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Science DOI:10.1126/science.1250255

Prostate cancer. Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer.

Publication TypeJournal Article
Year of Publication2014
AuthorsTheurillat, 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
JournalScience
Volume346
Issue6205
Pages85-9
Date Published2014 Oct 03
ISSN1095-9203
KeywordsBase 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
Abstract

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.

URLhttp://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=25278611
DOI10.1126/science.1250255
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25278611?dopt=Abstract

Alternate JournalScience
PubMed ID25278611
PubMed Central IDPMC4257137
Grant ListT32 GM007753 / GM / NIGMS NIH HHS / United States