Research on Ku70/80 that regulates immune functions and tumorigenesis

点击翻译按钮获取中文摘要

We investigated the role of Ku70/80 in immunoglobulin class switch and in development of lymphoid malignancy. To that end, we examined how Ku70/80 is degraded, the mode of interaction between Ku70/80 and High mobility group (HMG) family protein, physiological meaning of Ku70/80-HMG protein association, how Artemis, a critical molecule involved in a hairpin opening process during V(D)J recombination, is modified upon DNA damage signal, and how certain drug exert effects on class switching.Our data showed that Ku70/80 is degraded in the nucleus of pancreatic acinar cells and the interaction between importin-b and Ku70/80 is affected upon oxidative stress, culminating in defective expression of Ku70/80 in the nucleus and in apoptosis. The degradation is dependent on caspase-3, and on calpain.Our previous data showed that Ku70/80 is associated with intracellular region of CD40 through the region that has homology with HMG protein family. Through our investigation, it became apparent that s … More ome of the HMG proteins bind to Ku70/80 while others do not. The association is important in TCF1 driven reporter gene expression as well as in TCF1/β-catenin dependent gene expression in 293T cells.We have demonstrated that Artemis is hyperphosphorylated in an Ataxia-telangiectasia-mutated (ATM)-and Nijmegen breakage syndrome 1 (Nbs1) -dependent manner in response to ionizing radiation, and that S645 is an SQ/TQ site that contributes to retarded mobility of Artemis upon IR. Since Artemis plays a crucial role in the hairpin-opening step of antigen receptor V(D)J gene recombination in the presence of catalytic subunit of deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PKcs), it is speculated that Ku70/80 somehow involves in Artemis dependent DNA repair system as well.Finally our latest research demonstrates a certain anti-allergic drug exerts its function through inhibiting immunoglobulin class switching. The drug seems to inhibit translocation of Ku70/80 in the nucleus. The exact mechanism is now under investigation. Less