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Steroid Receptor Coactivator-1 Deficiency Causes Variable Alterations in the Modulation of T₃-Regulated Transcription of Genes in Vivo

Research Institute of Environmental Medicine, Nagoya University (Y.T., Y.H., H.S., Y.M.), Nagoya 464-8601, Japan; Departments of Medicine (R.E.W., S.R.), Pediatrics (S.R.), and Pathology (P.S.), J. P. Kennedy, Jr. Mental Retardation Center (S.R.), and the Committee on Genetics (S.R.), University of Chicago, Chicago, Illinois 60637; and Department of Molecular and Cellular Biology, Baylor College of Medicine (J.X., B.W.O.), Houston, Texas 77030

Address all correspondence and requests for reprints to: Samuel Refetoff, M.D., Department of Medicine, MC3090, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637-6940. E-mail: . refetoff{at}medicine.bsd.uchicago.edu

Thyroid hormone exerts its biological effect by binding to a TR. Both liganded and unliganded TRs regulate the transcription of T₃-responsive genes. Cofactors with activating or repressing function modulate the transcriptional regulation by TRs. We showed that steroid receptor coactivator 1 (SRC-1)-deficient mice (SRC-1^-/-) exhibit partial resistance to thyroid hormone at the level of the pituitary thyrotrophs. To determine whether SRC-1 deficiency affects globally T₃-dependent transcriptional regulation, we studied the effects of thyroid hormone deprivation and replacement on the expression of several genes in different tissues of SRC-1^-/- and wild-type mice (SRC-1^+/+). Thyroid hormone deficiency was induced by a low iodine diet (LoI) supplemented with propylthiouracil (PTU) for 2 wk. L-T₃ was injected ip for the last 4 d in one group (PTU+T₃ group), and another group (PTU group) received only vehicle. Levels of mRNAs for T₃-responsive genes were determined by Northern blotting: GH and TSHß in pituitary; type 1 iodothyronine 5'-deiodinase, spot 14 (S14), and malic enzyme in liver; and sarcoplasmic reticulum calcium adenosine triphosphatase 2 and myosin heavy chain and ß in heart. Serum parameters, TSH, total cholesterol, creatine kinase, and alkaline phosphatase (AP), were also measured.

Hypothyroidism produced a comparable increase in TSHß mRNA in both genotypes, but its suppression by L-T₃ was attenuated in SRC-1^-/- mice. In contrast, hypothyroidism failed to reduce S14 mRNA levels in SRC-1^-/- mice. As a consequence, the response to L-T₃ was not observed in these mice. SRC-1 deficiency had no effect on the expression of the rest of the T₃-responsive genes examined. Of the four serum parameters, the T₃-mediated decrease in TSH and changes in AP were attenuated in SRC-1^-/- mice. We conclude that SRC-1 deficiency altered the expression of only some of the T₃-responsive genes. SRC-1 appears to be involved not only in transcriptional activation by liganded TRs, but also in the suppression by liganded or unliganded TRs. Some of the effects of SRC-1 may be TR isoform specific.

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