The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

Aging Cell. 2018 Dec;17(6):e12831. doi: 10.1111/acel.12831. Epub 2018 Sep 14.


Calcium signaling is emerging as a key pathway controlling cellular senescence, a stable 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 targeting 160 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 the mitochondrial 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.

Keywords: ITPR2; calcium; nuclear receptor; p53; senescence.

MeSH terms

  • Calcium / metabolism
  • Calcium Channels / metabolism
  • Calcium Signaling* / drug effects
  • Cell Line
  • Cellular Senescence* / drug effects
  • Chelating Agents / pharmacology
  • DNA Damage
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism
  • Repressor Proteins / metabolism
  • Retinoid X Receptor alpha / metabolism*
  • Transcription, Genetic / drug effects
  • Tumor Suppressor Protein p53 / metabolism


  • Calcium Channels
  • Chelating Agents
  • ITPR2 protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • RNA, Small Interfering
  • RXRA protein, human
  • Reactive Oxygen Species
  • Repressor Proteins
  • Retinoid X Receptor alpha
  • Tumor Suppressor Protein p53
  • mitochondrial calcium uniporter
  • Calcium