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Florida Atlantic University
Thesis Advisor: Gary Brewer, PhD
Graduate Program in Cellular and Molecular Pharmacology
RWJMS Research Tower
Tuesday, April 14, 2009
Regulated gene expression at the level of messenger RNA is fundamental to cell fate and survival. The cytoplasmic abundance of mRNAs is dictated by rates of synthesis, processing, transport and decay. Crucial cis and trans-acting elements, as well as signaling pathways, exert their action on the transcripts in response to external stimuli. A+U rich elements (AREs) contained within 3í untranslated regions (UTR) of mRNAs are one of the best studied regulatory elements found in highly unstable transcripts, such as those encoding cytokines. AUF1 is an ARE-binding protein (AUBP) known to recruit several other factors to the ARE, forming the AUBP and Signal Transduction-Regulated Complex (ASTRC). AUF1 is phosphorylated in non-stimulated cells, and its binding to cytokine TNFalpha mRNA stimulates its rapid degradation. In response to activation by signaling cascades, AUF1 loses the phosphates, which corresponds to the stabilization of various cytokine mRNAs, among which is TNFalpha. We recently identified Hsp27 as one of the components of the ASTRC, and uncovered that this protein also binds and accelerates TNFalpha mRNA decay in THP-1 promonocytic leukemia cells. In this work, we investigate the role of Hsp27 phosphorylation upon the proteinís biointerfacial interactions with the ASTRC and with the TNFalpha transcript. We propose that phosphorylation of Hsp27 disrupts its interaction with ASTRC, promotes proteasomal degradation of AUF1, and consequentially stabilizes TNFalpha mRNA.