Circadian clock protein BMAL1 regulates cellular senescence in vivo

Cell Cycle. 2011 Dec 1;10(23):4162-9. doi: 10.4161/cc.10.23.18381. Epub 2011 Dec 1.

Abstract

Deficiency of the circadian clock transcriptional factor BMAL1 results in the development of premature aging in mice. In agreement with the accelerated aging phenotype, we observed an increase in the number of senescent cells in different tissues (lungs, liver and spleen) of Bmal1(-/-) mice, which suggests the important role of BMAL1 in the control of senescence in vivo. However, no difference in the rate of proliferation and senescence between primary fibroblasts isolated from wild-type and Bmal1(-/-) mice has been detected, suggesting that BMAL1 does not play a significant role in replicative senescence in vitro. BMAL1 deficient fibroblasts had an increased sensitivity to hydrogen peroxide treatment, and reduced sensitivity to DNA damaging anticancer drugs etoposide and daunorubicin. Increased sensitivity of Bmal1(-/-) cells to oxidative stress was p53 independent and correlated with the disrupted regulation of reactive oxygen species (ROS) homeostasis in BMAL1 deficient cells: indeed, circadian oscillations of ROS level can be induced in wild-type but not in Bmal1(-/-) cells. We propose that BMAL1 is important for the regulation of oxidative stress and DNA damage responses, while deregulation of these processes upon BMAL1 deficiency leads to development of stress induced senescence in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Death
  • Cellular Senescence*
  • Circadian Clocks*
  • Culture Media, Serum-Free / metabolism
  • DNA Damage*
  • Daunorubicin / pharmacology
  • Drug Screening Assays, Antitumor
  • Etoposide / pharmacology
  • Fibroblasts / drug effects
  • Gene Expression Regulation, Neoplastic
  • Homeostasis
  • Hydrogen Peroxide / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidative Stress*
  • Primary Cell Culture
  • Reactive Oxygen Species
  • Time Factors

Substances

  • ARNTL Transcription Factors
  • Antineoplastic Agents
  • Arntl protein, mouse
  • Culture Media, Serum-Free
  • Reactive Oxygen Species
  • Etoposide
  • Hydrogen Peroxide
  • Daunorubicin