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A more recent version of this article appeared on February 8, 2002
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M107946200v1
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Papers In Press, published online ahead of print December 10, 2001
J. Biol. Chem, 10.1074/jbc.M107946200
Submitted on August 17, 2001
Revised on November 27, 2001
Accepted on December 7, 2001

Distinct interaction of cortivazol with the ligand binding domain confers glucocorticoid receptor specificity

Noritada Yoshikawa, Yuichi Makino, Kensaku Okamoto, Chikao Morimoto, Isao Makino, and Hirotoshi Tanaka

Division of Clinical Immunology, Institute of Medical Science,, University of Tokyo, Minato-ku, Tokyo 108-8639

Corresponding Author: hirotnk{at}ims.u-tokyo.ac.jp

Ligand-receptor coupling is one of the important constituents of signal transduction and essential for physiological transmission of actions of endogenous substances including steroid hormones. However, molecular mechanisms of the redundancy between glucocorticoid and mineralocorticoid remains 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 of 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 TIF2 and the LBD when compared with cortisol, dexamethasone, and aldosterone. It, thus, is indicated that CVZ may be not 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.


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