Multiple messenger ribonucleic acid variants regulate cell-specific expression of human thyroid hormone receptor β1

Abstract

Thyroid hormones are essential for development, growth, and metabolism and act via T3 receptors (TR) α and β. 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 posttranscriptional mechanisms. Differences in the relative levels of expressed TRα and β 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) TRβ1 mRNAs, and identified five polyadenylation position elements in the 3′-UTR. At least six TRβ1 mRNAs between 1.35 and 7.5 kb in length were expressed in discrete temporospatial 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 TRβ1 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 β1 5′-UTR mRNAs may regulate T 3-responsiveness in target tissues by modulating TRβ protein translation and thereby controlling the ratio of expressed TRα and -β proteins.