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J. Biol. Chem., Vol. 276, Issue 10, 7493-7499, March 9, 2001
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From the Transactivation functions (AF2) in the
ligand-binding domains (LBD) of many steroid receptors are well
characterized, but there is little evidence to support such a function
for the LBD of the androgen receptor (AR). We report a mutant AR, with
residues 628-646 in the hinge region deleted, which exhibited
transactivation activity that was more than double that of the wild
type (WT) AR. Although no androgen-dependent AF2 activity
could be observed for the WT ARLBD fused to a heterologous
DNA-binding domain, the mutant ARLBD(
Ligand- and Coactivator-mediated Transactivation Function (AF2)
of the Androgen Receptor Ligand-binding Domain Is Inhibited by the
Cognate Hinge Region*
,¶
Department of Obstetrics and Gynecology, and
§ National University Medical Institutes, National
University of Singapore, Republic of Singapore 119074
628-646) was 30-40 times more
active than the WT ARLBD. In the presence of the p160 coactivator TIF2,
AR(628-646) was significantly more active than similarly treated WT
AR. Deletion of residues 628-646 also enhanced TIF2-ARLBD activity
8-fold, an effect not present when the LBD-interacting
LXXLL motifs of TIF2 were mutated, suggesting that the
negative modulatory activity of residues 628-646 were exerted via
coactivator pathways. Although the AP-1 (c-Jun/c-Fos) system and NcoR
have been reported to interact with and repress the activity of some
steroid receptors, c-Jun, c-Fos, c-Jun/c-Fos, nor NcoR function was
consistently affected by the absence or presence of residues 628-646,
implying that the AR hinge region exerts its silencing effects in a
manner independent of these corepressors. Our data provide evidence for
the novel finding that strong androgen-dependent AF2 exists
in the ARLBD and is the first report of a negative regulatory domain in
the AR. Because mutations in this region are commonly associated with prostate cancer, it is important to characterize the mechanisms by
which the hinge region exerts its repressor effect on ligand-activated and coactivator-mediated AF2 activity of the ARLBD.
*
This study was supported by the National Medical Research
Council, Singapore.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.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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