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J Biol Chem, Vol. 274, Issue 52, 37131-37138, December 24, 1999
From the Section of Microbiology, Division of Biological Sciences,
University of California, Davis, California 95616
Thyroid hormone receptors (T3Rs) are
hormone-regulated transcription factors. Different T3R isoforms are
expressed in a tissue-specific and developmentally regulated manner.
The T3R
Transcriptional Anti-repression
THYROID HORMONE RECEPTOR
-2 RECRUITS SMRT COREPRESSOR BUT
INTERFERES WITH SUBSEQUENT ASSEMBLY OF A FUNCTIONAL COREPRESSOR
COMPLEX*
,
-1,
-0, and
-1 isoforms typically repress target gene
expression in the absence of hormone and activate transcription in the
presence of hormone. Intriguingly, however, the T3R
-2 isoform fails
to repress, and instead is able to activate transcription in both the
absence and presence of hormone. We investigated the molecular
mechanism behind this absence of repression by T3R
-2. Repression by
T3R
-1,
-0, and
-1 is mediated by the ability of these isoforms
to physically recruit a SMRT/N-CoR corepressor complex. We determined
that the unliganded T3R
-2 also recruits the SMRT corepressor; in
contrast to the
-1,
-0, and
-1 isoforms, however, the T3R
-2
protein interacts not only with the C-terminal "receptor-interaction
domain" of SMRT, but also makes additional contacts with the
N-terminal "silencing domain" of the SMRT corepressor. These
additional, T3R
-2-specific contacts interfere with the subsequent
association of SMRT with mSin3, a crucial second subunit of the
corepressor holo-complex. Our results suggest that T3R
-2 regulates
transcription through a novel anti-repression mechanism, recruiting
SMRT, but preventing the subsequent formation of a functional
corepressor complex.
*
This work was supported in part by Public Health
Services/National Institutes of Health Grants R37 CA-53394 and R01
DK-53528.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.
Supported in part by a University of California-Davis
biotechnology fellowship.
§
To whom correspondence should be addressed. Tel.: 530-752-3013;
Fax: 530-752-9014; E-mail: mlprivalsky@ucdavis.edu.
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