title: Role of the glucocorticoid receptor for regulation of hypoxia-dependent gene expression.
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.
authors.affiliation: 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.
authors.forename: Tsunenori
authors.initials: T
authors.lastname: Kodama
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimizu
authors.forename: Noritada
authors.initials: N
authors.lastname: Yoshikawa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Makino
authors.forename: Rika
authors.initials: R
authors.lastname: Ouchida
authors.forename: Kensaku
authors.initials: K
authors.lastname: Okamoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hisada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D008164:Luminescent Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013256:Steroids / Q000378:metabolism; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D005938:Glucocorticoids; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D008164:Luminescent Proteins; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D013256:Steroids; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D012313:RNA; D003907:Dexamethasone