Estrogen receptor alpha, a molecular switch converting transforming growth factor-alpha-mediated proliferation into differentiation in neuroblastoma cells

Transforming growth factor-alpha (TGF-alpha) is known to promote both proliferation and differentiation of neural cell progenitors. Using the human neuroblastoma cell line SK-N-BE that is induced to proliferate by TGF-alpha, we demonstrated that the expression of a single transcription factor, the estrogen receptor-alpha (ERalpha), can reroute the TGF-alpha mitogenic signaling toward a path leading to differentiation. With selected mutations in ERalpha and signal transducer and activator of transcription 3 (Stat3), we demonstrated that the blockade of TGF-alpha mitotic potential was not dependent on ERalpha DNA binding activity but required a transcriptionally active Stat3. In neuroblastoma cells, 17beta-estradiol treatment induced a transient increase in the transcription of estrogen-responsive element-containing promoters including those regulating TGF-alpha and prothymosin alpha synthesis. Based on the data presented, we hypothesized that in the presence of prothymosin alpha, ERalpha activates its direct target genes and increases cell proliferation, whereas in the presence of high levels of TGF-alpha, ERalpha preferentially interacts with Stat3 and causes cell differentiation. Our results reveal a novel form of "end-product" regulation of an intracellular receptor that occurs through recruitment of membrane receptors and their signaling effector system. Cross-coupling between membrane and intracellular receptors has been described by several laboratories. This study proves the relevance of these interactions in cellular responses to growth factors.