Estrogen Receptor Inhibits c-Jun-dependent Stress-induced Cell Death by Binding and Modifying c-Jun Activity in Human Breast Cancer Cells

• Published in: The Journal of biological chemistry 2004-02, Vol.279 (8), p.6769-6777
• Main Authors: Qi, Xiaomei, Borowicz, Stanley, Pramanik, Rocky, Schultz, Richard M., Han, Jiahuai, Chen, Guan
• Format: Article
• Language: English
• Subjects: Animals; Breast Neoplasms - metabolism; c-Jun protein; 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
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M311492200

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.