MODIFICATION OF THYROID-HORMONE AND 9-CIS RETINOIC ACID SIGNALING BY OVEREXPRESSION OF THEIR COGNATE RECEPTORS USING ADENOVIRAL VECTOR

Tissue responsiveness to a hormone is dependent on the amounts of its receptor expressed under physiological conditions, In the present repo rt. we compared the magnitude of ligand-dependent transactivation medi ated by two nuclear hormone receptors, thyroid hormone receptor beta ( TR) and retinoid X receptor alpha (RXR), when overexpressed in a varie ty of cell lines. TR, RXR and reporter (luciferase) genes under the co ntrol of artificial hormone response elements were introduced into the cells using recombinant adenovirus (Ad) vectors, to ensure highly eff icient gene delivery. Although the amounts of TR expressed were simila r in the cell lines infected with Ad-TR, T3 dependent induction of rep orter gene expression was significantly greater in HepG2 than in Cos7, GH3, or JEG3 cells, indicating that factors other than TR are limitin g the responsiveness to T3. The enhanced response to 9-cis retinoic ac id in cells overexpressing RXR was much greater in JEG3 than in HepG2 which had the highest responsiveness to T3 under TR overexpression. Th ese results indicate that the factors affecting T3 responsiveness are not identical to those affecting the 9-cis retinoic acid responsivenes s. On the other hand, overexpression of RXR in addition to TR resulted in a decrease in T3-responsiveness in all the cell lines tested, sugg esting that some cofactors are common to TR and RXR. (C) 1997 Elsevier Science Ireland Ltd.