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

J Biol Chem. 2004 Feb 20;279(8):6769-77. doi: 10.1074/jbc.M311492200. Epub 2003 Nov 24.

Abstract

c-Jun, a major component of the AP-1 transcription factor, is either pro- or anti-apoptotic with cellular determinants unknown. Nuclear estrogen receptor (ER), on the other hand, regulates gene expression through both estrogen response elements and AP-1. Here we show that stress stimulates c-Jun phosphorylation and AP-1 activity in both ER+ and ER- human breast cancer cells and only induces cell death in ER- cells, indicating a determinant role of ER in c-Jun/AP-1 activity. The inhibitory effect of ER in stress-induced cell death is confirmed by ER transfection into ER- cells. Furthermore, inhibition of c-Jun activation by a dominant negative c-Jun blocks AP-1 activity in ER+ cells and attenuates stress-induced cell death but not AP-1 activity in ER- cells, suggesting that the c-Jun/AP-1 activity has distinct properties depending on ER status. ER was shown to inhibit stress-induced cell death through its physical interaction with c-Jun. This is because ER binds c-Jun in breast cancer cells, stress treatment further increases the ER-bound phosphorylated c-Jun, and the c-Jun binding-deficient ER mutant fails to protect stress-induced cell death. Together, our studies reveal a novel function of ER in stress response by modification of c-Jun activity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Death
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Separation
  • DNA, Complementary / metabolism
  • Female
  • Flow Cytometry
  • Genes, Dominant
  • Humans
  • Immunoblotting
  • Luciferases / metabolism
  • MAP Kinase Kinase 6
  • Mice
  • Mice, Nude
  • Models, Biological
  • Models, Genetic
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Receptors, Estrogen / metabolism
  • Receptors, Estrogen / physiology*
  • Time Factors
  • Transcription, Genetic
  • Transfection

Substances

  • DNA, Complementary
  • Proto-Oncogene Proteins c-jun
  • Receptors, Estrogen
  • Luciferases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • MAP Kinase Kinase 6
  • MAP2K6 protein, human
  • Map2k6 protein, mouse