Regulation of p110delta 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 p110delta catalytic subunit of PI3K, an enzyme that has attracted widespread interest because of its role in immunity and allergy.


RESULTS
We 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.


CONCLUSIONS
This study identifies a conserved PIK3CD promoter region that may account for the predominant leukocyte expression of p110delta.
Centre for Cell Signalling, Institute of Cancer, Queen Mary University of London, Charterhouse Square, London, United Kingdom.
Klaartje
K
Kok
Gemma E
GE
Nock
Elizabeth A G
EA
Verrall
Michael P
MP
Mitchell
Daan W
DW
Hommes
Maikel P
MP
Peppelenbosch
Bart
B
Vanhaesebroeck
D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D058534:Class I Phosphatidylinositol 3-Kinases; D019175:DNA Methylation; D005091:Exons; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006657:Histones / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020871:RNA Stability; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000502:physiology; D024363:Transcription Initiation Site
D020121:5' Untranslated Regions; D006657:Histones; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; C497132:PIK3CB protein, human