Biochemical and Biophysical Research Communications, Vol.440, No.1, 184-189, 2013
Mediator subunit MED1 is a T3-dependent and T3-independent coactivator on the thyrotropin beta gene promoter
The MEDI subunit of the Mediator transcriptional coregulator complex is a nuclear receptor-specific coactivator. A negative feedback mechanism of thyroid-stimulating hormone (TSH, or thyrotropin) expression in the thyrotroph in the presence of triiodothyronine (T3) is employed by liganded thyroid hormone receptor beta (TR beta) on the TSH beta gene promoter, where conventional histone-modifying coactivators act as corepressors. We now provide evidence that MEDI is a ligand-dependent positive cofactor on this promoter. TSH beta gene transcription was attenuated in MEDI mutant mice in which the nuclear receptor-binding ability of MED1 was specifically disrupted. MED1 stimulated GATA2- and Pit1-mediated TSH beta gene promoter activity in a ligand-independent manner in cultured cells. MEDI also stimulated transcription from the TSH beta gene promoter in a T3-dependent manner. The transcription was further enhanced when the T3-dependent corepressors SRC1, SRC2, and HDAC2 were downregulated. Hence, MED1 is a T3-dependent and -independent coactivator on the TSH beta gene promoter. (C) 2013 Elsevier Inc. All rights reserved.