Diagnostic and therapeutic application of cell-cycle checkpoint genes for oral squamous cell cancer.

细胞周期检查点基因在口腔鳞状细胞癌的诊断和治疗中的应用。

• 批准号: 18390545
• 负责人: TOKINO Takashi
• 金额: $ 11.36万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390545/
• 关键词: drug sensitivity; microtubule inhibitor; cell cycle; ubiquitinliease; checkpoint; translationalresearch; トランスレーショナル リサーチ

CHFR which contains a RING domain and has ubiquitin ligase activity, a novel mitotic checkpoint gene delays chromosome condensation in cells treated with microtubule poisons. CHFR is inactivated by promoter methylation, and cancer cells lacking CHFR are sensitive to microtubule inhibitors.(1) Proteins interacting with CHFR, mitotic-checkpoint ubiquitin ligase.In this study, we isolated cellular proteins capable of interacting with CHFR using yeast two-hybrid method to clarify the function of CHFR. As a result of the screening, we isolated canonical and noncanonical E2 ubiquitin conjugating enzymes as CHFR interacting proteins, which are involved in proteolytic and non-proteolytic ubiquitination respectively. This raises the possibility that CHFR is switching canonical and noncanonical ubiquitination depending on the situation of cells.On the other hand, we isolated gadd34 which interacted with the FHA domain of CHFR. Furthermore, CHFR moved in part from nucleus to cytoplasm in the pres … More ence of microtubule inhibitor docetaxel, which enabled colocalization of CHFR and gadd34 in cytoplasm. This colocalization was followed by cell death. These suggest that gadd34 and CHFR cooperate to mediate cell death in response to mitotic stress.(2) CHFR mitotic checkpoint protein inhibits the transcriptional activity of NF-kB.To clarify the molecular mechanisms by which CHFR modulates tumor growth, our analysis focused on transcriptional regulation mediated by CHFR. Using microarray analysis, we found that CHFR downregulated NF-kB signaling. NF-kB-dependent luciferase assay demonstrated that overexpression of CHFR inhibited NF-kB signaling. Moreover, knockdown of CHFR activated the NF-kB activity. Furthermore, we found that IL-8, one of the NF-kB target genes, was regulated by CHFR. mRNA and protein levels of IL-8 were significantly repressed by overexpression of CHFR. Altogether, our findings reveal a novel function of CHFR as a regulator of NF-kB signaling, and which might account for tumor suppression by CHFR. Less

CHFR含有RING结构域并具有泛素连接酶活性，是一种新的有丝分裂检查点基因，可延迟微管毒物处理细胞中的染色体凝聚。CHFR通过启动子甲基化失活，缺乏CHFR的癌细胞对微管抑制剂敏感。(1)与CHFR相互作用的蛋白质，有丝分裂检查点泛素连接酶：本研究利用酵母双杂交技术分离了能够与CHFR相互作用的细胞蛋白质，以阐明CHFR的功能。作为筛选的结果，我们分离出典型和非典型的E2泛素结合酶作为CHFR相互作用蛋白，它们分别参与蛋白水解和非蛋白水解泛素化。另一方面，我们分离了与CHFR的FHA结构域相互作用的gadd 34。此外，在正常对照组中，CHFR部分从细胞核转移到细胞质， ...更多信息 微管抑制剂多西他赛的作用，其使得CHFR和gadd 34能够在细胞质中共定位。这种共定位之后是细胞死亡。这些表明，gadd 34和CHFR合作介导细胞死亡，有丝分裂应激。(2)CHFR有丝分裂检查点蛋白抑制NF-κ B的转录活性。为了阐明CHFR调节肿瘤生长的分子机制，我们的分析集中在CHFR介导的转录调控。使用微阵列分析，我们发现CHFR下调NF-κ B信号转导。NF-kB依赖的荧光素酶检测表明CHFR的过表达抑制了NF-kB信号传导。此外，敲低CHFR激活NF-κ B活性。此外，我们发现，IL-8，NF-κ B的靶基因之一，是由CHFR调控。IL-8的mRNA和蛋白水平显著抑制CHFR的过表达。总之，我们的研究结果揭示了CHFR作为NF-κ B信号转导调节剂的新功能，这可能是CHFR抑制肿瘤的原因。少

项目成果

Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma

• DOI: 10.1111/j.1349-7006.2008.00769.x
• 发表时间: 2008-05-01
• 期刊: CANCER SCIENCE
• 影响因子: 5.7
• 作者: Imai, Takashi;Toyota, Minoru;Tokino, Takashi
• 通讯作者: Tokino, Takashi

Antitumor effect of adenovirus-mediated p53 family gene transfer on osteosarcoma cell lines

• DOI: 10.4161/cbt.6.7.4320
• 发表时间: 2007-07
• 期刊: Cancer Biology & Therapy
• 影响因子: 3.6
• 作者: Yuichiro Oshima;Y. Sasaki;H. Negishi;M. Idogawa;M. Toyota;T. Yamashita;T. Wada;S. Nagoya;Satoshi Satoshi-Satoshi;T. Yamashita;T. Tokino

Ku70 and poly (ADP-ribose) polymerase-1 competitively regulate beta-catenine and T-cell factor-4-mediated gene transactivation: possible linkage of DNA damage recognition and Wnt signaling.

Ku70 和聚 (ADP-核糖) 聚合酶-1 竞争性调节 β-连环蛋白和 T 细胞因子 4 介导的基因反式激活：DNA 损伤识别和 Wnt 信号传导之间可能存在联系。

• 发表时间: 2007
• 期刊: Cancer Research 67
• 作者: Mita H;et al;Sasaki Y;Kawamura YI;Sasaki Y;Suzuki H;Maruyama R;Imai T;Sogabe Y;Idogawa M
• 通讯作者: Idogawa M

Epigenetic silencing of microRNA-34b/c and BTG4 is associated with CpG island methylation in colorectal cancer.

microRNA-34b/c 和 BTG4 的表观遗传沉默与结直肠癌中的 CpG 岛甲基化相关。

• 发表时间: 2008
• 期刊: C a n c e r R e s e a r c h 68(11)
• 作者: Toyota M;Suzuki H;Sasaki Y;Maruyama R;Imai K;Shinomura Y;Tokino T
• 通讯作者: Tokino T

Cytoplasmic RASSF2A is a pro-appoptotic mediator whose expression is epigenetically silenced in gastric cancer.

细胞质 RASSF2A 是一种促凋亡介质，其表达在胃癌中被表观遗传沉默。

• 发表时间: 2008
• 期刊: C a r c i n o g e n e s i s 29(7): 29(7)
• 作者: Maruyama R;Akino K;Toyota M;Suzuki H;Imai T;Ohe-Toyota M;Yamamoto E;Nojima M;Fujikane;Sasaki Y;Yamashita T;Watanabe Y;Hiratsuka H;Hirata K;Itoh F;Imai K;Shinomura Y;Tokino T
• 通讯作者: Tokino T