Westbrook TF, Hu G, Ang XL, Mulligan P, Pavlova NN, Liang A et al. SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature 452: 370-374

Howard Hughes Medical Institute, Department of Genetics, Harvard Partners Center for Genetics and Genomics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 04/2008; 452(7185):370-4. DOI: 10.1038/nature06780
Source: PubMed


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 beta-TRCP (SCF(beta-TRCP)) as an E3 ubiquitin ligase responsible for REST degradation. beta-TRCP binds and ubiquitinates REST and controls its stability through a conserved phospho-degron. During neural differentiation, REST is degraded in a beta-TRCP-dependent manner. beta-TRCP is required for proper neural differentiation only in the presence of REST, indicating that beta-TRCP facilitates this process through degradation of REST. Conversely, failure to degrade REST attenuates differentiation. Furthermore, we find that beta-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 beta-TRCP-driven transformation and the beta-TRCP-REST axis is a new regulatory pathway controlling neurogenesis.

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Available from: Yang Shi, Sep 05, 2014
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    • "Mass spectrometry revealed that PLK1 phosphorylates REST on serine 1030 (Figure 2K and Figure S4). Although this analysis cannot definitively exclude phosphorylation by PLK1 on other phospho-sites within the REST C terminus (Guardavaccaro et al., 2008; Westbrook et al., 2008), it does indicate that PLK1 phosphorylates the critical serine within the REST phospho-degron (S1030) that is required for SCF bTRCP -binding, ubiquitylation , and degradation (Westbrook et al., 2008). Collectively, these data indicate that PLK1 directly phosphorylates the REST phospho-degron and is a potent regulator of REST stability. "
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    ABSTRACT: Defining the molecular networks that drive breast cancer has led to therapeutic interventions and improved patient survival. However, the aggressive triple-negative breast cancer subtype (TNBC) remains recalcitrant to targeted therapies because its molecular etiology is poorly defined. In this study, we used a forward genetic screen to discover an oncogenic network driving human TNBC. SCYL1, TEX14, and PLK1 ("STP axis") cooperatively trigger degradation of the REST tumor suppressor protein, a frequent event in human TNBC. The STP axis induces REST degradation by phosphorylating a conserved REST phospho-degron and bridging REST interaction with the ubiquitin-ligase βTRCP. Inhibition of the STP axis leads to increased REST protein levels and impairs TNBC transformation, tumor progression, and metastasis. Expression of the STP axis correlates with low REST protein levels in human TNBCs and poor clinical outcome for TNBC patients. Our findings demonstrate that the STP-REST axis is a molecular driver of human TNBC. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 11/2014; 9(4):1318-32. DOI:10.1016/j.celrep.2014.10.011 · 8.36 Impact Factor
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    • "rial Fig . S2C ) , suggesting that p120 - catenin modulates REST – CoREST destruction , which fits with published studies of REST ubiquitylation ( Westbrook et al . , 2008 ) . Given that p120 - catenin isoform 1 is likewise negatively regulated by ubiquitylation ( Hong et al . , 2010 ) , and both it and REST share the same E3 ligase ( b - TrCP ) ( Westbrook et al . , 2008 ) , REST destruction might be enhanced when associated with p120 - catenin ."
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    ABSTRACT: While the canonical-Wnt pathway and beta-catenin have been extensively studied, less is known about p120-catenin in the nuclear compartment. We report that p120-catenin binds and negatively regulates REST and CoREST, a repressive transcriptional complex having diverse developmental and pathologic roles. Using mouse embryonic stem cells (mESCs), mammalian cell lines, Xenopus embryos, and in vitro systems, we find that p120 directly binds REST/CoREST, displacing the complex from established gene-targets to permit their transcriptional activation. Importantly, p120 levels further modulate the mRNA and protein levels of Oct4, Nanog, and Sox2, and have an impact upon the differentiation of mESCs towards neural fates. In assessing potential upstream inputs to this novel p120-REST/CoREST pathway, REST gene targets were found to respond to the level of E-cadherin, with evidence suggesting that p120-catenin transduces such signals between E-cadherin and the nucleus. In summary, we provide the first evidence for a direct upstream modulator/pathway regulating REST/CoREST, and reveal a significant role of p120-catenin in the modulation of stem cell differentiation.
    Journal of Cell Science 07/2014; 127(18). DOI:10.1242/jcs.151944 · 5.43 Impact Factor
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    • "We demonstrated that Jade- 2-mediated LSD1 elimination plays an important role in ESC differentiation toward the neural lineage, during which process Jade-2 is required to relieve the braking function of LSD1 on neural commitment. Significantly, our discovery of Jade-2 as an E3 ubiquitin ligase for LSD1, which is different from the E3 ubiquitin ligase SCF b-TRCP for REST (Westbrook et al., 2008), adds a clue to the understanding of the suggestion that LSD1 might regulate a distinct neural transcriptome from REST in ESCs (Adamo et al., 2011; Whyte et al., 2012). Moreover , we demonstrated that the Jade-2-LSD1 pathway plays a critical role in cortical development and neuroectoderm induction , highlighting the importance of the Jade-2-LSD1 pathway in a broad scope of nervous system development. "
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    ABSTRACT: Histone H3K4 demethylase LSD1 plays an important role in stem cell biology, especially in the maintenance of the silencing of differentiation genes. However, how the function of LSD1 is regulated and the differentiation genes are derepressed are not understood. Here, we report that elimination of LSD1 promotes embryonic stem cell (ESC) differentiation toward neural lineage. We showed that the destabilization of LSD1 occurs posttranscriptionally via the ubiquitin-proteasome pathway by an E3 ubiquitin ligase, Jade-2. We demonstrated that Jade-2 is a major LSD1 negative regulator during neurogenesis in vitro and in vivo in both mouse developing cerebral cortices and zebra fish embryos. Apparently, Jade-2-mediated degradation of LSD1 acts as an antibraking system and serves as a quick adaptive mechanism for re-establishing epigenetic landscape without more laborious transcriptional regulations. As a potential anticancer strategy, Jade-2-mediated LSD1 degradation could potentially be used in neuroblastoma cells to induce differentiation toward postmitotic neurons.
    Molecular Cell 07/2014; 55(3). DOI:10.1016/j.molcel.2014.06.006 · 14.02 Impact Factor
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