title: The nuclear receptor NR2E1/TLX controls senescence.
abstract: The nuclear receptor NR2E1 (also known as TLX or tailless) controls the self-renewal of neural stem cells (NSCs) and has been implied as an oncogene which initiates brain tumors including glioblastomas. Despite NR2E1 regulating targets like p21(CIP1) or PTEN we still lack a full explanation for its role in NSC self-renewal and tumorigenesis. We know that polycomb repressive complexes also control stem cell self-renewal and tumorigenesis, but so far, no formal connection has been established between NR2E1 and PRCs. In a screen for transcription factors regulating the expression of the polycomb protein CBX7, we identified NR2E1 as one of its more prominent regulators. NR2E1 binds at the CBX7 promoter, inducing its expression. Notably CBX7 represses NR2E1 as part of a regulatory loop. Ectopic NR2E1 expression inhibits cellular senescence, extending cellular lifespan in fibroblasts via CBX7-mediated regulation of p16(INK4a) and direct repression of p21(CIP1). In addition NR2E1 expression also counteracts oncogene-induced senescence. The importance of NR2E1 to restrain senescence is highlighted through the process of knocking down its expression, which causes premature senescence in human fibroblasts and epithelial cells. We also confirmed that NR2E1 regulates CBX7 and restrains senescence in NSCs. Finally, we observed that the expression of NR2E1 directly correlates with that of CBX7 in human glioblastoma multiforme. Overall we identified control of senescence and regulation of polycomb action as two possible mechanisms that can join those so far invoked to explain the role of NR2E1 in control of NSC self-renewal and cancer.
authors.affiliation: Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.|Molecular Oncology Laboratory, CRUK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: O'Loghlen
authors.affiliation: Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors.forename: Nadine
authors.initials: N
authors.lastname: Martin
authors.affiliation: Cell Interactions and Cancer Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krusche
authors.affiliation: Molecular Oncology Laboratory, CRUK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Pemberton
authors.affiliation: Department of Medical Oncology, University Hospital of Navarra, Pamplona, Spain.
authors.forename: Marta M
authors.initials: MM
authors.lastname: Alonso
authors.affiliation: Molecular Oncology Laboratory, CRUK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Hollie
authors.initials: H
authors.lastname: Chandler
authors.affiliation: Molecular Oncology Laboratory, CRUK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Brookes
authors.affiliation: Cell Interactions and Cancer Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors.forename: Simona
authors.initials: S
authors.lastname: Parrinello
authors.affiliation: Molecular Oncology Laboratory, CRUK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Peters
authors.affiliation: Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors.forename: Jesús
authors.initials: J
authors.lastname: Gil
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D058953:Neural Stem Cells / Q000502:physiology; D057093:Orphan Nuclear Receptors; D063150:Polycomb Repressive Complex 1 / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*
chemical_list: C503627:CBX7 protein, human; C088601:NR2E1 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D063150:Polycomb Repressive Complex 1