Regulatory role of phosphorylation of tumor suppressor Fhit protein

抑癌Fhit蛋白磷酸化的调节作用

• 批准号: 17590275
• 负责人: ISHII Hideshi
• 金额: $ 2.01万
• 依托单位: Jichi Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17590275/
• 关键词: Biochemistry; Tumor Suppressor Gene; Checkpoints; genomic; Lgenomic Instability; Cancer Stem Cells; FHIT

The fragile FHIT gene is among the first targets of DNA damage in preneoplastic lesions and recent studies have shown that Fhit protein is involved in surveillance of genome integrity and checkpoint response after genotoxin exposure. We studied that Fhit modulate the checkpoint response via regulation of phosphorylation at Y114 of Fhit protein. The response was regulated Atr kinase, and define the responsiveness of normal and cancer cells. Furthermore, Fhit-deficient hematopoietic cells, exposed to the genotoxin hydroquinone, are resistant to the suppression of stem cell in vitro colony formation observed with wild type hematopoietic cells. The present results indicate that reduced oxidative stress, coupled with efficient but error-prone DNA damage repair, allows unscheduled, long-term survival of genotoxin-exposed Fhit-deficient hematopoietic stem cells carrying deleterious mutations, suggesting the significance in the multistep carcinogenesis.

脆弱的 FHIT 基因是癌前病变中 DNA 损伤的首要目标之一，最近的研究表明，Fhit 蛋白参与基因毒素暴露后基因组完整性和检查点反应的监测。我们研究了 Fhit 通过调节 Fhit 蛋白 Y114 的磷酸化来调节检查点反应。该反应受到 Atr 激酶的调节，并定义正常细胞和癌细胞的反应性。此外，暴露于基因毒素氢醌的Fhit缺陷造血细胞对野生型造血细胞在体外观察到的干细胞集落形成的抑制具有抵抗力。目前的结果表明，氧化应激的减少，加上有效但容易出错的 DNA 损伤修复，使得暴露于基因毒素、携带有害突变的 Fhit 缺陷造血干细胞能够意外长期存活，这表明其在多步致癌过程中的重要性。

项目成果

The epidermal growth factor receptor gene sequence is highly conserved in primary gastric cancers

• DOI: 10.1002/jso.20426
• 发表时间: 2006-01-01
• 期刊: JOURNAL OF SURGICAL ONCOLOGY
• 影响因子: 2.5
• 作者: Mimori, K;Nagahara, H;Mori, M
• 通讯作者: Mori, M

FHIT is up-regulated by inflammatory stimuli and inhibits prostaglandin E2-mediated cancer progression

• DOI: 10.1158/0008-5472.can-05-2509
• 发表时间: 2006-03-01
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: Mimori, K;Ishii, H;Mori, M
• 通讯作者: Mori, M

Differentially expressed genes in endothelial differentiation.

• DOI: 10.1089/dna.2005.24.432
• 发表时间: 2005-07
• 期刊: DNA and cell biology
• 影响因子: 3.1
• 作者: H. Ishii;K. Mimori;M. Mori;A. Vecchione

Histone deacetylase inhibitor depsipeptide (FK228) induces apoptosis in leukemic cells by facilitating mitochondrial translocation of Bax, which is enhanced by the proteasome inhibitor bortezomib.

组蛋白脱乙酰酶抑制剂 depsipeptide (FK228) 通过促进 Bax 的线粒体易位诱导白血病细胞凋亡，蛋白酶体抑制剂硼替佐米可增强这种易位。

• 发表时间: 2006
• 期刊: Acta Haematol. 115・1-2
• 作者: Sutheesophon;K.
• 通讯作者: K.

Rad9 modulates the P21WAF1 pathway by direct association with p53.

• DOI: 10.1186/1471-2199-8-37
• 发表时间: 2007-05-21
• 期刊: BMC molecular biology
• 作者: Ishikawa K;Ishii H;Murakumo Y;Mimori K;Kobayashi M;Yamamoto K;Mori M;Nishino H;Furukawa Y;Ichimura K
• 通讯作者: Ichimura K