Thyroid Hormone Receptor DNA Binding Is Required for Both Positive and Negative Gene Regulation

That DNA binding by TR-␤ is required on all nTREs known to regulate the H-P-T axis

Nobuyuki Shibusawa; Anthony N. Hollenberg; Fredric E. Wondisford

2003

Scholarcy highlights

  • The synthesis and secretion of thyroid hormones are exquisitely regulated by a negative feedback system that involves the hypothalamus, pituitary, and thyroid gland.1 The synthesis of thyrotropin-releasing hormone, produced in the paraventricular nucleus of the hypothalamus, and the ␣ and ␤ subunits of
  • The DNA Binding Affinity of the GS125 TR-␤ Is Reduced on Both Positive thyroid hormone-response elements and Negative TREs—Recent cell culture and TR knockout model studies suggest that the ␤2 isoform of the thyroid hormone receptor plays the predominant role in the feedback regulation of the H-P-T axis
  • A DRϩ4 probe was employed as a positive thyroid hormone-response elements and a TRH site 4 probe was utilized as a nTRE
  • The GS125 DNA binding domain mutant was defective in both ligand-induced transactivation on pTRE reporter genes and ligand-induced transrepression on the negatively regulated gene promoters, crucial in regulating the H-P-T axis
  • The negative TRE within the human thyroid-stimulating hormone-␤ genes is composed of single half-site motifs present near the TATA box and downstream of the transcription start site, which interact with the TR monomer
  • Precipitates were eluted with elution buffer, and 5 M NaCl was added to reverse cross-links at 65 °C for 4 h
  • The human TRH promoter contains three nTREs, including separate half-sites which are responsible for T3-dependent negative regulation and binding of TR
  • The GS125 DNA-binding mutant establishes the importance of DNA binding in negative regulation of gene transcription mediated by thyroid hormone receptors

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