Involvement of the Adenine/Uridine‐Rich Element Binding Proteins and microRNA Pathway in the Regulation of Human Interleukin‐3 mRNA

Abstract

Human Interleukin‐3 (hIL‐3) is a cytokine that promotes myelopoiesis, differentiation of macrophages and granulocytes. Aberrant expression of this pleiotrophic factor has been involved in multiple myeloma and other hematological cancer. hIL‐3 harbors Adenine/Uridine‐Rich Elements (AREs) in its 3′‐UTR that mediate its post‐transcriptional control. The main objective of this study is to characterize the role of the ARE‐mediated regulatory mechanism and the microRNA‐mediated pathway in the post‐transcriptional regulation of the hIL‐3 transcript. Previous results from our laboratory identified five ARE‐BP complexes from approximately 30 to 90 kDa using UV crosslinking assays. Gel retardation experiments identified HuR, an extensively studied ARE‐BP, as a potential factor that recognizes the hIL‐3 ARE and may mediate the post‐transcriptional regulation of hIL‐3 mRNA. Also, a RNA affinity approach coupled with Western blot analysis and RT‐PCR confirmed the presence of HuR as a component of this ARE‐BP complex. More recent studies in the laboratory have suggested that the hIL‐3 3′‐UTR, which mediates its interaction with HuR, is required to enhance IL‐3 protein levels during T‐cell activation. Bioinformatics analysis using TargetScan suggests that miR‐15a and miR‐16 recognize sequences within the hIL‐3 3′‐UTR. Together, these observations imply that both the AREmediated post‐transcriptional mechanism and the microRNA pathway play important roles in the regulation of hIL‐3 during T‐cell activation. Ultimately, elucidating the role of these post‐transcriptional pathways in hIL‐3 expression can provide powerful therapeutic targets for the development of effective drugs against multiple myeloma and leukemias caused by abnormal hIL‐3 expression.