Signalling by small molecules, such as retinoic acid, is mediated by heterodimers comprising a class II nuclear receptor and an RXR (retinoid X receptor) subunit. The receptors bind to DNA response elements and act as ligand-dependent transcription factors, but, in the absence of signal, the receptors bind the co-repressors SMRT [silencing mediator for RAR (retinoic acid receptor) and TR (thyroid hormone receptor)] and NCoR (nuclear receptor co-repressor) and repress gene expression. Alternative splicing of the SMRT transcript in mammals generates six isoforms containing 1, 2 or 3 CoRNR (co-repressor for nuclear receptor) box motifs which are responsible for the interactions with nuclear receptors. We show that human cell lines express all six SMRT isoforms and then determine the binding affinity of mouse SMRT isoforms for RAR/RXR and three additional class II nuclear receptor–DNA complexes. This approach demonstrates the importance of the full complement of CoRNR boxes within each SMRT protein, rather than the identity of individual CoRNR boxes, in directing the interaction of SMRT with nuclear receptors. Each class of SMRT isoform displays a distinct feature, as the 1-box isoform discriminates between DNA response elements, the 2-box isoforms promote high-affinity binding to TR complexes and the 3-box isoforms show differential binding to nuclear receptors. Consequently, the differential deployment of SMRT isoforms observed in vivo could significantly expand the regulatory capacity of nuclear receptor signalling.
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Research Article|
March 03 2009
Alternative splicing determines the interaction of SMRT isoforms with nuclear receptor–DNA complexes
Flavie Faist;
Flavie Faist
1
Institute of Biomedical and Biomolecular Science, School of Biological Science, University of Portsmouth, King Henry Building, King Henry 1st Street, Portsmouth PO1 2DY, U.K.
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Stephen Short;
Stephen Short
2
Institute of Biomedical and Biomolecular Science, School of Biological Science, University of Portsmouth, King Henry Building, King Henry 1st Street, Portsmouth PO1 2DY, U.K.
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G. Geoff Kneale;
G. Geoff Kneale
Institute of Biomedical and Biomolecular Science, School of Biological Science, University of Portsmouth, King Henry Building, King Henry 1st Street, Portsmouth PO1 2DY, U.K.
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Colinb R. Sharpe
Colinb R. Sharpe
3
Institute of Biomedical and Biomolecular Science, School of Biological Science, University of Portsmouth, King Henry Building, King Henry 1st Street, Portsmouth PO1 2DY, U.K.
3To whom correspondence should be addressed (email colin.sharpe@port.ac.uk).
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Publisher: Portland Press Ltd
Received:
July 15 2008
Revision Received:
August 22 2008
Accepted:
August 28 2008
Accepted Manuscript online:
August 28 2008
Online ISSN: 1573-4935
Print ISSN: 0144-8463
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biosci Rep (2009) 29 (3): 143–149.
Article history
Received:
July 15 2008
Revision Received:
August 22 2008
Accepted:
August 28 2008
Accepted Manuscript online:
August 28 2008
Citation
Flavie Faist, Stephen Short, G. Geoff Kneale, Colinb R. Sharpe; Alternative splicing determines the interaction of SMRT isoforms with nuclear receptor–DNA complexes. Biosci Rep 1 June 2009; 29 (3): 143–149. doi: https://doi.org/10.1042/BSR20080093
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