Journal article
Acetylation Directs Survivin Nuclear Localization to Repress STAT3 Oncogenic Activity
The Journal of biological chemistry, v 285(46), pp 36129-36137
12 Nov 2010
PMID: 20826784
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The multiple functions of the oncofetal protein survivin are dependent on its selective expression patterns within immunochemically distinct subcellular pools. The mechanism by which survivin localizes to these compartments, however, is only partly understood. Here we show that nuclear accumulation of survivin is promoted by CREB-binding protein (CBP)-dependent acetylation on lysine 129 (129K, Lys-129). We demonstrate a mechanism by which survivin acetylation at this position results in its homodimerization, while deacetylation promotes the formation of survivin monomers that heterodimerize with CRM1 and facilitate its nuclear export. Using proteomic analysis, we identified the oncogenic transcription factor STAT3 as a binding partner of nuclear survivin. We show that acetylated survivin binds to the N-terminal transcriptional activation domain of the STAT3 dimer and represses STAT3 transactivation of target gene promoters. Using multiplex PCR and DNA sequencing, we identified a single-nucleotide polymorphism (A → G) at Lys-129 that exists as a homozygous mutation in a neuroblastoma cell line and corresponds with a defect in survivin nuclear localization. Our results demonstrate that the dynamic equilibrium between survivin acetylation and deacetylation at amino acid 129 determines its interaction with CRM1, its subsequent subcellular localization, and its ability to inhibit STAT3 transactivation, providing a potential route for therapeutic intervention in STAT3-dependent tumors.
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Details
- Title
- Acetylation Directs Survivin Nuclear Localization to Repress STAT3 Oncogenic Activity
- Creators
- Haijuan Wang - Rhode Island HospitalMichael P. Holloway - Rhode Island HospitalLi Ma - Brown UniversityZachary A. Cooper - Rhode Island HospitalMatthew Riolo - Rhode Island HospitalAyman Samkari - Rhode Island HospitalKojo S. J. Elenitoba-Johnson - University of MichiganY. Eugene Chin - Rhode Island HospitalRachel A. Altura - Rhode Island Hospital
- Publication Details
- The Journal of biological chemistry, v 285(46), pp 36129-36137
- Publisher
- American Society for Biochemistry and Molecular Biology
- Grant note
- P20RR017695-6A2 / National Institutes of Health
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics
- Web of Science ID
- WOS:000283845300089
- Scopus ID
- 2-s2.0-78149238747
- Other Identifier
- 991021838288104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology