Staurosporine (STS) has been reported its not only a pro-apoptotic agent, but also a terminal differentiation inducer in several neuroblastoma cell lines. Here, we report involvement of amyloid precursor protein (APP) in it STS induced astrocytic differentiation of human neural progenitor cells (NT-2/D1). We found that STS-treated NT-2/D1 cells expressed astrocyte-specific glial fibrillary acidic protein (GFAP), aspartate transporter, and glutamate transporter-1 with a distinctive astrocytic morphology. STS treatment increased GFAP promoter activity and increased expression and secretion of APP in NT-2/D1 cell culture. Overexpressed A PP enhanced GFAP promoter activity and expression of GFAP, while gene silencing of APP by RNA interference decreased GFAP expression. These results indicate involvement of APP in STS induced astrocytic differentiation of NT-2/D1 cells. Furthermore, suppression of ERK1/2 phosphorylation, which is known to regulate APP expression by a MEK1 inhibitor, PD098059, reduced both APP and GFAP expression ill STS treated NT-2/D1 cells. Thus, STS may induce astrocytic differentiation of NT-2/D1 by increasing APP levels associate with activation of ERK pathway. (c) 2006 Elsevier Inc. All rights reserved.