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, Saverio Minucci

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)5374-5379
Number of pages6
JournalJournal of Biological Chemistry
Volume279
Issue number7
DOIs
Publication statusPublished - Feb 13 2004

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Proteasome Endopeptidase Complex
Drosophila
Degradation
Acute Promyelocytic Leukemia
Proteins
Aptitude
Fusion reactions
Proteolysis
Carcinogenesis
Substrates
Growth
Cell growth
Promyelocytic Leukemia Protein
Tripartite Motif Proteins
Neoplasms
Tumors

ASJC Scopus subject areas

  • Biochemistry

Cite this

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. / Fanelli, Mirco; Fantozzi, Anna; De Luca, Pasquale; Caprodossi, Sara; Matsuzawa, Shu Ichi; Lazar, Mitchell A.; Giuseppe Pelicci, Pier; Minucci, Saverio.

In: Journal of Biological Chemistry, Vol. 279, No. 7, 13.02.2004, p. 5374-5379.

Research output: Contribution to journalArticle

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AU - Fantozzi, Anna

AU - De Luca, Pasquale

AU - Caprodossi, Sara

AU - Matsuzawa, Shu Ichi

AU - Lazar, Mitchell A.

AU - Giuseppe Pelicci, Pier

AU - Minucci, Saverio

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