Activity and response to serum of the mammalian thyroid hormone deiodinase 3 gene promoter: identification of a conserved enhancer.

Dio3 is an imprinted gene that codes for the type 3 deiodinase (D3), a conserved selenocysteine-containing enzyme that degrades thyroid hormones (TH) into inactive metabolites. D3 is partially responsible for the very low TH levels that are found in utero as it is highly expressed in mammalian uterus, placenta, and fetal tissues. For this reason, it is presumed that D3 protects the developing fetus from high, adult-like levels of TH. To further understand the regulation of D3 expression, we analyzed the promoter activity of 6 kb of 5'-flanking regions of the human and mouse Dio3, by transient transfection studies. Both mouse and human Dio3 promoters are markedly responsive to serum and, to a lesser extent, to phorbol esters and fibroblast growth factor, but only in a cell line in which the endogenous Dio3 mRNA is also responsive to those factors. In addition, we identified a conserved enhancer located 3' of the gene containing putative AP-1 and serum response elements, and that further increases the serum responsiveness of the Dio3 promoter in a cell-specific manner. The cell-specific serum response of the Dio3 promoter and the identified enhancer may play critical roles in the regulation of gene expression at this imprinted locus.