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Multiple messenger ribonucleic acid variants regulate cell-specific expression of human thyroid hormone receptor
Sarah Frankton1, Clare B Harvey, Lisa M Gleason
1Molecular Endocrinology Group, Division of Medicine and Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom.
Molecular Endocrinology (Baltimore, Md.)
|April 24, 2004
Summary
Thyroid hormone receptor beta1 (TRbeta1) mRNA expression is regulated posttranscriptionally. Its 5' untranslated regions control TRbeta1 protein translation, influencing tissue responsiveness to thyroid hormone.
Area of Science:
- Molecular Endocrinology
- Gene Regulation
- Posttranscriptional Control
Background:
- Thyroid hormones are crucial for development, growth, and metabolism, acting through thyroid hormone receptors (TR) alpha and beta.
- While THRA and THRB genes have distinct roles, their mRNA expression overlaps, with poor correlation to protein levels suggesting posttranscriptional regulation.
- The ratio of TRalpha and TRbeta proteins is thought to modulate tissue sensitivity to thyroid hormone.
Purpose of the Study:
- To investigate the posttranscriptional regulation of human thyroid hormone receptor beta1 (TRbeta1).
- To determine the role of TRbeta1 5'-untranslated regions (5'-UTRs) in modulating protein expression and tissue responsiveness.
Main Methods:
- Determined the structure of the human THRB gene.
- Cloned seven alternately spliced 5'-UTR TRbeta1 mRNAs and identified five 3'-UTR polyadenylation elements.
- Analyzed TRbeta1 mRNA expression patterns in fetal and adult human tissues.
- Conducted transfection studies and in vitro translation assays to assess the impact of 5'-UTRs on protein expression.
Main Results:
- Identified at least six TRbeta1 mRNA variants (1.35–7.5 kb) with distinct temporospatial expression patterns.
- Discovered up to seven upstream short open reading frames in the 5'-UTRs, which did not affect TRbeta1 protein structure.
- Demonstrated cell-specific effects of 5'-UTRs on mRNA expression, consistent reduction in protein levels, and strong inhibition of translation in vitro.
Conclusions:
- Developmental and tissue-specific expression of human TRbeta1 5'-UTR mRNAs regulates T3 responsiveness.
- Modulation of TRbeta protein translation by 5'-UTRs controls the TRalpha/TRbeta protein ratio in target tissues.