Distinct interaction of cortivazol with the ligand binding domain confers glucocorticoid receptor specificity: cortivazol is a specific ligand for the glucocorticoid receptor.
Ligand-receptor coupling is one of the important constituents of signal transduction and is essential for physiological transmission of actions of endogenous substances including steroid hormones. However, molecular mechanisms of the redundancy between glucocorticoid and mineralocorticoid actions remain unknown because of complicated cross-talk among, for example, these adrenal steroids, their cognate receptors, and target genes. Receptor-specific ligand that can distinctly modulate target gene expression should be developed to overcome this issue. In this report, we showed that a pyrazolosteroid cortivazol (CVZ) does not induce either nuclear translocation or transactivation function of the mineralocorticoid receptor (MR) but does both for the glucocorticoid receptor (GR). Moreover, deletion analysis of the C-terminal end of the GR has revealed that CVZ interacts with the distinct portion of the ligand binding domain (LBD) and differentially modulates the ligand-dependent interaction between transcription intermediary factor 2 and the LBD when compared with cortisol, dexamethasone, and aldosterone. Thus, it is indicated that CVZ may not be only a molecular probe for the analysis of the redundancy between the GR and MR in vivo but also a useful reagent to clarify structure-function relationship of the GR LBD.
Yoshikawa
Noritada
N
Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan.
Makino
Yuichi
Y
Okamoto
Kensaku
K
Morimoto
Chikao
C
Makino
Isao
I
Tanaka
Hirotoshi
H
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D019556:COS Cells; D002460:Cell Line; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000737:chemistry* / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008164:Luminescent Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011281:Pregnatrienes / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011965:Receptors, Glucocorticoid / Q000737:chemistry* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection
D018076:DNA, Complementary; D005938:Glucocorticoids; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D008164:Luminescent Proteins; D011281:Pregnatrienes; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; C005924:cortivazol