Tissue-specific differential repression of gene expression by a dominant negative mutant of thyroid hormone beta 1 receptor

Resistance to thyroid hormone (RTH) is a genetic disease caused by the muta tions of the thyroid hormone beta receptor (TR beta) gene, producing recept ors with a dominant negative action. The present study addressed the questi on as to whether tissue-specific factors modulate the dominant negative fun ction in different tissues. We prepared stably transfected pituitary GH3 (G H3-PV) and liver SK-Hep-1 (SK-Hep-1-PV) cell lines with a potent dominant n egative mutant, PV. The growth hormone (GH) and the malic enzyme genes (ME) in GH3 and SK-Hep-l, respectively, are directly regulated by the thyroid h ormone, 3,3,'5-triiodo-L-thyronine (T-3) The ratio of the expressed PV/endo genous TR beta(1) proteins was approximately 20 and 5 for GH3-PV and SK-Hep -1-PV cells, respectively. However, the T-3-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/TR beta(1 ) protein ratio with the dominant negative potency of mutant PV. Furthermor e, the synergistic effect of the pituitary-specific factor 1 on the TR-medi ated CH promoter activity was not repressed by mutant PV. Taken together, t hese results suggest that the dominant negative effect of mutant TR is vari able in the tissues studied.