Nuclear cytoplasmic shuttling by thyroid hormone receptors - Multiple protein interactions are required for nuclear retention

In this report, we have studied the intracellular dynamics and distribution of the thyroid hormone receptor-beta (TR beta) in living cells, utilizing fusions to the green fluorescent protein. Wild-type TB beta was mostly nucl ear in both the absence and presence of triiodothyronine; however, triiodot hyronine induced a nuclear reorganization of TR beta. By mutating defined r egions of TR beta, we found that both nuclear corepressor and retinoid X re ceptor are involved in maintaining the unliganded receptor within the nucle us. A TR beta mutant defective in DNA binding had only a slightly altered n uclear/cytoplasmic distribution compared with wild-type TR beta; thus, site -specific DNA binding is not essential for maintaining TR beta within the n ucleus. Both AT beta depletion studies and heterokaryon analysis demonstrat ed that TR beta rapidly shuttles between the nuclear and the cytoplasmic co mpartments. Cotransfection of nuclear corepressor and retinoid X receptor m arkedly decreased the shuttling by maintaining unliganded TR beta within th e nucleus. In summary, our findings demonstrate that TR beta rapidly shuttl es between the nucleus and the cytoplasm and that protein-protein interacti ons of TR beta with various cofactors, rather than specific DNA interaction s, play the predominant role in determining the intracellular distribution of the receptor.