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J. Biol. Chem., Vol. 277, Issue 51, 49256-49266, December 20, 2002
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From the Steroid Hormones Section, NIDDK/LMCB, National Institutes
of Health, Bethesda, Maryland 20892
Coactivators such as TIF2 and SRC-1 modulate the
positioning of the dose-response curve for agonist-bound glucocorticoid
receptors (GRs) and the partial agonist activity of antiglucocorticoid
complexes. These properties of coactivators differ from their initially
defined activities of binding to, and increasing the total levels of
transactivation by, agonist-bound steroid receptors. We now report that
constructs of TIF2 and SRC-1 lacking the two activation domains (AD1
and AD2) have significantly less ability to increase transactivation but retain most of the activity for modulating the dose-response curve
and partial agonist activity. Mammalian two-hybrid experiments show
that the minimum TIF2 segment with modulatory activity (TIF2.4) does
not interact with p300, CREB-binding protein, or PCAF, which also modulates GR activities. DRIP150 and DRIP205 have been implicated in coactivator actions but are unable to modulate GR activities. The
absence of synergism by PCAF or DRIP150 with SRC-1 or TIF2, respectively, further suggests that these other factors are not involved. The ability of a TIF2.4 fragment (i.e. TIF2.37),
which is not known to interact with proteins, to block the actions of TIF2.4 suggests that an unidentified binder mediates the modulatory activity of TIF2. Pull-down experiments with GST/TIF2.4 demonstrate a
direct interaction of TIF2 with GR in a hormone-dependent
fashion that requires the receptor interaction domains of TIF2 and is equally robust with agonists and most antiglucocorticoids. These observations, which are confirmed in mammalian two-hybrid assays, suggest that the capacity of coactivators such as TIF2 to modulate the
partial agonist activity of antisteroids is mediated by the binding of
coactivators to GR-antagonist complexes. In conclusion, the modulatory
activity of coactivators with GR-agonist and -antagonist complexes is
mechanistically distinct from the ability of coactivators to augment
the total levels of transactivation and appears to involve the binding
to both GR-steroid complexes and an unidentified TIF2-associated factor(s).
Modulation of Induction Properties of Glucocorticoid
Receptor-Agonist and -Antagonist Complexes by Coactivators Involves
Binding to Receptors but Is Independent of Ability of Coactivators to
Augment Transactivation*
,, and
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally and should be considered as first authors.
§
To whom correspondence should be addressed: Bldg. 8, Rm. B2A-07,
NIDDK/LMCB, National Institutes of Health, Bethesda, MD 20892. Tel.:
301-496-6796; Fax: 301-402-3572; E-mail: steroids@helix.nih.gov.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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