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SIRT1 regulates apoptosis and Nanog expression in mouse embryonic stem cells by controlling p53 subcellular

Myung-Kwan Han1, Eun-Kyung Song, Ying Guo

  • 1Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202-5181, USA. iamtom@chonbuk.ac.kr

Cell Stem Cell
|March 29, 2008
PubMed

Insights

Sirtuin 1 (SIRT1) controls reactive oxygen species (ROS) sensitivity in mouse embryonic stem cells (mESCs). SIRT1 promotes ROS-induced apoptosis by blocking p53 nuclear entry, impacting mESC maintenance.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Stem Cell Biology

Background:

  • The tumor suppressor p53 has dual roles: nuclear p53 transactivates genes, while cytoplasmic p53 induces apoptosis independently of gene transactivation.
  • Sirtuin 1 (SIRT1), a deacetylase, inhibits p53-mediated gene transactivation, but its regulation of p53's diverse functions remains unclear.

Purpose of the Study:

  • To investigate how SIRT1 regulates the distinct functions of p53 in response to reactive oxygen species (ROS).
  • To elucidate the role of endogenous ROS in mouse embryonic stem cell (mES) maintenance and apoptosis.

Main Methods:

  • Utilized wild-type and SIRT1-deficient (SIRT1(-/-)) mouse embryonic stem (mES) cells.
  • Induce endogenous reactive oxygen species (ROS) through antioxidant-free culture conditions.
  • Tracked p53 localization (nuclear vs. mitochondrial) and BAX translocation using microscopy.
  • Assessed Nanog gene expression levels.

Main Results:

  • SIRT1 blocks the nuclear translocation of cytoplasmic p53 in response to endogenous ROS in mES cells.
  • Endogenous ROS trigger apoptosis in wild-type mES cells via mitochondrial translocation of p53 and BAX.
  • In SIRT1(-/-) mES cells, ROS induce nuclear p53 translocation, inhibit Nanog expression, and prevent apoptosis.

Conclusions:

  • SIRT1 confers sensitivity to ROS in mES cells by promoting p53-mediated apoptosis.
  • SIRT1 inhibits the p53-mediated suppression of Nanog expression, suggesting a role in maintaining pluripotency.
  • Endogenous ROS levels are critical for the maintenance of mES cells in culture.

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