Estrogen receptor inhibits c-Jun-dependent stress-induced cell death by binding and modifying c-Jun activity in human breast cancer cells.
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.
Qi
Xiaomei
X
Department of Radiation Oncology and Division of Biochemistry of the Department of Cell Biology, Neurobiology, and Anatomy, Loyola University of Chicago, Maywood, Illinois 05163.
Borowicz
Stanley
S
Pramanik
Rocky
R
Schultz
Richard M
RM
Han
Jiahuai
J
Chen
Guan
G
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005799:Genes, Dominant; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D048669:MAP Kinase Kinase 6; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D008957:Models, Genetic; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
D018076:DNA, Complementary; D016755:Proto-Oncogene Proteins c-jun; D011960:Receptors, Estrogen; D008156:Luciferases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; C482567:Map2k6 protein, mouse