Thyroid hormone (T3) exerts most of its effects through nuclear thyroid hormone receptors (TRα, TRβ). What is the molecular mechanism by which T3 converts a transcriptional repressor to an activator?
- A T3 dissociates the TR from DNA; cytoplasmic T3-TR complex then acts as a transcription factor
- B T3 activates membrane-bound integrin αVβ3 receptors that activate MAPK signaling for all genomic effects
- C Unliganded TR binds TRE with corepressors (NCoR/SMRT with HDAC); T3 binding causes conformational change displacing corepressors and recruiting coactivators (SRC-1 with HAT), activating transcription ✓
- D T3 binds thyroid hormone binding protein (THBP) in the nucleus; the complex directly acetylates histones
Explanation
Unliganded thyroid hormone receptor (TR) forms a heterodimer with RXR (retinoid X receptor) bound to thyroid hormone response elements (TREs) in target gene promoters. Without T3, TR recruits corepressor complexes (NCoR or SMRT) that associate with histone deacetylases (HDACs), compacting chromatin and repressing transcription — explaining why hypothyroidism and hyperthyroidism have opposite effects. When T3 binds TR, helix-12 of the ligand binding domain repositions, displacing corepressors and attracting coactivator complexes (SRC-1/2, p300/CBP with histone acetyltransferase activity), relaxing chromatin and activating gene transcription.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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