Identification and Characterization of Au-Rich Elements and Trans-Acting Factors Involved in the Posttranscriptional Regulation of Human Interleukin-3

Abstract

An important aspect of the regulation of gene expression in eukaryotes is the post-transcriptional control. Adenosine/Uridine-rich elements (AU-rich elements or AREs) within the 3'-untranslated region (3'-UTR) of mRNAs play a crucial role in the post-transcriptional regulation by affecting mRNA stability and/or translation. Cells involved in the immune response produce several pleiotropic lymphokines that contain AU-rich elements in their mRNAs. Interlukin-3 is one of these lymphokines that harbor an AU-rich element in its 3'-UTR. The aberrant expression of IL-3 is related to cancer, sickle cell disease and asthma, among others. At present, little is known about the ARE-mediated post-transcriptional regulation of human IL-3. In order to fill this scientific gap, the main focus of this dissertation is to understand the human IL-3 ARE-mediated post-transcriptional regulatory pathway. This manuscript is divided in four chapters. Chapter I consists of an introduction to the ARE-mediated post-transcriptional regulatory mechanism. Chapter II focuses on the characterization of the IL-3 ARE post-transcriptional role. Chapter III describes and characterizes the ARE-BPs that recognize the hIL-3 ARE and their roles in mRNA stability and translation. Finally, Chapter IV elucidates the role of T-cell activation in the hIL-3 ARE-mediated post-transcriptional regulation and its effects in the IL-3 ARE-binding protein complexes. Altogether, the results presented in this dissertation provide new evidence regarding the IL-3 ARE-mediated post-transcriptional regulation in human cells.