Clinical appliciation of cancer treatment by revealing alternative splicing mechanism of c-myc transcriptional suppressor FBP-interacting repressor

揭示c-myc转录抑制因子FBP相互作用阻遏蛋白的选择性剪接机制在癌症治疗中的临床应用

• 批准号: 23591891
• 负责人: MATSUSHITA Kazuyuki
• 金额: $ 2.91万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23591891/
• 关键词: がん診断; バイオマーカー; がん治療; 癌治療; c-myc; alternative splicing; cancer; SF3b1; SAP155; therapy; protein interaction; がん; c-myc転写調節; ＦＩＲ; スプライシング

Recently, an interaction between FBP-interacting repressor, FIR, and TFIIH/p89/XPB helicase was found to repress c-myc transcription and so might be important for sippressing tumor formation. Further, enforced expression of FIR induced apoptosis. Deletion of FIR's amino terminal repression domain rescued thecells from apoptosis, as did co-expression of c-Myc with FIR. Thus repression of c-myc mediates FIR-driven apoptosis. A splicing variant of FIR unable to repress c-myc nor driving apoptosis was frequently discovered in human primary colorectal cancers, but not in the adjacent normal tissues. In this study, adeno- or Sendai virus FIR expression vector was examined its anti-tumor efficacy. Additionally, FIR splicing variant was detected at their protein or mRNA level in the peripheral blood of colorectal cancer patients.

最近，fbp相互作用抑制因子，FIR和TFIIH/p89/XPB解旋酶之间的相互作用被发现抑制c-myc转录，因此可能对抑制肿瘤形成很重要。此外，强制表达FIR诱导细胞凋亡。FIR的氨基末端抑制域的缺失使细胞免于凋亡，c-Myc与FIR的共表达也是如此。因此，抑制c-myc介导了fir驱动的细胞凋亡。在人类原发性结直肠癌中经常发现一种不能抑制c-myc也不能驱动细胞凋亡的FIR剪接变体，但在邻近的正常组织中却没有发现。本研究用腺或仙台病毒FIR表达载体检测其抗肿瘤效果。此外，在结直肠癌患者外周血中检测到FIR剪接变异体的蛋白或mRNA水平。

项目成果

千葉大学大学院医学研究院分子病態解析学

千叶大学医学研究科，分子病理学分析

Alternative splicing of FBP-interacting repressor coordinates c-Myc, P27Kip1/cyclinE and Ku86/XRCC5 expression as a molecular sensor for bleomycin-induced DNA damage pathway.

FBP相互作用的阻遏物坐标C-MYC，P27KIP1/Cycline和KU86/XRCC5表达的替代剪接作为博来霉素诱导的DNA损伤途径的分子传感器。

• DOI: 10.18632/oncotarget.1650
• 发表时间: 2014-05-15
• 期刊: Oncotarget
• 作者: Rahmutulla B;Matsushita K;Satoh M;Seimiya M;Tsuchida S;Kubo S;Shimada H;Ohtsuka M;Miyazaki M;Nomura F
• 通讯作者: Nomura F

Interactions between SAP155 and FUSE-binding protein-interacting repressor bridges c-Myc and P27Kip1 expression.

SAP155与融合结合蛋白相互作用的阻遏桥C-MYC和P27KIP1表达之间的相互作用。

• DOI: 10.1158/1541-7786.mcr-12-0673
• 发表时间: 2013-07
• 期刊: Molecular cancer research : MCR
• 作者: Matsushita K;Tamura M;Tanaka N;Tomonaga T;Matsubara H;Shimada H;Levens D;He L;Liu J;Yoshida M;Nomura F
• 通讯作者: Nomura F