Phosphoinositide 3-kinase regulates a subset of interferon-alpha-stimulated genes

IFN alpha activates JAK-STAT signaling, followed by up-regulation of a cohort of genes. Also the PI3K pathway is activated by IFNa, but the significance of this activation for IFN-induced gene expression and biological functions remains unclear. We used a cDNA microarray to identify IFN alpha target genes whose expression is dependent on PI3K signaling. cDNAs from U266-1984 cells, untreated and IFN alpha-treated with or without PI3K inhibitor, Ly294002, was used in hybridization to a microarray representing 7000 genes. Among the 260 genes stimulated by IFNa, the expression of 95.4% was not affected by the presence of Ly294002. Luciferase reporter assays using consensus IFN-stimulated sequences confirmed that general regulation of transcription by IFN alpha is not altered by Ly294002. Up-regulation of 10 genes (3.8%) was affected in the presence of Ly294002. Bioinformatic analysis revealed the presence of consensus sequences of both STAT-specific and the PI3K pathway-regulated transcription factors, further suggesting that these genes are regulated by both pathways. We have recently shown that IFN alpha-induced apoptosis in the myeloma cell line U266-1984 was efficiently blocked by inhibition of PI3K. Therefore we suggest that the genes that are regulated by both the STAT and the PI3K pathways by IFNa in these cells may be specifically involved in the induction of apoptosis. (c) 2006 Elsevier Inc. All rights reserved.