CROSS-COUPLING BETWEEN INSULIN AND ESTROGEN-RECEPTOR IN HUMAN NEUROBLASTOMA-CELLS

Insulin is a well known mitotic agent for neuroblastoma cells. Human S K-N-BE neuroblastoma cells stably transfected with the estrogen recept or, however, undergo growth arrest and differentiation when treated wi th insulin. These effects were shown to be due to an insulin-dependent activation of the unliganded estrogen receptor. Here, we demonstrate that this activation involves the AF-2 COOH-terminal domain of the est rogen receptor and that the communication between estrogen and insulin receptor systems occurs via selected and specific transduction signal s. In fact, by the use of dominant negative and dominant positive muta nts we demonstrate that p21(ras) is essential for insulin and estrogen receptor coupling. With pharmacological tools, we prove that PI 3'kin ase does not contribute to this cross-talk and that protein kinase C t riggers transduction signals that act in synergism with p21(ras). Thes e results prove the intricacy of all these intracellular paths of comm unication. The finding that, in neuroblastoma cells, selected signal t ransduction systems are involved in the insulin-dependent activation o f estrogen receptor is of particular interest considering that estroge n receptor might restrict the role played by insulin during the differ entiation of neural cells and interfere with its proliferative potenti al while allowing its regulation of other functions related to cell su rvival.