Tissue-specific differential repression of gene expression by a dominant negative mutant of thyroid hormone beta1 receptor.
Resistance to thyroid hormone (RTH) is a genetic disease caused by the mutations of the thyroid hormone beta receptor (TRbeta) 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 TRbeta1 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/TRpbeta1 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.
D000818:Animals; D004268:DNA-Binding Proteins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics*; D005799:Genes, Dominant; D006801:Humans; D009154:Mutation / Q000235:genetics* / Q000502:physiology*; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000494:pharmacology; D015533:Transcriptional Activation / Q000502:physiology; D014284:Triiodothyronine / Q000502:physiology; D014407:Tumor Cells, Cultured