A Novel Mechanism of Thyroid Hormone-dependent Negative Regulation by Thyroid Hormone Receptor, Nuclear Receptor Corepressor (NCoR), and GAGA-binding Factor on the Rat CD44 Promoter

摘要: CD44 is an adhesion molecule in the extracellular matrix that shows various functions, including tumor genesis and metastasis. A recent study showed expression level was strongly correlated with generation of papillary thyroid carcinomas, most prevalent malignancy gland. We report here negatively regulated by hormone (T3) through a novel mechanism. demonstrate nuclear receptor corepressor (NCoR) enhances (TR)-mediated basal transactivation weak TR·DNA interaction absence T3, which repressed T3 transient TR ·DNA interaction. Initially, we identified directly transcriptionally -responsive. Deletion mutation analysis indicated both GAGA-binding factor (GAF) binding sites on promoter were required for negative regulation T3. The further confirmed electrophoretic gel mobility shift assay, chromatin immunoprecipitation, transfection assays using non-DNA-binding TRα1 mutant. More interestingly, NCoR acted as co-activator to enhance TR-mediated This effect eliminated removal or binding. Most strikingly, induced remarkable increase at 40–60 min after exposure rapidly returned levels, suggesting T3-induced remodeling structure early stage stimulation resulting repression. Therefore, propose mechanism NCoR, GAF, interact T3-responsive element transactivation, whereas induces