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Thyroid Hormone Receptor-Specific Interactions with Steroid Receptor Coactivator-1 in the Pituitary

Departments of Medicine (P.M.S., E.K., R.E.W.) and Pathology (P.M.S.), The University of Chicago, Chicago, Illinois 60637; Laboratoire de Biologie Moleculaire et Cellulaire de l’Ecole Normale Supérieure de Lyon (O.C., K.G., J.S.), Lyon 69364, France; Department of Molecular and Cellular Biology (J.X., B.W.O’M.), Baylor College of Medicine, Houston, Texas 77030; and Research Institute of Environmental Medicine (H.S., Y.M.), Nagoya University, Nagoya 464-8601, Japan

Address all correspondence and requests for reprints to: Roy E. Weiss, M.D., Ph.D., Thyroid Study Unit, MC 3090, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois. E-mail: rweiss{at}medicine.bsd.uchicago.edu.

Steroid receptor coactivator-1 (SRC-1) is a transcription cofactor that enhances the hormone-dependent action mediated by the thyroid hormone (TH) receptor (TR) as well as other nuclear receptors. However, it is not known whether the SRC-1-mediated activation of TH-regulated gene transcription is TR isoform specific in the pituitary. We generated mice that were deficient in TR and SRC-1 (TR^0/0SRC-1^-/-), as well in TRß and SRC-1 (TRß^-/-SRC-1^-/-), and thyroid function tests and effects of TH deprivation and TH treatment were compared with wild-type mice or mice with deletion of either TRs or SRC-1 alone. We have shown that 1) TRß^-/-SRC-1^-/- mice demonstrate more severe TH resistance than either the SRC-1^-/- or TRß^-/- mice; the additive effect indicates that SRC-1 has an independent role in TH action over that of TRß; 2) SRC-1 facilitates TRß and TR-mediated down-regulation of TSH, as TR^0/0SRC-1^-/- mice demonstrate TH resistance rather than hypersensitivity as seen in TR^0/0mice; and 3) a compensatory increase in SRC-1 expression is associated with the TH hypersensitivity seen in TR-deficient animals. We conclude that SRC-1 action in the pituitary mediates TH action via specific TR subtypes.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Coregulators:   SRC-1  |  GRIP1  |  AIB1

Ligands:   Thyroid hormone

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