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Am J Physiol Endocrinol Metab 284: E36-E46, 2003. First published September 17, 2002; doi:10.1152/ajpendo.00226.2002
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Vol. 284, Issue 1, E36-E46, January 2003

Specificity of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action

Peter M. Sadow1,2, Olivier Chassande3, Karine Gauthier3, Jacques Samarut3, Jianming Xu4, Bert W. O'Malley4, and Roy E. Weiss1

Departments of 1 Medicine and 2 Pathology, University of Chicago, Chicago, Illinois 60637; 3 Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, 69364 Lyon, France; and 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

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.

knockout; resistance to thyroid hormone; thyrotropin


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