TRIIODOTHYRONINE (T3) DECREASES BINDING TO DNA BY T3-RECEPTOR HOMODIMERS BUT NOT RECEPTOR-AUXILIARY PROTEIN HETERODIMERS

Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that bind to thyroid hormone response elements (TREs) to mediate positive and negative regulation of transcription of thyroid hormone-responsive genes. TR binding to TREs can be enhanced by interaction with a nuclear protein, triiodothyronine (T3) receptor auxiliary protein (TRAP). There are two major isoforms of thyroid hormone receptors, TR-alpha-1 and TR-beta-1, which are encoded on two separate genes. We studied the binding of TR-alpha-1 and TR-beta-1 to several TREs: the chick lysozyme TRE (F2), which is positively regulated by T3; rabbit beta-myosin heavy chain TRE, which is negatively regulated by T3; and an idealized inverted palindrome, TRE(lap). We demonstrate the formation of homodimers, TR-alpha/TR-beta dimers, and TR/TRAP heterodimers when receptor is bound to these DNA sequences. Surprisingly, we found that T3 decreased TR-alpha-1 and TR-beta-1 homodimer binding in a dose-dependent manner to these TREs as well as TR-alpha/TR-beta dimer binding to F2. In contrast, T3 did not affect TR/TRAP heterodimer binding to TREs suggesting that this heterodimer may be the stable complex occupying TREs in the presence of ligand.