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J Biol Chem, Vol. 274, Issue 52, 37131-37138, December 24, 1999

Transcriptional Anti-repression
THYROID HORMONE RECEPTOR -2 RECRUITS SMRT COREPRESSOR BUT INTERFERES WITH SUBSEQUENT ASSEMBLY OF A FUNCTIONAL COREPRESSOR COMPLEX^*

Zhihong Yang, Suk-Hyun Hong, and Martin L. Privalsky^§

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-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.

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