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Activation of Peroxisome Proliferator-Activated Receptor- and Retinoid X Receptor Inhibits Aromatase Transcription via Nuclear Factor-B

Department of Medicine and Bioregulatory Science (W.F., T.Y., H.M., M.N., T.O., K.G., H.N.), Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582 Japan; Core Research for Evolutional Science and Technology (CREST) (T.Y., H.M., M.N., T.O., K.G., H.N.), Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan; Department of Endocrinology (Y.-M.M.), Chinese PLA General Hospital, Beijing 100853, China; and Department of Biochemistry (N.H.), School of Medicine, Fujita Health University, 470-1192 Aichi, Japan

Address all correspondence and requests for reprints to: Toshihiko Yanase, M.D., Ph.D., Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: yanase{at}intmed3.med.kyushu-u.ac.jp.

Our previous studies demonstrated that a peroxisome proliferator-activated receptor (PPAR)- ligand, troglitazone (TGZ),and/or a retinoid X receptor (RXR) ligand, LG100268 (LG), decreased the aromatase activity in both cultured human ovarian granulosa cells and human granulosa-like tumor KGN cells. In the present study, we further found that a combined treatment of TGZ+LG decreased aromatase promoter II (ArPII) activity in both ovarian KGN cells and fibroblast NIH-3T3 cells in a PPAR-dependent manner. Furthermore, the inhibition of both aromatase activity and the transcription of ArPII by TGZ+LG was completely eliminated when nuclear factor-B (NF-B) signaling was blocked by specific inhibitors, suggesting NF-B, which is endogenously expressed in both fibroblast and granulosa cells, might be a mediator of this inhibition. Interestingly, activation of NF-B by either forced expression of the p65 subunit or NF-B-inducing kinase up-regulated ArPII activity. Positive regulation of aromatase by endogenous NF-B was also suggested by the fact that NF-B-specific inhibitors suppress basal activity of the aromatase gene. A concomitant formation of high-order complex between NF-B p65 and ArPII was also observed by chromatin immunoprecipitation assay. Although activation of PPAR and RXR affected endogenous expression levels of neither inhibitory B nor p65, it impaired the interaction between NF-B and ArPII and the p65 based transcription as well. Altogether, these results indicate that activation of a nuclear receptor system, constituted by PPAR and RXR, down-regulates aromatase expression through the suppression of NF-B-dependent aromatase activation and thus provide a new insight in the mechanism of regulation of the aromatase gene.

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