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This version published online on April 22, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0346
A more recent version of this article appeared on July 1, 2004
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Submitted on September 10, 2003
Accepted on April 12, 2004

MULTIPLE mRNA VARIANTS REGULATE CELL-SPECIFIC EXPRESSION OF HUMAN THYROID HORMONE RECEPTOR {beta}1

Sarah Frankton, Clare B. Harvey, Lisa M. Gleason, Abdessamad Fadel, and Graham R. Williams*

Molecular Endocrinology Group, Division of Medicine & MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK

* To whom correspondence should be addressed. E-mail: graham.williams{at}imperial.ac.uk.

Thyroid hormones are essential for development, growth and metabolism and act via T3 receptors (TR) {alpha} and {beta}. The THRA and THRB genes have discrete physiological roles but their mRNAs are expressed widely in overlapping patterns. There is poor correlation between TR mRNA and protein, indicating that expression may be regulated by post-transcriptional mechanisms. Differences in the relative levels of expressed TR{alpha} and {beta} proteins have been suggested to modulate tissue T3-responsiveness. We determined the structure of the human THRB gene, cloned seven alternately spliced 5'-untranslated region (5'-UTR) TR{beta}1 mRNAs and identified five polyadenylation position elements in the 3'-UTR. At least six TR{beta}1 mRNAs between 1.35 and 7.5kb in length were expressed in discrete temporo-spatial patterns in fetal and adult human tissues. The 5'-UTRs contained up to seven upstream short open reading frames, which did not influence the structure of the TR{beta}1 protein. In transfection studies, 5'-UTRs exerted cell-specific effects on mRNA expression, but consistently reduced protein expression. Furthermore, each 5'-UTR strongly inhibited translation in vitro. Thus, developmental and tissue-specific expression of human thyroid hormone receptor {beta}1 5'-UTR mRNAs may regulate T3-responsiveness in target tissues by modulating TR{beta} protein translation and thereby controlling the ratio of expressed TR{alpha} and {beta} proteins.


Key words: Thyroid hormone receptor • 5'-UTR • alternative mRNA splicing • translation • 3'-UTR

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ
Ligands:   Thyroid hormone



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