Abstract
GMEB-1 was initially described as a component of a 550-kDa heteromeric DNA binding complex that is involved in the modulation of two properties of glucocorticoid receptor (GR) transactivation, the dose-response curve of agonists and the partial agonist activity of antagonists. Subsequently, GMEB-1 was also found to bind to hsp27, to associate with the coactivator TIF2 in yeast cells, and to participate in Parvovirus replication. To understand these multiple activities of GMEB-1 at a molecular level, we have now determined which regions are associated with the various activities associated with the modulation of GR transactivation properties. These activities include, homooligomerization, heterooligomerization, DNA binding, binding to GR and the transcriptional cofactor CBP, and GR modulation. Complex activities such as DNA binding and GR modulation, are found to require the physical combination of those domains that would be predicted from the involved biochemical processes. We have previously documented that GMEB-1 possesses both GR modulatory and intrinsic transactivation activity. However, the domains for these two activities of GMEB-1 are found not to overlap. This separation of activities provides a structural basis for our prior biological observations that the modulation of the dose-response curve and partial agonist activity of GR complexes is independent of the total levels of gene activation by the same GR complexes.
Highlights
From the Steroid Hormones Section, NIDDK/Laboratory of Molecular and Cellular Biology, National Institutes of Health, Bethesda, Maryland 20892
GMEB-1 was initially described as a component of a 550-kDa heteromeric DNA binding complex that is involved in the modulation of two properties of glucocorticoid receptor (GR) transactivation, the dose-response curve of agonists and the partial agonist activity of antagonists
This binding of GMEB-1, as part of the larger protein complex, to the GME is closely associated with the ability of the GME to modulate selected transcriptional properties of GR-agonist and -antagonist complexes [29]
Summary
From the Steroid Hormones Section, NIDDK/Laboratory of Molecular and Cellular Biology, National Institutes of Health, Bethesda, Maryland 20892. A major function of steroid receptors is to translate the intracellular concentration of cognate ligands into graded amounts of specific biological responses These responses most commonly involve either the induction or repression of gene expression due to changes in transcription. To the extent that the antisteroid blocks only the target gene and retains agonist activity for all other responsive genes, one can minimize the side effects that result from an antisteroid indiscriminately preventing the expression of all responsive genes It is not as much the absolute level of partial agonist activity that is important as the percentage of the maximal response elicited by an agonist steroid. As for the EC50 of the dose-response, the partial agonist activity of an antisteroid is independent of the basal and fully induced levels of the responsive gene (8 –13)
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