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Direct Regulation of Androgen Receptor-Associated Protein 70 by Thyroid Hormone and Its Receptors

Department of Biochemistry (P.-J.T., Y.-H.H., C.-H.S., R.-N.C., C.-D.C., K.-H.L.), Chang-Gung University, and First Cardiovascular Division (W.-J.C.), Chang Gung Memorial Hospital, Taoyuan, Taiwan 333, Republic of China; and Department of General Surgery (C.-S.W.), Chang Gung Memorial Hospital at Chiayi, Taiwan 613, Republic of China

Address all correspondence and requests for reprints to: Dr. Kwang-Huei Lin, Department of Biochemistry, Chang-Gung University, 259 Wen-hwa 1 Road, Taoyuan, Taiwan 333, Republic of China. E-mail: khlin{at}mail.cgu.edu.tw.

Thyroid hormone (T₃) regulates multiple physiological processes during development, growth, differentiation, and metabolism. Most T₃ actions are mediated via thyroid hormone receptors (TRs) that are members of the nuclear hormone receptor superfamily of ligand-dependent transcription factors. The effects of T₃ treatment on target gene regulation was previously examined in TR1-overexpressing hepatoma cell lines (HepG2-TR1). Androgen receptor (AR)-associated protein 70 (ARA70) was one gene found to be up-regulated by T₃. The ARA70 is a ligand-dependent coactivator for the AR and was significantly increased by 4- to 5-fold after T₃ treatment by Northern blot analyses in the HepG2-TR1 stable cell line. T₃ induced a 1- to 2-fold increase in the HepG2-TRß1 stable cell line. Both stable cell lines attained the highest fold expression after 24 h treatment with 10 nM T₃. The ARA70 protein was increased up to 1.9-fold after T₃ treatment in HepG2-TR1 cells. Similar findings were obtained in thyroidectomized rats after T₃ application. Cycloheximide treatment did not suppress induction of ARA70 transcription by T₃, suggesting that this regulation is direct. A series of deletion mutants of ARA70 promoter fragments in pGL2 plasmid were generated to localize the thyroid hormone response element (TRE). The DNA fragments (–234/–190 or +56/+119) gave 1.55- or 2-fold enhanced promoter activity by T₃. Thus, two TRE sites exist in the upstream-regulatory region of ARA70. The TR-TRE interaction was further confirmed with EMSAs. Additionally, ARA70 could interfere with TR/TRE complex formation. Therefore, the data indicated that ARA70 suppresses T₃ signaling in a TRE-dependent manner. These experimental results suggest that T₃ directly up-regulates ARA70 gene expression. Subsequently, ARA70 negatively regulates T₃ signaling.

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