Isoform-specific transcriptional regulation by thyroid hormone receptors: hormone-independent activation operates through a steroid receptor mode of co-activator interaction.
Thyroid hormone receptors (T3Rs) are hormone-regulated transcription factors 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 co-activator proteins and mediate transcriptional activation only in the presence of thyroid hormone. The pituitary-specific T3Rbeta-2 isoform departs from this general rule and is able to interact with p160 co-activators, and to mediate transcriptional activation in both the absence and presence of hormone. We report here that this hormone-independent activation is mediated by contacts between the unique N terminus of T3Rbeta-2 and an internal interaction domain in the SRC-1 (steroid receptor co-activator-1) and GRIP-1 (glucocorticoid receptor interacting protein 1) co-activators. These hormone-independent contacts between T3Rbeta-2 and the p160 co-activators are distinct in sequence and function from the LXXLL motifs that mediate hormone-dependent transcriptional activation and resemble instead a mode of co-activator recruitment previously observed only for 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, antirepression, and hormone-independent and hormone-dependent activation functions that operate in conjunction to determine the ultimate transcriptional outcome.
Yang
Z
Z
Section of Microbiology Division of Biological Chemistry University of California at Davis Davis, California 95616, USA.
Privalsky
M L
ML
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002645:Chickens; D005786:Gene Expression Regulation / Q000187:drug effects; D005973:Glutamine; D005982:Glutathione Transferase / Q000235:genetics; D051548:Histone Acetyltransferases; D006801:Humans; D008969:Molecular Sequence Data; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology; D010902:Pituitary Gland / Q000737:chemistry; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D010446:Peptide Fragments; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D005973:Glutamine; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D005982:Glutathione Transferase