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

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 lineages1,2,3. 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 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.

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Figure 1: Identification of β-TRCP and FBW4 ubiquitin ligases as regulators of REST stability.
Figure 2: A conserved phospho-degron in REST is required for regulation by β-TRCP.
Figure 3: β-TRCP targets REST during oncogenic transformation.
Figure 4: The β-TRCP-REST pathway controls neural differentiation.

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Acknowledgements

We thank G. Mandel and R. Truant for providing REST-C antibodies and mRFP-REST cDNA, respectively. We thank J. Luo, D. Nguyen and D. Lee for suggestions and reading of the manuscript. We are grateful to R. Mulligan, A. Balazs, J. Jin, M. Sheng and V. Dixit for providing reagents, and to D. Guardavaccaro and M. Pagano for communicating results before publication. T.F.W. is a fellow of the Susan G. Komen for the Cure. G.H. is a Helen Hay Whitney post-doctoral fellow. X.L.A. is supported by a National Institutes of Health predoctoral fellowship. This work was supported by National Institutes of Health grants to Y.S., J.W.H., and a US Army Innovator Award to S.J.E. S.J.E. is an Investigator with the Howard Hughes Medical Institute.

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Correspondence to J. Wade Harper or Stephen J. Elledge.

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Westbrook, T., Hu, G., Ang, X. et al. SCFβ-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature 452, 370–374 (2008). https://doi.org/10.1038/nature06780

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