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Thyroid Hormone Causes Mitogen-Activated Protein Kinase-Dependent Phosphorylation of the Nuclear Estrogen Receptor

Research Service, Stratton Veterans Affairs Medical Center, the Ordway Research Institute, Inc. and the Wadsworth Center, New York State Department of Health, Albany, New York 12208

Address all correspondence and requests for reprints to: Faith B. Davis, M.D., Ordway Research Institute, Inc., 150 New Scotland Avenue, Albany, New York 12208. E-mail: fdavis{at}ordwayresearch.org.

Activated by thyroid hormone, the MAPK (ERK1/2) signaling pathway causes serine phosphorylation by MAPK of several nucleoproteins, including the nuclear thyroid hormone receptor ß1. Because estrogen can activate MAPK and cause MAPK-dependent serine phosphorylation of nuclear estrogen receptor (ER), we studied whether thyroid hormone also promoted MAPK-mediated ER phosphorylation. Human breast cancer (MCF-7) cells were incubated with physiological concentrations of L-T₄ or 17ß-estradiol (E₂) for 15 min to 24 h, and nuclear ER and serine-118-phosphorylated ER were identified by Western blotting. Serine-118-phosphorylated ER was recovered at 15 min in nuclei of MCF-7 cells exposed to either T₄ or E₂. The T₄ effect was apparent at 15 min and peaked at 2 h, whereas the E₂ effect was maximal at 4–6 h. T₄-agarose was as effective as T₄ in causing phosphorylation of ER. T₄ action on ER was inhibited by PD 98059, an inhibitor of ERK1/2 phosphorylation, and by tetraiodothyroacetic acid, a T₄ analog that blocks cell surface-initiated actions of T₄ but is not itself an agonist. Electrophoretic mobility shift assay of nuclear extracts from T₄-treated and E₂-treated cells showed similar specific protein-DNA-binding. Indexed by [³H]thymidine incorporation and nuclear proliferating cell nuclear antigen, MCF-7 cell proliferation was stimulated by T₄ and T₄-agarose to an extent comparable with the effect of E₂. This T₄ effect was blocked by either PD 98059 or ICI 182,780, an ER antagonist. Thus, T₄, like E₂, causes phosphorylation by MAPK of nuclear ER at serine-118 in MCF-7 cells and promotes cell proliferation through the ER by a MAPK-dependent pathway.

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