The long term goal of this project is to elucidate the mechanism of action of thyroid hormone (T3). A beta-type c-erbA cDNA cone (erb62) has been isolated from a GH3 cell library. The erb62 protein binds T3 with high affinity, and the T3-erb62 complex stimulates gene expression directed by eh rat growth hormone (rGH) promoter. The isolation of other c-erbA cDNA clones suggests these all may encode T3 receptors with distinct functions. The objective of this proposal is to use the erb62 cDNA to rest the hypothesis that the organ specificity and developmental specificity of many T3 actions may be due to: a) differential expression of functionally distinct classes of T3 receptor molecules, or b) the requirement of other, tissue specific, factors in addition to the T3 receptor to generate a T3 response. Transient transfection studies will be used to study whether the T3-erb62 complex can stimulate rGH promoter directed gene activity in a broad range of cell lines, or whether host factors limit the response. The ability of other endogenously expressed erbA molecules to support T3 inducible rGH promoter activity also will be assessed. Stable transfectants will be used to assess other T3-erb62 effects, e.g. induction of enzyme activities and mRNA levels. The results will help define the functional role of erb62 as a T3 receptor, and assess the importance of other factors in determining the tissue specific nature of many T3 effects. This research is relevant to the diagnosis and treatment of both hypothyroidism and hyperthyroidism. It is relevant to understanding the role of thyroid hormones in brain development.
| O'Donnell, A L; Koenig, R J (1990) Mutational analysis identifies a new functional domain of the thyroid hormone receptor. Mol Endocrinol 4:715-20 |
| Dalman, F C; Koenig, R J; Perdew, G H et al. (1990) In contrast to the glucocorticoid receptor, the thyroid hormone receptor is translated in the DNA binding state and is not associated with hsp90. J Biol Chem 265:3615-8 |
| Cook, C B; Koenig, R J (1990) Expression of erbA alpha and beta mRNAs in regions of adult rat brain. Mol Cell Endocrinol 70:13-20 |
