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Estrogen receptor inhibits c-Jun-dependent stress-induced cell death by binding and modifying c-Jun activity in human

Xiaomei Qi1, Stanley Borowicz, Rocky Pramanik

  • 1Department of Radiation Oncology and Division of Biochemistry of the Department of Cell Biology, Neurobiology, and Anatomy, Loyola University of Chicago, Maywood, Illinois 05163.

The Journal of Biological Chemistry
|November 26, 2003
PubMed

Insights

Estrogen receptor (ER) determines if stress-induced c-Jun/AP-1 activation leads to cell death in breast cancer. ER inhibits cell death by interacting with phosphorylated c-Jun, revealing a novel role in stress response.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • c-Jun, a component of the AP-1 transcription factor, can be pro- or anti-apoptotic, but cellular determinants are unknown.
  • Nuclear estrogen receptor (ER) regulates gene expression and interacts with AP-1.
  • The role of ER in stress-induced apoptosis mediated by c-Jun/AP-1 is unclear.

Purpose of the Study:

  • To investigate the role of estrogen receptor (ER) status in stress-induced c-Jun/AP-1 activity and apoptosis in human breast cancer cells.
  • To elucidate the mechanism by which ER influences c-Jun/AP-1-mediated cell death.
  • To identify novel functions of ER in cellular stress response.

Main Methods:

  • Western blotting to assess c-Jun phosphorylation and AP-1 activity.
  • Cell viability assays to measure stress-induced cell death.
  • ER transfection into ER- cells.
  • Dominant-negative c-Jun transfection.
  • Co-immunoprecipitation to study ER-c-Jun interaction.
  • Analysis of ER mutants deficient in c-Jun binding.

Main Results:

  • Stress stimulates c-Jun phosphorylation and AP-1 activity in both ER-positive (ER+) and ER-negative (ER-) breast cancer cells.
  • Stress-induced cell death occurs only in ER- cells, indicating ER's inhibitory role.
  • ER transfection into ER- cells confers resistance to stress-induced cell death.
  • Inhibition of c-Jun activation attenuates stress-induced cell death in ER- cells but not AP-1 activity.
  • ER physically interacts with c-Jun, and this interaction is crucial for inhibiting stress-induced cell death.

Conclusions:

  • Estrogen receptor (ER) status is a critical determinant of apoptosis in response to stress via the c-Jun/AP-1 pathway in breast cancer.
  • ER inhibits stress-induced cell death by directly binding to and modulating the activity of phosphorylated c-Jun.
  • This study reveals a novel mechanism for ER in regulating cellular stress response and apoptosis, with implications for breast cancer treatment.

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