Thyroid Hormone Dependent Regulation of Target Genes and Their Physiological Significance

Thyroid hormone (T3) regulates growth, development anddifferentiation. These activities are mediated by nuclear thyroidhormone receptors (TRs), which belong to the steroid/thyroidhormone receptor superfamily of ligand-dependent transcriptionfactors. In an effort to study the mechanism of targetgenes regulation and their physiological significance after T3treatment in a TRα-overexpressing hepatoma cell line(HepG2-TRα), c-DNA microarrays were performed. The datademonstrated that approximately 149 genes represented werepositively regulated by T3, including fibrinogen, transferrin,fibronectin (FN), androgen receptor (AR)-associated protein(ARA70), and dehydroepiandrosterone sulfotransferase family1A member 2 (SULT2A1). To further confirm the microarrayresults, a quantitative-reverse transcription polymerase chainreaction (Q-RT-PCR) was applied. The protein synthesisinhibitor, cycloheximide was used to determine whether the regulation was direct or indirect.A promoter assay further showed that T3 regulation was largely at the level of transcription.Although those genes were isolated from a human tumor cell line, they are regulatedsimilarly in rats and humans. These results indicate that T3 might play an importantrole in the process of blood coagulation, inflammation, metabolism and cell proliferation.This may help to explain the association between thyroid diseases and the mis-regulation ofthe inflammatory and clotting profiles evident in the circulatory systems of these patients.