SCFβ-TRCP controls oncogenic transformation and neural differentiation through REST degradation

Thomas F. Westbrook, Guang Hu, Xiaolu L. Ang, Peter Mulligan, Natalya N. Pavlova, Anthony Liang, Yumei Leng, Rene Maehr, Yang Shi, J. Wade Harper, Stephen J. Elledge

Research output: Contribution to journalArticle

232 Scopus citations

Abstract

The RE1-silencing transcription factor (REST, also known as NRSF) is a master repressor of neuronal gene expression and neuronal programmes in non-neuronal lineages. Recently, REST was identified as a human tumour suppressor in epithelial tissues, suggesting that its regulation may have important physiological and pathological consequences. However, the pathways controlling REST have yet to be elucidated. Here we show that REST is regulated by ubiquitin-mediated proteolysis, and use an RNA interference (RNAi) screen to identify a Skp1-Cul1-F-box protein complex containing the F-box protein β-TRCP (SCFβ-TRCP) as an E3 ubiquitin ligase responsible for REST degradation. β-TRCP binds and ubiquitinates REST and controls its stability through a conserved phospho-degron. During neural differentiation, REST is degraded in a β-TRCP-dependent manner. β-TRCP is required for proper neural differentiation only in the presence of REST, indicating that β-TRCP facilitates this process through degradation of REST. Conversely, failure to degrade REST attenuates differentiation. Furthermore, we find that β-TRCP overexpression, which is common in human epithelial cancers, causes oncogenic transformation of human mammary epithelial cells and that this pathogenic function requires REST degradation. Thus, REST is a key target in β-TRCP-driven transformation and the β-TRCP-REST axis is a new regulatory pathway controlling neurogenesis.

Original languageEnglish (US)
Pages (from-to)370-374
Number of pages5
JournalNature
Volume452
Issue number7185
DOIs
StatePublished - Mar 20 2008

ASJC Scopus subject areas

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    Westbrook, T. F., Hu, G., Ang, X. L., Mulligan, P., Pavlova, N. N., Liang, A., Leng, Y., Maehr, R., Shi, Y., Harper, J. W., & Elledge, S. J. (2008). SCFβ-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature, 452(7185), 370-374. https://doi.org/10.1038/nature06780