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J. Biol. Chem., Vol. 279, Issue 7, 5374-5379, February 13, 2004

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The Coiled-coil Domain Is the Structural Determinant for Mammalian Homologues of Drosophila Sina-mediated Degradation of Promyelocytic Leukemia Protein and Other Tripartite Motif Proteins by the Proteasome^*

Mirco Fanelli¶, Anna Fantozzi, Pasquale De Luca, Sara Caprodossi, Shu-ichi Matsuzawa||, Mitchell A. Lazar**, Pier Giuseppe Pelicci, and Saverio Minucci

From the Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy, Centro di Biotecnologie, Facoltà di Scienze MM.FF.NN., University of Urbino, 61032 Fano, Italy, Department of Biomolecular Sciences and Biotechnologies, Faculty of Biological Sciences, University of Milan, 20132 Milan, Italy, ^||Burnham Institute, La Jolla, California 92037, and ^**Department of Medicine, Genetics, and Biochemistry, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104

Mammalian homologues of Drosophila Seven in Absentia (SIAHs) target for proteasome-mediated degradation several factors involved in cell growth and tumorigenesis. Here we show that SIAH-1/2 binds and targets for proteasome-mediated degradation the putative tumor suppressor and tripartite motif (TRIM) family member PML, leading to the loss of its transcriptional co-activating properties and a reduction in the number of endogenous PML nuclear bodies. Association with PML requires the substrate-binding domain (SBD) of SIAH-1/2 through an interacting surface apparently distinct from those predicted by the structural studies, or shown experimentally to mediate binding to SIAH-associated factors. Within PML, the coiled-coil domain is required for Siah- and proteasome-mediated degradation, and deletions of regions critical for the integrity of this region impair the ability of Siah to trigger PML-RAR degradation. Fusion of the coiled-coil domain to heterologous proteins resulted in the capacity of mSiah-2 to target their degradation. All of the TRIM proteins tested were degraded upon mSiah-2 overexpression. Finally, we show that the fusion protein PML-RAR (that retains the coiled-coil domain), which causes acute promyelocytic leukemias, is also a potential substrate of mSiah-2. As a result of mSiah-2 overexpression and subsequent degradation of the fusion protein, the arrest in hematopoietic differentiation because of expression of PML-RAR is partially rescued. These results identify PML and other TRIMs as new factors post-translationally regulated by SIAH and involve the coiled-coil region of PML and of other SIAH substrates as a novel structural determinant for targeted degradation.

Received for publication, June 17, 2003 , and in revised form, November 24, 2003.

^* 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.

^¶ To whom correspondence should be addressed: Centro di Biotecnologie, University of Urbino "Carlo Bo," Via Campanella 1, 61032 Fano, Italy. Tel.: 39-0721-862832; Fax: 39-0721-862834; E-mail: mirco.fanelli{at}uniurb.it.

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