Isoform-selective induction of human p110δ PI3K expression by TNFα: identification of a new and inducible PIK3CD promoter

PI3Ks (phosphoinositide 3-kinases) are signalling molecules and drug targets with important biological functions, yet the regulation of PI3K gene expression is poorly understood. Key PI3Ks are the class 1A PI3Ks that consist of a catalytic subunit (p110 alpha, p110 beta and p110 delta) in complex with a p85 regulatory subunit. Whereas p110 alpha and p110 beta are ubiquitously expressed, high levels of p110 delta are mainly found in white blood cells, with most non-leucocytes expressing low levels of p110 delta. In the present paper we report that TNF alpha (tumour necrosis factor a) stimulation induces p110 delta expression in human ECs (endothelial cells) and synovial fibroblasts, but not in leucocytes, through transcription start sites located in a novel promoter region in the p110 delta gene (PIK3CD). This promoter is used in all cell types, including solid tumour cell lines that express p110 delta, and is activated by TNF alpha in ECs and synovial fibroblasts. We further present a detailed biochemical and bioinformatic characterization of p110 delta gene regulation, demonstrating that PIK3CD has distinct promoters, some of which can be dynamically activated by pro-inflammatory mediators. This is the first molecular identification of a PI3K promoter under the control of acute extracellular stimulation.