title: TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation.
abstract: REST/NRSF is a transcriptional repressor of neuronal genes that has been implicated in development and cancer. In epithelial tissues, REST acts as a tumor suppressor and in breast cancer, loss of REST is associated with disease recurrence and poor prognosis. Here, we identify TSPYL2 (also known as CDA1 and DENTT) as a novel component of the REST protein complex. We show that REST and TSPYL2 are regulators of TGFβ signaling and that cell-cycle arrest induced by TGFβ requires both REST and TSPYL2. Importantly, knockdown of REST or TSPYL2 resulted in transformation of human mammary epithelial cells. Mechanistically, we demonstrate that the TSPYL2/REST complex promotes TGFβ signaling by repressing the expression of genes, such as the proto-oncogene neurotrophic tyrosine kinase receptor C (TrkC). These data provide insight into the role of REST as a tumor suppressor in epithelial tissues through the regulation of the TGFβ pathway.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Epping
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lunardi
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Nachmani
authors.affiliation: Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Castillo-Martin
authors.affiliation: Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Thin
authors.affiliation: Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Cordon-Cardo
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: P P
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins; D006801:Humans; D013058:Mass Spectrometry; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D000099229:RE1-Silencing Transcription Factor; C000715470:MAS1 protein, human; C432963:TSPYL2 protein, human