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Papers In Press, published online ahead of print January 25, 2002
J. Biol. Chem, 10.1074/jbc.M112330200
Submitted on December 21, 2001
Revised on January 25, 2002
Accepted on January 25, 2002
Steroid Hormones Section/LMCB, NIDDK/NIH, Bethesda, MD 20892-0805
Corresponding Author: steroids{at}helix.nih.gov
The EC50 of agonists and the partial agonist activity of antagonists are crucial parameters for steroid hormone control of gene expression and endocrine therapies. These parameters have been shown to be modulated by a naturally occurring cis-acting element, called the GME (glucocorticoid modulatory element) that binds two proteins, GMEB-1 and -2. We now present evidence that the GMEBs contact Ubc9, which is the mammalian homolog of a yeast E2 ubiquitin-conjugating enzyme. Ubc9 also binds to glucocorticoid receptors (GRs). Ubc9 displays no intrinsic transactivation activity but modifies both the absolute amount of induced gene product and the fold induction by GR. With high concentrations of GR, added Ubc9 also reduces the EC50 of agonists and increases the partial agonist activity of antagonists in a manner that is independent of the ability of Ubc9 to transfer SUMO-1 to proteins. This new activity of Ubc9 requires only the ligand binding domain of GR, and part of the hinge region. Interestingly, Ubc9 modulation of full length GR transcriptional properties can be seen in the absence of a GME. This, though, is consistent with the GME acting by increasing the local concentration of Ubc9, which then activates a previously unobserved target in the transcriptional machinery. With high concentrations of Ubc9 and GR, Ubc9 binding to GR appears to be sufficient to permit Ubc9 to act independently of the GME.
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