Thyroid hormone receptor-specific interactions with steroid receptor coactivator-1 in the pituitary.
Steroid receptor coactivator-1 (SRC-1) is a transcription cofactor that enhances the hormone-dependent action mediated by the thyroid hormone (TH) receptor (TR) as well as other nuclear receptors. However, it is not known whether the SRC-1-mediated activation of TH-regulated gene transcription is TR isoform specific in the pituitary. We generated mice that were deficient in TRalpha and SRC-1 (TRalpha(0/0)SRC-1(-/-)), as well in TRbeta and SRC-1 (TRbeta(-/-)SRC-1(-/-)), and thyroid function tests and effects of TH deprivation and TH treatment were compared with wild-type mice or mice with deletion of either TRs or SRC-1 alone. We have shown that 1) TRbeta(-/-)SRC-1(-/-) mice demonstrate more severe TH resistance than either the SRC-1(-/-) or TRbeta(-/-) mice; the additive effect indicates that SRC-1 has an independent role in TH action over that of TRbeta; 2) SRC-1 facilitates TRbeta and TRalpha-mediated down-regulation of TSH, as TRalpha(0/0)SRC-1(-/-) mice demonstrate TH resistance rather than hypersensitivity as seen in TRalpha(0/0)mice; and 3) a compensatory increase in SRC-1 expression is associated with the TH hypersensitivity seen in TRalpha-deficient animals. We conclude that SRC-1 action in the pituitary mediates TH action via specific TR subtypes.
Sadow
Peter M
PM
Department of Medicine, University of Chicago, Illinois, USA.
Koo
Eugene
E
Chassande
Olivier
O
Gauthier
Karine
K
Samarut
Jacques
J
Xu
Jianming
J
O'Malley
Bert W
BW
Seo
Hisao
H
Murata
Yoshiharu
Y
Weiss
Roy E
RE
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D051548:Histone Acetyltransferases; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D056921:Nuclear Receptor Coactivator 3; D010902:Pituitary Gland / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000187:drug effects; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D013960:Thyroid Function Tests; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta; D018382:Thyroid Hormone Resistance Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D013963:Thyroid Hormones / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology; D013972:Thyrotropin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D037322:Thyrotropin, beta Subunit / Q000187:drug effects / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism
D051958:Nuclear Receptor Coactivator 2; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D037322:Thyrotropin, beta Subunit; D015534:Trans-Activators; D014157:Transcription Factors; D014284:Triiodothyronine; D013972:Thyrotropin; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; C538867:Ncoa3 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D056921:Nuclear Receptor Coactivator 3