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The nuclear receptor NR2E1/TLX controls senescence

Oncogene volume 34, pages 4069–4077 (2015)Cite this article

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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 p21CIP1 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 p16INK4a and direct repression of p21CIP1. 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.

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Acknowledgements

We are grateful to G Dharmalingam and S. Khadayate for help with bioinformatics and to I Fariñas and JM Morente for advise and help with NSCs. Core support was received from MRC and grants from MRCT, CRUK and the AICR funded the research in J Gil’s laboratory. N Martin was funded by EMBO and Marie Curie fellowships. J Gil is also supported by the EMBO Young Investigator Program.

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Author notes

  1. A O'Loghlen

    Present address: 6Current address: Epigenetics & Cellular Senescence Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street; London E1 2AT, UK.,

  2. A O'Loghlen and N Martin: These authors contributed equally to this work.

Authors and Affiliations

  1. Cell Proliferation Group, Epigenetic Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, UK

    A O'Loghlen, N Martin, S Brookes & J Gil

  2. Molecular Oncology Laboratory, CRUK London Research Institute, London, UK

    A O'Loghlen, H Pemberton, H Chandler, S Brookes & G Peters

  3. Cell Interactions and Cancer Group, Epigenetic Section, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, UK

    B Krusche & S Parrinello

  4. Department of Medical Oncology, University Hospital of Navarra, Pamplona, Spain

    M M Alonso

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  1. A O'Loghlen
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Correspondence to J Gil.

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O'Loghlen, A., Martin, N., Krusche, B. et al. The nuclear receptor NR2E1/TLX controls senescence. Oncogene 34, 4069–4077 (2015). https://doi.org/10.1038/onc.2014.335

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