Regulation of PrPC expression: Nerve growth factor (NGF) activates the prion gene promoter through the MEK1 pathway in PC12 cells

A high expression of PrPC in cells is one factor that increases the risk of conversion to the misfolded, disease-associated form (PrPSc) characteristic of transmissible spongiform encephalopathies. Thus, developing a method to control the level of PrPC expression in cells could be one way to delay or prevent the onset of clinical signs of these diseases. In this study the mechanisms controlling the expression of the Prnp gene in PC12 cells and in rat brain were examined. We observed a slight activation of a cloned fragment of the human PRNP gene promoter using the luciferase reporter system in PC12 cells stimulated with nerve growth factor (NGF). The activating effect of NGF was enhanced by mitogen-activated protein kinase (MEK1) and suppressed by myristylated serine/threonine kinase (myrAKT). These results suggest that MEK1 is a positive activator of the PRNP promoter that inhibits the AKT pathway. Independent experiments suggested that high expression of PrPC in the brain depends on the rate of translation and/or the efficiency of PrPC stabilization. We also investigated the epigenic status of the Prnp promoter. We observed no increase of PrPC or Prnp mRNA levels in PC12 cells after treatment with the DNA-demethylating agent. The Prnp promoter did not display methylation either in NGF-treated and untreated PC12 cells, or in the rat brain. These results improve the understanding of the regulation of the Prnp gene promoter, a DNA regulatory element controlling the expression of PrPC, a protein involved in several neurological diseases.