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Papers In Press, published online ahead of print October 17, 2002
Biology Institute, Division of Molecular Cell Biology, University of Oslo, Oslo 0316
Corresponding Author: fahris{at}bio.uio.no
Nuclear receptors are ligand-modulated transcription factors that transduce the presence of lipophilic ligands into changes in gene expression. Nuclear receptor activity is regulated by ligand-induced interactions with coactivator or corepressor molecules. From a positive hormone response element (pHRE) and in the absence of hormone, corepressors SMRT and N-CoR are bound to some nuclear receptors, such as thyroid hormone and retinoic acid receptors (T3Rs and RARs), and mediate inhibition of basal levels of transcription. Ligand binding results in dissociation of corepressors and association of coactivators, resulting in the reversal of inhibition and a net activation of transcription. However, the role of cofactors on the activity of nuclear receptors from negative HREs (nHREs) is poorly understood. Here we show that corepressor SMRT can act as a potent coactivator for T3Ra from a nHRE. Mutagenesis of residues in the hinge region of T3Ra which block binding of SMRT inhibits ligand-independent transcriptional activation by T3Ra from a nHRE. These mutations also abrogate SMRT-mediated increase in transcriptional activity by T3Ra at a nHRE without significantly affecting ligand-dependent activation at a pHRE. Partial protease digestion coupled to the mobility shift assay indicate differences in the conformation of T3Ra-SMRT complexes bound to a pHRE versus a nHRE. These results suggest that allosteric changes resulting from binding of T3Ra to different response elements, i.e. pHREs versus nHREs, dictate whether a cofactor will function as a coactivator or a corepressor. This, in turn, greatly expands the repertoire of mechanisms used in modulating transcription without the need for expression of new regulatory molecules.
J. Biol. Chem, 10.1074/jbc.M209546200
Submitted on September 17, 2002
Revised on October 17, 2002
Accepted on October 17, 2002
Corepressor SMRT functions as a coactivator for T3Ra from a negative hormone response element
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