The AU-rich transcriptome: More than interferons and cytokines, and its role in disease

The AU-rich elements (AREs) are among the predominant cis-acting factors that exist primarily in the 3' untranslated region ( 3'-UTR) of messenger RNAs ( mRNAs) and regulate mRNA stability. AREs were previously believed to be restricted to relatively few mRNAs, including those of interferons (IFNs) and cytokines, growth factors, and proto-oncogenes. Our recent analysis, however, showed that ARE mRNAs represent as much as 8% of mRNAs transcribed from human genes that encode functionally diverse proteins important in many transient biologic processes. Among those processes are cell growth and differentiation, immune responses, signal transduction, transcriptional and translational control, hematopoiesis, apoptosis, nutrient transport, and metabolism. Several recent studies examined signaling pathways that regulate ARE-mediated mRNA stability, notably the p38 mitogen-activated protein kinase ( MAPK) pathway. In addition, several AU-rich binding proteins that regulate the ARE mRNA pathways have been characterized. Dysregulation of regulatory signaling pathways and regulatory proteins affecting ARE mRNA stability can lead to abnormalities in many critical cellular processes and to specific disease conditions. Thus, the heterogeneity in AREs, their signaling pathways, and effector proteins contribute to the functional diversity of the ARE gene family, which encompasses more than IFNs and cytokines.