Regulation of p110δ PI 3-kinase gene expression

Klaartje Kok*, Gemma E. Nock, Elizabeth A.G. Verrall, Michael P. Mitchell, Daan W. Hommes, Maikel P. Peppelenbosch, Bart Vanhaesebroeck

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

45 Citations (Scopus)
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Abstract

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 p110δ catalytic subunit of PI3K, an enzyme that has attracted widespread interest because of its role in immunity and allergy. Principal Findings: We show that p110δ expression is mainly regulated at the transcriptional level. In fibroblasts, lymphocytes and myeloid cells, p110δ gene transcription appears to be constitutive and not subject to acute stimulation. 5′RACE experiments revealed that p110δ 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 p110δ transcripts are higher in leukocytes compared to non-leukocytes, with the p110δ transcript containing exon -2a most abundantly expressed. We have identified a highly conserved transcription factor (TF) binding cluster in the p110δ 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 p110δ.

Original languageEnglish
Article numbere5145
JournalPLoS ONE
Volume4
Issue number4
DOIs
Publication statusPublished - 9 Apr 2009
Externally publishedYes

Bibliographical note

Funding:
Current and previous funding from PIramed, AstraZeneca and UCB. The funders had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript. Personal support was from the AMC, Amsterdam, The Netherlands (KK), the Medical Research Council UK (EV, GEN) and
the Ludwig Institute for Cancer Research (KK, GEN, EV, BV).

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