1. Howard Hughes Medical Institute, Department of Genetics, Harvard Partners Center for Genetics and Genomics,
2. Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
3. Department of Stem Cell and Regenerative Biology, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA
4. Present address: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
5. These authors contributed equally to this work.

Correspondence to: J. Wade Harper²Stephen J. Elledge¹ Correspondence and requests for materials should be addressed to S.J.E. (Email: selledge@genetics.med.harvard.edu) or J.W.H. (Email: wade_harper@hms.harvard.edu).

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^{1, 2, 3}. Recently, REST was identified as a human tumour suppressor in epithelial tissues⁴, 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 -TRCP (SCF^-TRCP) as an E3 ubiquitin ligase responsible for REST degradation. -TRCP binds and ubiquitinates REST and controls its stability through a conserved phospho-degron. During neural differentiation, REST is degraded in a -TRCP-dependent manner. -TRCP is required for proper neural differentiation only in the presence of REST, indicating that -TRCP facilitates this process through degradation of REST. Conversely, failure to degrade REST attenuates differentiation. Furthermore, we find that -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 -TRCP-driven transformation and the -TRCP–REST axis is a new regulatory pathway controlling neurogenesis.

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