Modulation by steroid receptor coactivator-1 of target-tissue responsiveness in resistance to thyroid hormone.
Mutations in the thyroid hormone receptor-beta gene (TR beta) cause resistance to thyroid hormone. How the action of mutant thyroid hormone nuclear receptors (TRs) is regulated in vivo is not clear. We examined the effect of a TR coactivator, steroid receptor coactivator-1 (SRC-1), on target-tissue responsiveness by using a mouse model of resistance to thyroid hormone, TR beta PV knockin mice, in the SRC-1 null background. Lack of SRC-1 intensified the dysfunction of the pituitary-thyroid axis and impaired growth in TR beta(PV/+) mice but not in TR beta(PV/PV) mice. In TR beta(PV/PV) mice, however, lack of SRC-1 intensified the pathological progression of thyroid follicular cells to papillary hyperplasia, reminiscent of papillary neoplasia. In contrast, lack of SRC-1 did not affect responsiveness in the liver in regulating serum cholesterol in either TR beta(PV/+) or TR beta(PV/PV) mice. Lack of SRC-1 led to changes in the abnormal expression patterns of several T(3) target genes in the pituitary and liver. Thus, the present studies show that a coactivator such as SRC-1 could modulate the in vivo action of TR beta mutants in a tissue-dependent manner.
Kamiya
Yuji
Y
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264, USA.
Zhang
Xiao-Yong
XY
Ying
Hao
H
Kato
Yusuhito
Y
Willingham
Mark C
MC
Xu
Jianming
J
O'Malley
Bert W
BW
Cheng
Sheue-Yann
SY
D000818:Animals; D001846:Bone Development / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D005260:Female; D015870:Gene Expression; D013006:Growth Hormone / Q000235:genetics; D051548:Histone Acetyltransferases; D008099:Liver / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D056920:Nuclear Receptor Coactivator 1; D009929:Organ Size; D010902:Pituitary Gland / Q000378:metabolism / Q000503:physiopathology; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D037042:Thyroid Hormone Receptors beta; D037322:Thyrotropin, beta Subunit / Q000097:blood / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism*
D011988:Receptors, Thyroid Hormone; D037042:Thyroid Hormone Receptors beta; D037322:Thyrotropin, beta Subunit; D014157:Transcription Factors; D014284:Triiodothyronine; D013006:Growth Hormone; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1