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J Biol Chem. 2003 Aug 29;278(35):33384-91. Epub 2003 Jun 16.

Role of the glucocorticoid receptor for regulation of hypoxia-dependent gene expression.

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1
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.

Abstract

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 fine-tune 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 alpha. 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.

PMID:
12810720
DOI:
10.1074/jbc.M302581200
[Indexed for MEDLINE]
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