Mediator subunit MED1 is a T3-dependent and T3-independent coactivator on the thyrotropin β gene promoter.
The MED1 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 β (TRβ) on the TSHβ gene promoter, where conventional histone-modifying coactivators act as corepressors. We now provide evidence that MED1 is a ligand-dependent positive cofactor on this promoter. TSHβ gene transcription was attenuated in MED1 mutant mice in which the nuclear receptor-binding ability of MED1 was specifically disrupted. MED1 stimulated GATA2- and Pit1-mediated TSHβ gene promoter activity in a ligand-independent manner in cultured cells. MED1 also stimulated transcription from the TSHβ 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 TSHβ gene promoter.
Laboratory of Hematology, Division of Medical Biophysics, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142, Japan.
Keiji
K
Matsui
Kasumi
K
Oda
Shumpei
S
Mizuta
Ruri
R
Ishino
Norinaga
N
Urahama
Natsumi
N
Hasegawa
Robert G
RG
Roeder
Mitsuhiro
M
Ito
D000818:Animals; D002460:Cell Line; D005260:Female; D050989:GATA2 Transcription Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D056913:Mediator Complex Subunit 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011401:Promoter Regions, Genetic; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D037322:Thyrotropin, beta Subunit / Q000235:genetics*; D050817:Transcription Factor Pit-1 / Q000378:metabolism; D015533:Transcriptional Activation; D014284:Triiodothyronine / Q000378:metabolism*
D050989:GATA2 Transcription Factor; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D021122:Protein Subunits; D037322:Thyrotropin, beta Subunit; D050817:Transcription Factor Pit-1; D014284:Triiodothyronine
MED1; Mediator; Negative TR-responsive element; TRβ; TSHβ gene promoter