Multiple messenger ribonucleic acid variants regulate cell-specific expression of human thyroid hormone receptor beta1.
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 posttranscriptional mechanisms. Differences in the relative levels of expressed TRalpha 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) TRbeta1 mRNAs, and identified five polyadenylation position elements in the 3'-UTR. At least six TRbeta1 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 TRbeta1 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 beta1 5'-UTR mRNAs may regulate T3-responsiveness in target tissues by modulating TRbeta protein translation and thereby controlling the ratio of expressed TRalpha and -beta proteins.
Frankton
Sarah
S
Molecular Endocrinology Group, Division of Medicine and Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom.
Harvey
Clare B
CB
Gleason
Lisa M
LM
Fadel
Abdessamad
A
Williams
Graham R
GR
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D005091:Exons; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D009928:Organ Specificity; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics* / Q000378:metabolism; D024363:Transcription Initiation Site; D014284:Triiodothyronine / Q000378:metabolism
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D012333:RNA, Messenger; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine