The precise signaling pathways which contribute to amyloid precursor protein (APP) gene expression remain incompletely characterized. We evaluated the role of protein kinases, calcium and phospholipase C (PLC) in modulating APP mRNA levels. There was a rapid 35-40% reduction in the steady state level of APP mRNA upon stimulation of peripheral blood mononuclear cells (PBMC) with phorbol 12-myristate 13-acetate (PMA), A23187 or ionomycin. However the protein kinase C (PKC), protein kinase A (PKA) or PLC pathways did not mediate these changes in APP mRNA levels. Rather, PMA or ionophore caused a rapid activation of extracellular-regulated kinase (ERK). This effect was independent of PKC and sensitive to U0126. After 4 h of PMA treatment, the remaining APP mRNA became indefinitely stable. We propose a model for the biphasic decay of APP mRNA in which ERK activation by PMA causes sequential upregulation of two APP mRNA binding proteins, nucleolin and hnRNP C. We attribute the initial rapid loss of APP mRNA to the helicase activity associated with nucleolin and later stabilization to hnRNP C binding to the 29 base instability element in the 3'-UTR of APP mRNA.