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M306407200v1
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Papers In Press, published online ahead of print November 25, 2003
J. Biol. Chem, 10.1074/jbc.M306407200
Submitted on June 17, 2003
Revised on November 24, 2003
Accepted on November 25, 2003

The coiled-coil domain is the structural determinant for SIAH-mediated degradation of PML and other TRIM 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

Centro di Biotecnologie, University of Urbino Carlo Bo, FANO 61032

Corresponding Author: mirco.fanelli{at}uniurb.it

Mammalian SIAHs target for proteasome-mediated degradation several factors involved in cell growth and tumorigenesis. Here we show that SIAH-1/2 bind and target for proteasome-mediated degradation the putative tumor suppressor and tripartite-motif (TRIM) family member PML, leading to loss of its transcriptional co-activating properties and 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 are degraded upon mSiah-2 overexpression. Finally, we show that the fusion protein PML-RAR (that retains the coiled coil domain), causing 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 due to 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.


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