The role of P13K p1168 in the regulation of gene expression in murine macrophages.

Abstract

PI3K are a family of lipid kinase enzymes that are involved in a broad spectrum of cellular, physiological and pathological processes. Notably, PI3K dysfunction is associated with cancer, inflammation and metabolism. The PI3K family consists of three classes, Class I, Class II and Class III, which are defined according to their structure, function and lipid specificity. Class I is further subdivided into Class IA, which consists of p110, p110 and p110, and Class IB, which consists of p110. Both p110 and p110 are ubiquitously expressed. Conversely, p110and p110 have a restricted tissue distribution, limited mainly to leukocytes, where they are highly enriched. In this work, we have focused on understanding the role of p110 in macrophages and specifically, on gaining insight into its role in genome-wide transcriptional regulation. Our results suggest that the contribution of p110δ activity to transcriptional regulation in growing primary macrophages is very limited. Genetic or pharmacological inactivation of p110δ resulted in differential regulation of less than twenty-five unique genes. Interestingly, at the level of genome-wide transcription, we have observed a significant difference between the effects of pharmacological and genetic inactivation. Indeed, none of the genes identified were differentially regulated as a result of both pharmacological and genetic inactivation of p110δ. We discovered that the majority of the genes differentially regulated in p110δ KI macrophages are located within close proximity to the Pik3cd gene. We propose that the differential regulation of these genes represents an artefact of the genetic engineering strategy employed to generate the p110δ KI mice. We have confirmed that genetic inactivation of p110δ results in reduced expression of Rab6b, a gene which is not linked to Pik3cd. We have confirmed that this does translate into a reduced level of rab6b protein in p110δ KI macrophages.