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

Xiaomei Qi,Stanley Borowicz,Rocky Pramanik,Richard M Schultz,Jiahuai Han,Guan Chen

doi:10.1074/jbc.m311492200

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.

Highlights

C-Jun, a major component of AP-1 transcription factor, is activated by both mitogenic and stress signals downstream of ERK1, JNK (c-Jun Nterminal kinase), and p38 MAPKs through phosphorylation and trans-activation
ERK, on the other hand, activates AP-1 through phosphorylation of ternary complex factors, leading to the induction of fos genes in response to mitogenic signaling [2]. p38 MAPK stimulates c-jun gene expression by activation of ATF-2 or MEF2s [3, 4], and our recent results demonstrated that the p38 pathways can regulate c-Jun expression and phosphorylation in human breast cancer cells [5, 6]. c-Jun serves as a central transcription factor downstream of three major MAPK pathways (ERK, JNK, and p38) and converts various extracellular signals into target gene expressions and distinct biological responses. c-Jun phosphorylation in neurons and fibroblasts is linked to apoptosis activated by JNK and p38 stress MAPKs [7,8,9]
Stress Induces Cell Death in ERϪ but Not in ERϩ Human Breast Cancer Cells—To examine whether endogenous estrogen receptor (ER) expression may affect stress-induced cell death, ERϪ human breast cancer 468 and ERϩ MCF-7 cells were infected with adenovirus expressing a constitutively active p38 stress kinase activator MKK6 or the adenovirus vector

Summary

Introduction

C-Jun, a major component of AP-1 transcription factor, is activated by both mitogenic and stress signals downstream of ERK1 (extracellular signal-regulated kinase), JNK (c-Jun Nterminal kinase), and p38 MAPKs (mitogen-activated protein kinases) through phosphorylation and trans-activation. C-Jun serves as a central transcription factor downstream of three major MAPK pathways (ERK, JNK, and p38) and converts various extracellular signals into target gene expressions and distinct biological responses. ER inhibition of stress-induced cell death was further shown to be independent of estrogen and ER transcription activity but dependent on ER-c-Jun complex formation. These studies suggest a dual function of ER in breast cancer progression. Under mitogenic conditions, such as in response to estrogen and/or growth factors, ER may function as a transcription factor to increase breast cancer cell proliferation through gene regulation. Under pathological or therapeutic stress conditions, ER may inhibit stress-induced and c-Jun-dependent cell death via a direct interaction with c-Jun, thereby facilitating breast cancer growth

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