p75 mediated apoptosis in neuroblastoma cells is inhibited by expression of TrkA

Background. Neurotrophins mediate their effects by binding to members of the Trk family of receptor tyrosine kinases and to the low-affinity nerve growth factor receptor p75. Nerve growth factor (NGF) has been demonstrated to support survival and differentiation of neuroblastoma (NB) cells by activation of the TrkA receptor. The p75 receptor belongs to the tumor necrosis factor (TN Fl family of death receptors and has been suggested as a receptor that mediates apoptosis in neuronal and NE cells. Procedure. To investigate the effect of p75 expression in NE, we transfected the p75 cDNA into SH-SY5Y cells, an NE cell line lacking expression of both p75 and TrkA. Results. Cell clones expressing elevated levels of p75 showed a high degree of apoptosis even in 10% serum-supplemented medium. Apoptotic signaling by p75 was ligand-independent and only partly caspase-dependent. The level of apoptosis correlated directly with the expression level of the receptor, indicating that p75 may activate the cell death program directly. How ever, additional transfection of TrkA into SY5Y-p75 cells resulted in a significantly reduced rate of apoptosis even in the absence of NGF. Conclusions. Thus, expression of the TrkA receptor itself inhibits p75 mediated apoptosis in NE cells. (C) 2000 Wiley-Liss, Inc.