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Domains of Estrogen Receptor (ER) Required for ER/Sp1-Mediated Activation of GC-Rich Promoters by Estrogens and Antiestrogens in Breast Cancer Cells

Department of Veterinary Physiology & Pharmacology (K.K., N.T., S.S.) and Department of Biochemistry & Biophysics (B.S.), Texas A&M University, College Station, Texas 77843-4466

Address all correspondence and requests for reprints to: Stephen H. Safe, Department of Veterinary Physiology & Pharmacology, Texas A&M University, 4466 TAMU, College Station, Texas 77843-4466. E-mail: ssafe{at}cvm.tamu.edu.

Estrogen receptor (ER)/Sp1 activation of GC-rich gene promoters in breast cancer cells is dependent, in part, on activation function 1 (AF1) of ER, and this study investigates contributions of the DNA binding domain (C) and AF2 (DEF) regions of ER on activation of ER/Sp1. 17ß-Estradiol (E2) and the antiestrogens 4-hydroxytamoxifen and ICI 182,780 induced reporter gene activity in MCF-7 and MDA-MB-231 cells cotransfected with human or mouse ER (hER or MOR), but not ERß and GC-rich constructs containing three tandem Sp1 binding sites (pSp1₃) or other E2-responsive GC-rich promoters. Estrogen and antiestrogen activation of hER/Sp1 was dependent on overlapping and different regions of the C, D, E, and F domains of ER. Antiestrogen-induced activation of hER/Sp1 was lost using hER mutants deleted in zinc finger 1 [amino acids (aa) 185–205], zinc finger 2 (aa 218–245), and the hinge/helix 1 (aa 265–330) domains. In contrast with antiestrogens, E2-dependent activation of hER/Sp1 required the C-terminal F domain (aa 579–595), which contains a ß-strand structural motif. Moreover, in peptide competition experiments overexpression of a C-terminal (aa 575–595) F domain peptide specifically blocked E2-dependent activation of hER/Sp1, suggesting that F domain interactions with nuclear cofactors are required for ER/Sp1 action.

NURSA Molecule Pages Link:

Nuclear Receptors:   RARα  |  ERα  |  ERβ

Coregulators:   p68  |  SRC-1  |  GRIP1  |  AIB1

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen

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