Regulation of p110delta PI 3-kinase gene expression.

Abstract

BackgroundDespite an intense interest in the biological functions of the phosphoinositide 3-kinase (PI3K) signalling enzymes, little is known about the regulation of PI3K gene expression. This also applies to the leukocyte-enriched p110delta catalytic subunit of PI3K, an enzyme that has attracted widespread interest because of its role in immunity and allergy.Principal findingsWe show that p110delta expression is mainly regulated at the transcriptional level. In fibroblasts, lymphocytes and myeloid cells, p110delta gene transcription appears to be constitutive and not subject to acute stimulation. 5'RACE experiments revealed that p110delta mRNA transcripts contain distinct upstream untranslated exons (named exon -1, -2a, -2b, -2c and -2d), which are located up to 81 kb upstream of the translational start codon in exon 1. The levels of all the different p110delta transcripts are higher in leukocytes compared to non-leukocytes, with the p110delta transcript containing exon -2a most abundantly expressed. We have identified a highly conserved transcription factor (TF) binding cluster in the p110delta gene which has enhanced promoter activity in leukocytes compared to non-leukocytes. In human, this TF cluster is located immediately upstream of exon -2a whilst in mouse, it is located within exon -2a.ConclusionThis study identifies a conserved PIK3CD promoter region that may account for the predominant leukocyte expression of p110delta.