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J. Biol. Chem., Vol. 278, Issue 35, 33384-33391, August 29, 2003

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Role of the Glucocorticoid Receptor for Regulation of Hypoxia-dependent Gene Expression^*

Tsunenori Kodama, Noriaki Shimizu, Noritada Yoshikawa, Yuichi Makino, Rika Ouchida, Kensaku Okamoto, Tetsuya Hisada, Hiroshi Nakamura, Chikao Morimoto and Hirotoshi Tanaka 

From the Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 08-8639, Japan

Glucocorticoids are secreted from the adrenal glands and act as a peripheral effector of the hypothalamic-pituitary-adrenal axis, playing an essential role in stress response and homeostatic regulation. In target cells, however, it remains unknown how glucocorticoids finetune the cellular pathways mediating tissue and systemic adaptation. Recently, considerable evidence indicates that adaptation to hypoxic environments is influenced by glucocorticoids and there is cross-talk between hypoxia-dependent signals and glucocorticoid-mediated regulation of gene expression. We therefore investigated the interaction between these important stress-responsive pathways, focusing on the glucocorticoid receptor (GR) and hypoxia-inducible transcription factor HIF-1. Here we show that, under hypoxic conditions, HIF-1-dependent gene expression is further up-regulated by glucocorticoids via the GR. This up-regulation cannot be substituted by the other steroid receptors and is suggested to result from the interaction between the GR and the transactivation domain of HIF-1. Moreover, our results also indicate that the ligand binding domain of the GR is essential for this interaction, and the critical requirement for GR agonists suggests the importance of the ligand-mediated conformational change of the GR. Because these proteins are shown to colocalize in the distinct compartments of the nucleus, we suggest that these stress-responsive transcription factors have intimate communication in close proximity to each other, thereby enabling the fine-tuning of cellular responses for adaptation.

Received for publication, March 13, 2003 , and in revised form, June 11, 2003.

^* This work is supported in part by grants from the Ministry of Education, Science, Technology, Sports, and Culture, Japan, the Ministry of Health, Labor, and Welfare, Japan, the Takeda Science Foundation, the Uehara Memorial Foundation, the Vehicle Racing Commemorative Foundation, Novartis Foundation, and the Cell Science Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel. and Fax: 81-3-5449-5547; E-mail: hirotnk{at}ims.u-tokyo.ac.jp.

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