Study of the function and target genes of BACH transcripton factors.

BACH转录因子的功能及靶基因研究。

• 批准号: 13670778
• 负责人: TOKI Tsutomu
• 金额: $ 2.18万
• 依托单位: Hirosaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670778/
• 关键词: Thrombopoiesis; Erythropoiesis; BACH1; BACH2; NF-E2; Transcription factor

Transcription factor BACH1 and BACH2 bind to Maf recongnition elements by dimerizing with the small Maf transcription factors. The BACH1 mRNA was abundantly expressed in erythroid-megakaryocytic lineage cells. The MARE is known to act as a critical cis element of erythroid and megakaryocytic specific genes. The BACH1 gene is localized to chromosome 21q22.1, within the potential Down's syndrome-associated gene region. Actually, BACH1 was abundantly transcribed in cel lines derived from Down's syndrome-related megakaryocytic leukemia. To investigate the in vivo role of BACH1 overexpression in hematopoiesis, we generated BACH1 transgenic mice bearing the human BACH1 gene under the control of the regulatory element of the GATA-1 gene. Peripheral blood analysis in the transgenic mice revealed a significant reduced number of platelets without anemia. Histological analysis of bone marrow disclosed that the reticulin fibers were markedly increased. Megakaryocytes from the BACH1 transgenic mice … More exhibited significantly reduced proplatelet formation and maturation arrest. These results suggest that BACH1 plays important roles in transcriptional regulation of megakaryocyte-specific genes. Next, we also show here that BACH2 modifies the in vitro cytotoxicity of anticancer drugs in lymphoid leulemic cells. The inhibition of BCR/ABL tyrosine kinase activity by STI571 in Ph1 positive lymphoid leukemic cells results in induction of BACH2 expression. The cytotoxic effects of anticancer agents were studied by overexpression of BACH2 in Raji lymphoid cells. Clones overexpressing BACH2 were more sensitive to anticancer agents producing oxidative stress than control Raji cells. Interestingly, we found that these oxidative stressors induced the nuclear accumulation of BACH2. These results show that BACH2 promotes oxidative stress-induced cell death, suggest that combination chemotherapy involving STI571 and anticancer drugs that produce ROS may be of benefit in the treatment of Ph1-positive leukemia. Less

转录因子BACH 1和BACH 2通过与小Maf转录因子二聚化而与Maf转录元件结合。BACH 1 mRNA在红系-巨核系细胞中大量表达。已知MARE作为红细胞和巨核细胞特异性基因的关键顺式元件。BACH 1基因定位于染色体21q22.1，在潜在的唐氏综合征相关基因区域内。事实上，BACH 1在唐氏综合征相关的巨核细胞白血病细胞系中大量转录。为了研究BACH 1过表达在造血中的体内作用，我们产生了携带人BACH 1基因的BACH 1转基因小鼠，该转基因小鼠在加塔-1基因的调节元件的控制下。转基因小鼠的外周血分析显示血小板数量显著减少，但没有贫血。骨髓组织学分析显示，网状硬蛋白纤维明显增加。BACH 1转基因小鼠的巨核细胞 ...更多信息 表现出显著减少的前血小板形成和成熟停滞。这些结果表明BACH 1在巨核细胞特异性基因的转录调控中起重要作用。接下来，我们还显示BACH 2在淋巴白血病细胞中改变抗癌药物的体外细胞毒性。STI 571抑制Ph 1阳性淋巴白血病细胞BCR/ABL酪氨酸激酶活性，诱导BACH 2表达。通过在Raji淋巴细胞中过表达BACH 2来研究抗癌剂的细胞毒性作用。过表达BACH 2的克隆比对照Raji细胞对产生氧化应激的抗癌剂更敏感。有趣的是，我们发现这些氧化应激诱导BACH 2的核积累。这些结果表明BACH 2促进氧化应激诱导的细胞死亡，表明涉及STI 571和产生ROS的抗癌药物的联合化疗可能有益于治疗Ph 1阳性白血病。少

项目成果

Kanazaki R, Toki T, Yokoyama M, Yomogida K, Sugiyama K, Yamamoto M, Igarashi K, Ito E: "Transcription factor BACH1 is recruited to the nucleus by its novel alternative spliced isoform"Journal of Biological Chemistry. 276-9. 7276-7284 (2001)

Kanazaki R、Toki T、Yokoyama M、Yomogida K、Sugiyama K、Yamamoto M、Igarashi K、Ito E：“转录因子 BACH1 通过其新颖的选择性剪接亚型被招募到细胞核”《生物化学杂志》。

丹代 諭, 佐藤秀子, 金崎里香, 土岐 力, 伊藤悦朗, 五十嵐和彦: "B細胞特異的転写因子BACH2によるBCL-2関連遺伝子Alの発現抑制機構"弘前医学. 54. 8-20 (2002)

Satoshi Tanyo、Hideko Sato、Rika Kanazaki、Chikara Toki、Etsuro Ito、Kazuhiko Igarashi：“B 细胞特异性转录因子 BACH2 抑制 BCL-2 相关基因 A1 表达的机制”弘前医学科学 54. 8-20。 (2002)

Kanazaki R, Toki T, Yokoyama M, Yomogida K, Sugiyama K, Yamamoto M, Igarashi K, Ito E: "Transcription factor BACH1 is recruited to the nucleus by its novel alternative spliced isoform"Journal of Biological Chemistry. 276. 7278-7284 (2001)

Kanazaki R、Toki T、Yokoyama M、Yomogida K、Sugiyama K、Yamamoto M、Igarashi K、Ito E：“转录因子 BACH1 通过其新颖的选择性剪接亚型被招募到细胞核”《生物化学杂志》。

Tandai S, Sato H, Kanezaki R, Toki T, Ito E, Igarashi K: "B cell specific transcription factor BACH2 negatively reglates expression of BCL-2 rekated A1 gene."Hirosaki Medical Journal. 54-1. 8-20 (2002)

Tandai S、Sato H、Kanezaki R、Toki T、Ito E、Igarashi K：“B 细胞特异性转录因子 BACH2 负向调节 BCL-2 相关 A1 基因的表达。”弘前医学杂志。