2004 Fiscal Year Final Research Report Summary
Research on Ku70/80 that regulates immune functions and tumorigenesis
| Project/Area Number |
15591092
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
MORIO Tomohiro Tokyo Medical and Dental University, Graduate School Department of Developmental Biology and Pediatrics, Associate Professor, 大学院・医歯学総合研究科, 助教授 (30239628)
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| Co-Investigator(Kenkyū-buntansha) |
MINEGISHI Yoshiyuki Tokyo Medical and Dental University, Graduate School of Department of Allergy and Immunology, Associate Professor, 大学院・医歯学総合研究科, 助教授 (10343154)
TERAOKA Hirobumi Tokyo Medical and Dental University, Medical Research Institute Division of Pathological Biochemistry, Professor, 難治疾患研究所, 教授 (30019137)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Ku70 / Ku80 / apoptosis / Immunoglobulin Class Switch / TCF-1 |
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| Research Abstract |
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
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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
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