The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling
| Autor: | Xingjie Ma, Clotilde Raynard, Pierre-Antoine Defossez, Marine Warnier, David Bernard, Olivier Kirsh, Mylène Ferrand, Nadine Martin |
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| Přispěvatelé: | Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), ATMEL [Rousset], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
p53
0301 basic medicine Senescence Aging senescence Transcription Genetic DNA damage [SDV]Life Sciences [q-bio] chemistry.chemical_element Calcium Biology Endoplasmic Reticulum Cell Line 03 medical and health sciences Humans Inositol 1 4 5-Trisphosphate Receptors nuclear receptor Calcium Signaling RNA Small Interfering Transcription factor ComputingMilieux_MISCELLANEOUS Cellular Senescence Chelating Agents Calcium signaling Original Paper Gene knockdown Retinoid X Receptor alpha calcium Retinoid X receptor alpha ITPR2 Cell Biology Mitochondria Cell biology Repressor Proteins 030104 developmental biology chemistry Nuclear receptor Calcium Channels Tumor Suppressor Protein p53 Reactive Oxygen Species DNA Damage |
| Zdroj: | Aging Cell Aging Cell, Wiley Open Access, 2018, 17 (6), pp.e12831. ⟨10.1111/acel.12831⟩ |
| ISSN: | 1474-9718 |
| DOI: | 10.1111/acel.12831⟩ |
| Popis: | International audience; Calcium signaling is emerging as a key pathway controlling cellular senescence, astable cell proliferation arrest playing a fundamental role in pathophysiological conditions, such as embryonic development, wound healing, cancer, and aging. However, how calcium signaling is regulated is still only partially understood. The inositol 1, 4, 5‐trisphosphate receptor type 2 (ITPR2), an endoplasmic reticulum calcium release channel, was recently shown to critically contribute to the implementation of senescence, but how ITPR2 expression is controlled is unclear. To gain insights into the regulation of ITPR2 expression, we performed an siRNA screen targeting160 transcription factors and epigenetic regulators. Interestingly, we discovered that the retinoid X receptor alpha (RXRA), which belongs to the nuclear receptor family,represses ITPR2 expression and regulates calcium signaling though ITPR2 and themitochondrial calcium uniporter (MCU). Knockdown of RXRA induces the production of reactive oxygen species (ROS) and DNA damage via the ITPR2‐MCU calcium signaling axis and consequently triggers cellular senescence by activating p53,whereas RXRA overexpression decreases DNA damage accumulation and then delays replicative senescence. Altogether, our work sheds light on a novel mechanism controlling calcium signaling and cellular senescence and provides new insights into the role of nuclear receptors. |
| Databáze: | OpenAIRE |
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