Identification of 24p3 as a Direct Target of Foxo3a Regulated by Interleukin-3 through the Phosphoinositide 3-Kinase/Akt Pathway

Pro-apoptotic protein 24p3, a member of lipocalin family, is induced upon interleukin-3 (IL-3) deprivation and plays a pivotal role in induction of apoptosis in hematopoietic cells. However, the molecular mechanism by which IL-3 regulates 24p3 expression remains largely unknown. Here, we show that 24p3 is a direct target of Foxo3a and that phosphoinositide 3-kinase (PI3K)/Akt mediates IL-3-repressed 24p3 through regulation of Foxo3a. Inhibition of the PI3K/Akt (but not MAPK) pathway induced 24p3 expression and programmed cell death in FL5.12 cells. Furthermore, constitutively active Akt largely attenuated 24p3 expression and apoptosis in response to IL-3 withdrawal. Foxo3a directly bound to the 24p3 promoter and induced promoter activity. Akt abrogated wild-type Foxo3a-induced (but notAkt-non-phosphorylatable Foxo3a(3A)-induced) 24p3expression and promoter activity. Therefore, these data indicate for the first time that 24p3 is a Foxo3a target gene and that PI3K/Akt (but not MAPK) mediates IL-3-regulated 24p3 expression in hematopoietic cells.