Specificity of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action.
Isoforms of the thyroid hormone receptor (TR)alpha and TRbeta genes mediate thyroid hormone action. How TR isoforms modulate tissue-specific thyroid hormone (TH) action remains largely unknown. The steroid receptor coactivator-1 (SRC-1) is among a group of transcriptional coactivator proteins that bind to TRs, along with other members of the nuclear receptor superfamily, and modulate the activity of genes regulated by TH. Mice deficient in SRC-1 possess decreased tissue responsiveness to TH and many steroid hormones; however, it is not known whether or not SRC-1-mediated activation of TH-regulated gene transcription in peripheral tissues, such as heart and liver, is TR isoform specific. We have generated mice deficient in TRalpha and SRC-1, as well as in TRbeta and SRC-1, and investigated thyroid function tests and effects of TH deprivation and TH treatment compared with wild-type (WT) mice or those deficient in either TR or SRC-1 alone. The data show that 1) in the absence of TRalpha or TRbeta, SRC-1 is important for normal growth; 2) SRC-1 modulates TRalpha and TRbeta effects on heart rate; 3) two new TRbeta-dependent markers of TH action in the liver have been identified, osteopontin (upregulated) and glutathione S-transferase (downregulated); and 4) SRC-1 may mediate the hypersensitivity to TH seen in liver of TRalpha-deficient mice.
Sadow
Peter M
PM
Departments of Medicine and Pathology, University of Chicago, Illinois 60637, USA.
Chassande
Olivier
O
Gauthier
Karine
K
Samarut
Jacques
J
Xu
Jianming
J
O'Malley
Bert W
BW
Weiss
Roy E
RE
D000818:Animals; D004734:Energy Metabolism; D015870:Gene Expression / Q000187:drug effects; D005838:Genotype; D006339:Heart Rate; D051548:Histone Acetyltransferases; D020738:Leptin / Q000097:blood; D008099:Liver / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056920:Nuclear Receptor Coactivator 1; D020411:Oligonucleotide Array Sequence Analysis; D011988:Receptors, Thyroid Hormone / Q000172:deficiency / Q000502:physiology*; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013961:Thyroid Gland / Q000502:physiology; D037021:Thyroid Hormone Receptors alpha / Q000172:deficiency / Q000502:physiology*; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones / Q000494:pharmacology*; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology*; D014284:Triiodothyronine / Q000097:blood; D015430:Weight Gain
D020738:Leptin; D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D014157:Transcription Factors; D014284:Triiodothyronine; D013972:Thyrotropin; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D013974:Thyroxine