Tissue-Specific Differential Repression of Gene Expression by a Dominant Negative Mutant of Thyroid Hormone β 1 Receptor

Abstract

Resistance to thyroid hormone (RTH) is a genetic disease caused by the mutations of the thyroid hormone β receptor (TRβ) gene, producing receptors with a dominant negative action. The present study addressed the question as to whether tissue-specific factors modulate the dominant negative function in different tissues. We prepared stably transfected pituitary GH3 (GH3-PV) and liver SK-Hep-1 (SK-Hep-1-PV) cell lines with a potent dominant negative mutant, PV. The growth hormone (GH) and the malic enzyme genes (ME) in GH3 and SK-Hep-1, respectively, are directly regulated by the thyroid hormone, 3,3,′5-triiodo-L-thyronine (T₃). The ratio of the expressed PV/endogenous TRβ₁ proteins was approximately 20 and 5 for GH3-PV and SK-Hep-1-PV cells, respectively. However, the T₃-activated expression of the GH gene in GH3-PV and ME gene in SK-Hep-1-PV was repressed by approximately 30% and 90%, respectively, indicating the lack of correlation of PV/TRβ₁ protein ratio with the dominant negative potency of mutant PV. Furthermore, the synergistic effect of the pituitary-specific factor 1 on the TR-mediated GH promoter activity was not repressed by mutant PV. Taken together, these results suggest that the dominant negative effect of mutant TR is variable in the tissues studied.