SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation.
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.
Westbrook
Thomas F
TF
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.
Hu
Guang
G
Ang
Xiaolu L
XL
Mulligan
Peter
P
Pavlova
Natalya N
NN
Liang
Anthony
A
Leng
Yumei
Y
Maehr
Rene
R
Shi
Yang
Y
Harper
J Wade
JW
Elledge
Stephen J
SJ
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D017124:Conserved Sequence; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000473:pathology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D013379:Substrate Specificity; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*; D000099229:RE1-Silencing Transcription Factor
D012097:Repressor Proteins; D044843:SKP Cullin F-Box Protein Ligases; D014157:Transcription Factors; D025801:Ubiquitin; D044844:beta-Transducin Repeat-Containing Proteins; D000099229:RE1-Silencing Transcription Factor; C471644:BTRC protein, human