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Cobalt Chloride-Induced Estrogen Receptor Down-Regulation Involves Hypoxia-Inducible Factor-1 in MCF-7 Human Breast Cancer Cells

College of Life Science (J.C., Y.L.), Institute of Biotechnology, Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747; Department of Medicine (D.K.), Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul 135-710; and College of Pharmacy (S.L.), Seoul National University, Seoul 151-742, Korea

Address all correspondence and requests for reprints to: YoungJoo Lee, Ph. D., Department of Bioscience and Biotechnology, Sejong University, Kwang-Jin-Gu, Seoul 143-747, Korea. E-mail: yjlee{at}sejong.ac.kr.

The estrogen receptor (ER) is down-regulated under hypoxia via a proteasome-dependent pathway. We studied the mechanism of ER degradation under hypoxic mimetic conditions. Cobalt chloride-induced ER down-regulation was dependent on the expression of newly synthesized protein(s), one possibility of which was hypoxia-inducible factor-1 (HIF-1). To examine the role of HIF-1 expression in ER down-regulation under hypoxic-mimetic conditions, we used a constitutively active form of HIF-1, HIF-1/herpes simplex viral protein 16 (VP16), constructed by replacing the transactivation domain of HIF-1 with that of VP16. Western blot analysis revealed that HIF-1/VP16 down-regulated ER in a dose-dependent manner via a proteasome-dependent pathway. The kinase pathway inhibitors PD98059, U0126, wortmannin, and SB203580 did not affect the down-regulation. A mammalian two-hybrid screen and immunoprecipitation assays indicated that ER interacted with HIF-1 physically. These results suggest that ER down-regulation under hypoxia involves protein-protein interactions between the ER and HIF-1.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol

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