Abstract
Human Interleukin‐3 is a lymphokine that supports a broad range of hematopoietic cells. Aberrant expression of IL‐3 has been implicated in chronic inflammation, cancer and other human diseases. IL‐3 is a member of a class of transiently expressed mRNAs that harbor Adenosine/Uridine‐Rich Elements (ARE) in their 3’‐UTRs. Previous results from our laboratory have suggested a translational role for the hIL‐3 ARE. To understand the hIL‐3 AREs role in translational regulation, we conducted site‐directed mutagenesis of the ARE cluster. Firefly luciferase reporters harboring these ARE mutations were transfected into HeLa and T cells. In order to identify the ARE‐ Binding Proteins (ARE‐BPs) involved in this regulatory process electrophoretic mobility shift assays (EMSAs) and UV‐catalyzed crosslinking were performed using cytoplasmic Jurkat cell extracts. The luciferase chimeras lacking the hIL‐3 ARE showed an increase in luciferase activity. ARE mutations showed specific clusters involved on translational repression. EMSA analysis demonstrated that HuR is a component of the hIL‐3 ARE‐specific protein complex and its binding is modulated upon T‐cell stimulation. Together, these results suggest that HuR and specific ARE clusters play a role in the post‐transcriptional regulation of human IL‐3 mRNA upon T cell stimulation.
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