AP-1 antagonizes thyroid hormone receptor action on the thyrotropin beta-subunit gene.
Thyrotropin-releasing hormone (TRH) stimulates and thyroid hormone (T3) inhibits transcription of the thyrotropin beta-subunit gene (TSH-beta). The first exon contains DNA sequences necessary for both responses and binds both AP-1 and thyroid hormone receptor (T3R). T3 did not inhibit TSH-beta gene expression in a T3R-deficient cell line. Transfection of a T3R expression vector, however, resulted in a 70% inhibition of expression by T3, which was abolished by cotransfection of c-jun and c-fos expression vectors. Mutations surrounding the transcription initiation site and DNA binding studies demonstrate both a functional and structural interaction between c-jun and T3R. Thus, TRH, acting through AP-1, may alter the set point and magnitude of thyroid hormone negative feedback of the TSH-beta gene through an interaction between AP-1 and T3R. Other regulatory pathways acting through AP-1 may alter thyroid hormone action in man.
Wondisford
F E
FE
Charles A. Dana Research Institute, Boston, Massachusetts 02215.
Steinfelder
H J
HJ
Nations
M
M
Radovick
S
S
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005091:Exons; D005786:Gene Expression Regulation; D016762:Genes, fos; D016758:Genes, jun; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D012045:Regulatory Sequences, Nucleic Acid; D012689:Sequence Homology, Nucleic Acid; D013329:Structure-Activity Relationship; D013972:Thyrotropin / Q000235:genetics*; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology; D014162:Transfection
D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D013973:Thyrotropin-Releasing Hormone; D013972:Thyrotropin