|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Theurillat, J-PP, Udeshi, ND, Errington, WJ, Svinkina, T, Baca, SC, Pop, M, Wild, PJ, Blattner, M, Groner, AC, Rubin, MA, Moch, H, Privé, GG, Carr, SA, Garraway, LA|
|Date Published||2014 Oct 03|
|Keywords||Base Sequence, Binding Sites, Carcinogenesis, Carrier Proteins, Cell Line, Tumor, Chromosomal Proteins, Non-Histone, Humans, Male, Molecular Sequence Data, Mutation, Neoplasm Invasiveness, Nuclear Proteins, Oncogene Proteins, Prostatic Neoplasms, Proteasome Endopeptidase Complex, Repressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination|
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.
|PubMed Central ID||PMC4257137|
|Grant List||T32 GM007753 / GM / NIGMS NIH HHS / United States|