Research on Ku70/80 that regulates immune functions and tumorigenesis

Ku70/80调节免疫功能与肿瘤发生的研究

• 批准号: 15591092
• 负责人: MORIO Tomohiro
• 金额: $ 2.3万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591092/
• 关键词: Ku70; Ku80; apoptosis; Immunoglobulin Class Switch; TCF-1; degradation

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

我们研究了 Ku70/80 在免疫球蛋白类别转换和淋巴恶性肿瘤发展中的作用。为此，我们研究了 Ku70/80 是如何降解的、Ku70/80 与高迁移率族 (HMG) 家族蛋白之间的相互作用模式、Ku70/80-HMG 蛋白关联的生理意义、参与 V(D)J 重组过程中发夹打开过程的关键分子 Artemis 如何根据 DNA 损伤信号进行修饰，以及某些药物如何对类别转换产生影响。我们的数据表明， Ku70/80 在胰腺腺泡细胞的细胞核中被降解，并且 importin-b 和 Ku70/80 之间的相互作用受到氧化应激的影响，最终导致细胞核中 Ku70/80 的表达缺陷和细胞凋亡。降解依赖于caspase-3和calpain。我们之前的数据表明Ku70/80通过与HMG蛋白家族同源的区域与CD40的胞内区域相关。通过我们的调查，很明显，一些 HMG 蛋白与 Ku70/80 结合，而另一些则不结合。这种关联对于 TCF1 驱动的报告基因表达以及 293T 细胞中的 TCF1/β-连环蛋白依赖性基因表达非常重要。我们已经证明，Artemis 在响应电离辐射时以共济失调毛细血管扩张突变 (ATM) 和奈梅亨断裂综合征 1 (Nbs1) 依赖性方式过度磷酸化，并且 S645 是一种 SQ/TQ 位点有助于降低 Artemis 在 IR 上的移动性。由于Artemis在脱氧核糖核酸（DNA）依赖性蛋白激酶（DNA-PKcs）催化亚基存在下，在抗原受体V（D）J基因重组的发夹打开步骤中发挥着至关重要的作用，因此推测Ku70/80也以某种方式参与了Artemis依赖性DNA修复系统。 抗过敏药通过抑制免疫球蛋白类别转换发挥作用。该药物似乎抑制 Ku70/80 在细胞核中的易位。确切的机制目前正在研究中。较少的

项目成果

Type Two Hyper-IgM Syndrome caused by Mutation in Activation-Induced Cytidine Deaminase.

由激活诱导的胞苷脱氨酶突变引起的二型高 IgM 综合征。

• 发表时间: 2003
• 期刊: J Med Dent Sci. 50(1)
• 作者: Zhu Y;Nonoyama S;Morio T;Muramatsu M;Honjo T;Mizutani M.
• 通讯作者: Mizutani M.

ATM dependent phosphorylation of Artemis in response to DNA damage.

Artemis 响应 DNA 损伤的 ATM 依赖性磷酸化。

• 发表时间: 2005
• 期刊: Cancer Sci. 96
• 作者: Chen L.;Morio T.;Minegishi Y.;Nakada S.;Nagasawa M.;Komatsu K.;Chessa L.;Villa A.;Delia D.;Mizutani S.
• 通讯作者: Mizutani S.

Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2

• DOI: 10.1016/j.clim.2005.02.003
• 发表时间: 2005-06-01
• 期刊: CLINICAL IMMUNOLOGY
• 影响因子: 8.6
• 作者: Imai, K;Zhu, Y;Durandy, A
• 通讯作者: Durandy, A

Allogeneic hematopoietic stem cell transplantation for seven children with X‐linked hyper‐IgM syndrome: A single center experience

• DOI: 10.1002/ajh.20044
• 发表时间: 2004-05
• 期刊: American Journal of Hematology
• 影响因子: 12.8
• 作者: D. Tomizawa;K. Imai;Sukeyuki Ito;M. Kajiwara;Y. Minegishi;M. Nagasawa;T. Morio;S. Nonoyama;S. Mizutani

Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage

• DOI: 10.1111/j.1349-7006.2005.00019.x
• 发表时间: 2005-02-01
• 期刊: CANCER SCIENCE
• 影响因子: 5.7
• 作者: Chen, L;Morio, T;Mizutani, S
• 通讯作者: Mizutani, S