase activity. In addition the novel protein is evolutionarily conserved; the two following orthologous proteins have been identified with protein-protein BLAST: posterior end mark-3 (PEM-3) of Ciona savignyi and muscle excess protein-3 (MEX-3) of Caenorhabditis elegans. Upon binding, TINO destabilizes a chimeric reporter construct containing the BCL-2 ARE sequence, revealing a negative regulatory action on BCL-2 gene expression at the posttranscriptional level.

Received for publication, December 23, 2003 , and in revised form, February 2, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF458084.

^* This work was supported by grants from the Italian Association for Cancer Research (AIRC), Ministero della Università e Ricerca (MIUR), Ente Cassa di Risparmio di Firenze, and Consiglio Nazionale delle Ricerche/MIUR (Grant Progetto Finalizzato Oncologia, Ministero della Salute) (to S. C.) and by National Institutes of Health Grant CA 52443 (to G. B.). 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.

^¶ Recipient of a fellowship from Fullbright and Fondazione Italiana per la Ricerca sul Cancro.

To whom correspondence may be addressed. Tel.: 390554282309; Fax: 390554282333; E-mail: sergio{at}unifi.it. ¶¶ To whom correspondence may be addressed. Tel.: 390554282309; Fax: 390554282333; E-mail: nicola{at}unifi.it.

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