Study of the mechanism of apoptosis and drug resistance in leukemic cells

白血病细胞凋亡及耐药机制研究

• 批准号: 15591112
• 负责人: TASHIRO Satoshi
• 金额: $ 2.3万
• 依托单位: HIROSHIMA 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-15591112/
• 关键词: CML; Bach2; PML; imatinib; ABL; PML; STI571; Abl遺伝子; Rad51

Imatinib is a molecular targeting drug against chronic myelocytic leukemia (CML), and induces apoptosis of leukemic cells. Bach2, a B cell specific transcription factor and a proapoptotic factor, is upregulated by imatinib in CML. To study the mechanism of the induction of apoptosis by imatinib via Bach2 in CML cells, we analyzed the localization and dynamics of Bach2. We found that Bach2 relocated from cytoplasm into cell nucleus and forms nuclear foci around PML body upon oxidative stress. Bach2 selectively repressed transcriptional activity associated with PML body. Furthermore, Bach2 required protein modification for the envelopment of PML body. Since PML is a known pro-apoptotic factor, these results suggest that Bach2 might induce apoptosis through the transcription repression of genes associated with PML body in CML cells after treatment with imatinib.

伊马替尼是一种抗慢性粒细胞白血病（CML）的分子靶向药物，可诱导白血病细胞凋亡。Bach 2是一种B细胞特异性转录因子和促凋亡因子，在CML中被伊马替尼上调。为了研究伊马替尼通过Bach2诱导CML细胞凋亡的机制，我们分析了Bach2的定位和动力学。我们发现Bach 2在氧化应激时从细胞质迁移到细胞核，并在PML小体周围形成核灶。Bach 2选择性抑制与PML体相关的转录活性。此外，Bach 2需要蛋白质修饰以实现PML体的表达。由于PML是一种已知的促凋亡因子，因此这些结果表明，Bach 2可能通过伊马替尼治疗后CML细胞中与PML体相关的基因的转录抑制来诱导凋亡。

项目成果

XRCC3 deficiency results in a defect in recombination and increased endoreduplication in human cells

• DOI: 10.1038/sj.emboj.7600087
• 发表时间: 2004-02
• 期刊: The EMBO Journal
• 作者: Takashi Yoshihara;M. Ishida;A. Kinomura;M. Katsura;Takanori Tsuruga;S. Tashiro;T. Asahara;K. Miyagawa

Tashiro, S.: "Repression of PML nuclear body-associated transcription by oxidative stress-activated Bach2"Mol.Cell.Bioi.. (in press). (2004)

Tashiro, S.：“氧化应激激活的 Bach2 对 PML 核体相关转录的抑制”Mol.Cell.Bioi..（出版中）。

Suzuki, H.: "Cadmium induces nuclear export of Bach1, a transcriptional repressor of heme oxygenase-1 gene"J.Biol.Chem.. 278. 49246-49253 (2003)

Suzuki, H.：“镉诱导 Bach1 的核输出，Bach1 是血红素加氧酶-1 基因的转录抑制因子”J.Biol.Chem.. 278. 49246-49253 (2003)

The transcriptional programme of antibody class switching involves the repressor Bach2

• DOI: 10.1038/nature02596
• 发表时间: 2004-06-03
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Muto, A;Tashiro, S;Igarashi, K
• 通讯作者: Igarashi, K

Selective repression of transcription associated with PML Body by oxidative stress activated Bach2.

氧化应激激活 Bach2，选择性抑制与 PML Body 相关的转录。

• 发表时间: 2004
• 期刊: Jikken-igaku (Japanese) 22
• 作者: Ishii E;et al.;Watanabe N et al.;Tashiro S
• 通讯作者: Tashiro S