Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/23751
Title: THE ROLE OF INTERFERON REGULATORY FACTORS IN REGULATING THE EXPRESSION OF NKG2D LIGANDS
Authors: XIONG MINRU GORDON
Keywords: DNA damage, ATR, IRF3, TBK1, NKG2D, Sike1
Issue Date: 19-Jan-2011
Source: XIONG MINRU GORDON (2011-01-19). THE ROLE OF INTERFERON REGULATORY FACTORS IN REGULATING THE EXPRESSION OF NKG2D LIGANDS. ScholarBank@NUS Repository.
Abstract: The DNA damage response (DDR) is a cellular response to genotoxic stress that triggers cell cycle arrest and DNA repair mechanisms. It has been previously shown that NKG2D ligands are upregulated by the DDR in a p53-independent manner. We provide evidence in this study that the upregulation of NKG2D ligand expression in response to DNA damage depends on the serine/threonine kinase TBK1 and its phosphorylation target IRF3. The activation of IRF3 in response to DNA damage was evidenced by its phosphorylation and nuclear translocation. TBK1 is upstream of IRF3 and similarly, its phosphorylation was observed during DNA damage. The pharmacological inhibition or knockdowns of either IRF3 or TBK1 reduced the DNA damage-mediated induction of NKG2D ligands. The overexpression of Sike1, an inhibitor of TBK1, abrogated the DNA damage-mediated expression of NKG2D ligands. IRF3 and TBK1 are also required for the maintenance of constitutive NKG2D ligand expression on tumour cell lines. The DNA damage sensor ATR was found to be implicated in IRF3 and TBK1 activation as inhibition of ATR kinase activity reduced the DNA damage-induced phosphorylation of IRF3 and TBK1. It remains to be elucidated if the ATR can directly phosphorylate TBK1, but the observation that phospho-ATM co-localized with Sike1 during DNA damage hinted that both ATM and ATR may be required for activation of the pathway and that the link from the DNA damage sensors to TBK1 is complex and indirect. These findings allow us to propose that genotoxic stress results in the activation of the TBK1/IRF3 pathway.
URI: http://scholarbank.nus.edu.sg/handle/10635/23751
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