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Modulation by Steroid Receptor Coactivator-1 of Target-Tissue Responsiveness in Resistance to Thyroid Hormone

Laboratory of Molecular Biology (Y.K., X.-Y.Z., H.Y., Y.K., S.-Y.C.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264; Department of Pathology (M.C.W.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157; and Department of Cell Biology (J.X., B.W.O.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. S.-Y. Cheng, Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Drive, Room 5128, Bethesda, Maryland 20892-4264. E-mail: sycheng{at}helix.nih.gov.

Mutations in the thyroid hormone receptor-ß gene (TRß) 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, TRßPV knockin mice, in the SRC-1 null background. Lack of SRC-1 intensified the dysfunction of the pituitary-thyroid axis and impaired growth in TRß^PV/+ mice but not in TRß^PV/PV mice. In TRß^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 TRß^PV/+ or TRß^PV/PV mice. Lack of SRC-1 led to changes in the abnormal expression patterns of several T₃ 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 TRß mutants in a tissue-dependent manner.

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