Cross-coupling between insulin and estrogen receptor in human neuroblastoma cells.

Abstract

Insulin is a well known mitotic agent for neuroblastoma cells. Human SK-N-BE neuroblastoma cells stably transfected with the estrogen receptor, however, undergo growth arrest and differentiation when treated with 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 estrogen receptor and that the communication between estrogen and insulin receptor systems occurs via selected and specific transduction signals. In fact, by the use of dominant negative and dominant positive mutants we demonstrate that p21ras is essential for insulin and estrogen receptor coupling. With pharmacological tools, we prove that PI 3'kinase does not contribute to this cross-talk and that protein kinase C triggers transduction signals that act in synergism with p21ras. These results prove the intricacy of all these intracellular paths of communication. The finding that, in neuroblastoma cells, selected signal transduction systems are involved in the insulin-dependent activation of estrogen receptor is of particular interest considering that estrogen receptor might restrict the role played by insulin during the differentiation of neural cells and interfere with its proliferative potential while allowing its regulation of other functions related to cell survival.

17β-Estradiol Stimulates Mouse Neuropeptide Y-Y₁ Receptor Gene Transcription by Binding to Estrogen Receptor Alpha in Neuroblastoma Cells

“…The increase in basal transcription observed when ERα was added to the transfection mixture, was attributed to the presence of growth factors present in the stripped serum and responsible for ligand-independent activation of ER. Such an effect has been already reported by our and other groups [32]. …”

“…Attempts were made to carry out the cotransfection experiments also in neuroblastoma SK-N-BE, a cell system proved to be useful to investigate other estrogen-responsive promoters [32, 33](fig. 1B).…”

Structure–function relationship of estrogen receptor α and β: Impact on human health

“…In line with this cross-talk between ERa and EGF, mice which have ERa inactivated (aERKO mice) lack the uterine E2-like response to EGF even though the EGF signaling pathway is not disrupted (Curtis et al, 1996). Other growth factors which activate ERa signaling include insulin (Newton et al, 1994;Patrone et al, 1996Patrone et al, , 1998, insulin-like growth factor-1 (IGF-1) (Aronica and Katzenellenbogen, 1993;Ma et al, 1994;Newton et al, 1994;Ignar-Trowbridge et al, 1996), and TGF-b (Ignar-Trowbridge et al., 1996). In addition, heregulin, interleukin-2, and dopamine (Power et al, 1991;Smith et al, 1993;Pietras et al, 1995) can also modulate ER activity.…”

Role of estrogen receptor α in membrane-initiated signaling in neural cells: Interaction with IGF-1 receptor

“…The role of IGF-1 receptor as regulator of ER␣ transcriptional activity has also been characterized in neuronal cells. Maggi and co-workers have determined that insulin/IGF-1 signaling can activate the unliganded ER␣ in neuronal cells via the ras/MAPK pathway [63,64] and that this activation involved the N-terminal activation function 1 (AF-1) domain of the receptor [65]. More recent studies have shown that although IGF-1 promotes ligand-independent ER transcriptional activity, it has a different effect in the presence of estradiol.…”