Open AccessDissertation
Destabilization of IL-8 mRNA by Anthrax Lethal Toxin: Demonstration of the Requirement for TTP and Examination of its Cellular Interactions
Man Chi Edith Chow
- 06 Dec 2012
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TL;DR: This thesis shows that an AUBP, TTP, is dephosphorylated by LeTx and MAPK inhibitors, and knock-down of its expression stabilized IL-8 transcripts, and increased the stability of ARE-containing mRNAs.
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Abstract: Control of mRNA stability is an important aspect in the regulation of gene expression. A well studied signal for rapid transcript decay in mammalian cells is the AU-rich element (ARE), which is found in the 3’ untranslated region (UTR) of many labile transcripts. These sequence elements confer destabilization of transcripts by binding to AU-binding proteins (AUBPs) that can recruit cellular decay enzymes. The stability of ARE-containing mRNAs can be regulated by extracellular stimuli, which allows for cells to adapt to the changing environment. AREs are found in many transcripts that encode for inflammatory genes, including TNFα, GM-CSF, and IL-8. Pathogens evolve and devise mechanisms to subvert the immune response of the host to aid in its infection. Bacillus anthracis is one such infectious agent that can disable numerous arms of the host immune response. Its secreted toxin, anthrax lethal toxin (LeTx), causes the accelerated decay of the IL-8 mRNA. IL-8 is a dual function cytokine and chemokine that can recruit and activate neutrophils at the site of infection. Through the inactivation of MAPK pathways, LeTx activity causes the destabilization of IL-8 transcripts through its ARE. In this thesis, I show that an AUBP, TTP, is dephosphorylated by LeTx and MAPK inhibitors, and knock-down of its expression stabilized IL-8 transcripts. LeTx activity also increased the
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Citations
Neutrophil activation by monomeric interleukin-8
Krishna Rajarathnam,B.D. Sykes,Cyril M. Kay,Beatrice Dewald,Thomas Geiser,Marco Baggiolini,Ian Clark-Lewis +6 more
TL;DR: An IL-8 analog was chemically synthesized, with the amide nitrogen of leucine-25 methylated to selectivity block formation of hydrogen bonds between monomers and thereby prevent dimerization.
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Ester Carballo,Heping Cao,Heping Cao,Wi S. Lai,Wi S. Lai,Elizabeth A. Kennington,Elizabeth A. Kennington,Douglas Campbell,Perry J. Blackshear,Perry J. Blackshear +9 more
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Structure/function analysis of tristetraprolin (TTP): p38 stress-activated protein kinase and lipopolysaccharide stimulation do not alter TTP function.
William F. C. Rigby,Kristen Roy,Jane E. Collins,Sam Rigby,John E. Connolly,Daniel Bloch,Seth A. Brooks +6 more
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