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Endocrinology Vol. 139, No. 10 4197-4204
Copyright © 1998 by The Endocrine Society

ARTICLES

Lack of Coactivator Interaction Can Be a Mechanism for Dominant Negative Activity by Mutant Thyroid Hormone Receptors1

Ying Liu, Akira Takeshita, Silvia Misiti, William W. Chin and Paul M. Yen

Division of Genetics (A.T., S.M., W.W.C.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; Molecular and Cellular Endocrinology Branch (Y.L., P.M.Y.), NIDDK/National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Paul M. Yen, Molecular and Cellular Endocrinology Branch, NIDDK/National Instiutes of Health, Building 10, Room 8D04, 9000 Rockville Pike, Bethesda, Maryland 20892. E-mail: PaulY{at}Bdg10.NIDDK.NIH.Gov

We studied the interactions of two natural thyroid hormone receptor (TR) mutants from patients with resistance to thyroid hormone (RTH) and an artificial TR mutant with a nuclear receptor corepressor, N-CoR, and a steroid receptor coactivator, SRC-1. In electrophoretic mobility shift assays, wild-type TRß-1 interacted with N-CoR in the absence of ligand, whereas T3 caused dissociation of the TRß-1/N-CoR complex and formation of TRß-1/SRC-1 complex. In contrast, a natural mutant (G345R) with poor T3-binding affinity formed TRß-1/N-CoR complex, both in the absence and presence of T3, but could not form TRß-1/SRC-1 complex. Another TR mutant, which bound T3 with normal affinity and containing a mutation in the AF-2 region (E457D), had normal interactions with N-CoR but could not bind SRC-1. Both these mutants had strong dominant negative activity on wild-type TR transactivation. Studies with a TR mutant that had slightly decreased T3-binding affinity (R320H) showed a T3-dependent decrease in binding to N-CoR and increase in binding to SRC-1 that reflected its decreased ligand binding affinity. Additionally, when N-CoR and SRC-1 were added to these receptors at various T3 concentrations in electrophoretic mobility shift assays, TR/N-CoR and TR/SRC-1 complexes, but not intermediate complexes were observed, suggesting that N-CoR release is necessary before SRC-1 binding to TR. Our data provide new insight on the molecular mechanisms of dominant negative activity in RTH and suggest that the inability of mutant TRs to interact with coactivators such as SRC-1, which results from reduced T3-binding affinity, is a determinant of dominant negative activity.




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