Rapid membrane effects of steroids in neuroblastoma cells: effects of estrogen on mitogen activated protein kinase signalling cascade and c-fos immediate early gene transcription.

Rapid effects of steroid hormones have been observed in neuronal cells for many years. We show here, that in the human neuroblastoma cell line SK-N-SH, the membrane impermeable conjugated 17beta-estradiol (E2BSA) activates mitogen activated protein kinase kinase (MAPKK or MEK) and induces the phosphorylation and activation of both ERK-1 and ERK-2 (mitogen activated protein kinase or MAPK). Additionally, E2BSA induces the transcription of a reporter gene construct driven by the promoter of the mouse c-fos proto-oncogene. The effects of this membrane impermeable estrogen on c-fos transcription are not inhibited by the estrogen receptor antagonists Tamoxifen or ICI 182,780, further excluding the involvement of the intracellular estrogen receptor. This is also illustrated by the observation that E2BSA does not activate estrogen response element (ERE) mediated transcription. This is the first report of rapid membrane effects of 17beta-estradiol on growth factor related signalling pathways in neuronal cells, and indicates a potential mechanism by which 17beta-estradiol might affect the expression of genes whose promoters do not contain EREs but are responsive to factors acting through other response elements such as AP-1 and SRE sites.