Journal
SCIENCE
Volume 346, Issue 6205, Pages 85-89Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1250255
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Funding
- Swiss Science foundation [SSMBS PASMP3_145764]
- SystemX.ch grant (PhophoNet PPM), the Swiss initiative in systems biology
- Novartis Foundation Medicine
- Boehringer Ingelheim
- Millennium/Takeda
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Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.
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