Regulation of p110[delta] PI 3-Kinase Gene Expression

Background Despite 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 p110[delta] catalytic subunit of PI3K, an enzyme that has attracted widespread interest because of its role in immunity and allergy. Principal Findings We show that p110[delta] expression is mainly regulated at the transcriptional level. In fibroblasts, lymphocytes and myeloid cells, p110[delta] gene transcription appears to be constitutive and not subject to acute stimulation. 5'RACE experiments revealed that p110[delta] 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 p110[delta] transcripts are higher in leukocytes compared to non-leukocytes, with the p110[delta] transcript containing exon -2a most abundantly expressed. We have identified a highly conserved transcription factor (TF) binding cluster in the p110[delta] 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. Conclusion This study identifies a conserved PIK3CD promoter region that may account for the predominant leukocyte expression of p110[delta].