NEGATIVE TRANSCRIPTIONAL REGULATION BY NUCLEAR RECEPTORS

Steroid and thyroid hormones, and vitamins A and D bind to nuclear rec eptors, which act as ligand-modulated transcription factors. In many c ases, ligand-activated nuclear receptor binds to positively acting hor mone response elements (p-HREs) to induce gene transcription. However, ligand activated receptors also repress transcription of specific gen es and several mechanisms that account for negative regulation have re cently emerged. One major form of negative regulation is based on tran scriptional interference between nuclear receptors and other transcrip tion factors, such as AP-1. In this case, the liganded receptor preven ts AP-1 or other positively acting transcription factors from fruitful interaction with the transcription initiation complex. A second form of negative regulation is based on binding of nuclear receptors to spe cialized negative HREs (n-HREs). Binding of unliganded receptor to suc h an element results in constitutive activation, which is terminated b y the binding of ligand. While transcriptional interference with AP-1 has been described for many members of the nuclear receptor family, ne gative regulation through n-HREs so far has been shown only for one of the thyroid hormone receptors. However, this type of negative regulat ion is likely to be widespread.