Isoform-selective induction of human p110? PI3K expression by TNF?: identification of a new and inducible PIK3CD promoter.

ABSTRACT: 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 IA PI3Ks that consist of a catalytic subunit (p110?, p110? and p110?) in complex with a p85 regulatory subunit. Whereas p110? and p110? are ubiquitously expressed, high levels of p110? are mainly found in white blood cells, with most non-leucocytes expressing low levels of p110?. In the present paper we report that TNF? (tumour necrosis factor ?) stimulation induces p110? 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? gene (PIK3CD). This promoter is used in all cell types, including solid tumour cell lines that express p110?, and is activated by TNF? in ECs and synovial fibroblasts. We further present a detailed biochemical and bioinformatic characterization of p110? 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.

SUBMITTER: Whitehead MA 

PROVIDER: S-EPMC3328000 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature