Isoform-specific transcriptional regulation by thyroid hormone receptors: Hormone-independent activation operates through a steroid receptor mode of coactivator interaction

Thyroid hormone receptors (T3Rs) are hormone-regulated transcription factor s that play important roles in vertebrate homeostasis, differentiation, and development. T3Rs are synthesized as multiple isoforms that display tissue -specific expression patterns and distinct transcriptional properties. Most T3R isoforms associate with coactivator proteins and mediate transcription al activation only in the presence of thyroid hormone, The pituitary-specif ic T3R beta -2 isoform departs from this general rule and is able to intera ct with p160 coactivators, acid to mediate transcriptional activation in bo th the absence and presence of hormone. We report here that this hormone-in dependent activation is mediated by contacts between the unique N terminus of T3R beta -2 and an internal interaction domain in the SRC-1 (steroid rec eptor coactivator-1) and GRIP-1 (glucocorticoid receptor interacting protei n 1) coactivators. These hormone-independent contacts between T3R beta -2 a nd the p160 coactivators are distinct in sequence and function from the LXX LL motifs that mediate hormone-dependent transcriptional activation and res emble instead a mode of coactivator recruitment previously observed only fo r the steroid hormone receptors and only in the presence of steroid hormone . Our results suggest that the transcriptional properties of the different T3R isoforms represent a combinatorial mixture of repression, antirepressio n, and hormone-independent and hormone-dependent activation functions that operate in conjunction to determine the ultimate transcriptional outcome.