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Growth Factors Change Nuclear Distribution of Estrogen Receptor- via Mitogen-Activated Protein Kinase or Phosphatidylinositol 3-Kinase Cascade in a Human Breast Cancer Cell Line

Department of Obstetrics and Gynecology (T.T, M.O., J.K., M.D., T.O., M.S., A.M.-A., B.D., H.I., K.T., H.K.) and Division of Nursing (C.O.), Yamagata University, School of Medicine, Yamagata 990-9585, Japan

Address all correspondence and requests for reprints to: Dr. Masahide Ohmichi, Department of Obstetrics and Gynecology, Yamagata University, School of Medicine, 2-2-2 Iidanishi, Yamagata 990-9585, Japan. E-mail: masa{at}med.id.yamagata-u.ac.jp.

In the present study, to examine the dynamic changes in the localization of nuclear estrogen receptor (ER) induced by growth factors, we used time-lapse confocal microscopy to directly visualized ER fused with green fluorescent protein (GFP-ER) in single living cells treated with epidermal growth factor (EGF) or IGF-I. We observed that 17ß-estradiol (E2) changed the normally diffuse distribution of GFP-ER throughout the nucleoplasm to a hyperspeckled distribution within 10 min. Both EGF and IGF-I also changed the nuclear distribution of GFP-ER, similarly to E2 treatment. However, the time courses of the nuclear redistribution of GFP-ER induced by EGF or IGF-I were different from that induced by E2 treatment. In the EGF-treated cells, the GFP-ER nuclear redistribution was observed at 30 min and reached a maximum at 60 min, whereas in the IGF-I-treated cells, the GFP-ER nuclear redistribution was observed at 60 min and reached a maximum at 90 min. The EGF-induced redistribution of GFP-ER was blocked by pretreatment with a MAPK cascade inhibitor, PD98059, whereas the IGF-I-induced redistribution of GFP-ER was blocked by pretreatment with a phosphatidylinositol 3-kinase inhibitor, LY294002. Analysis using an activation function-2 domain deletion mutant of GFP-ER showed that the change in the distribution of GFP-ER was not induced by E2, EGF, or IGF-I treatment. These data suggest that MAPK and phosphatidylinositol 3-kinase cascades are involved in the nuclear redistribution of ER by EGF and IGF-I, respectively, and that the activation function-2 domain of ER may be needed for the nuclear redistribution of ER.

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