Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment

被引:39
作者
Toki, T
Katsuoka, F
Kanezaki, F
Xu, G
Kurotaki, H
Sun, JY
Kamio, T
Watanabe, S
Tandai, S
Terui, K
Yagihashi, S
Komatsu, N
Igarashi, K
Yamamoto, M
Ito, E [1 ]
机构
[1] Hirosaki Univ, Sch Med, Dept Pediat, Hirosaki, Aomori 036, Japan
[2] Univ Tsukuba, JST,ERATO, Ctr Tsukuba Adv Res Alliance, TARA Ctr, Tsukuba, Ibaraki, Japan
[3] Hirosaki Univ, Sch Med, Dept Pathol, Hirosaki, Aomori 036, Japan
[4] Hirosaki Univ, Sch Med, Dept Anat, Hirosaki, Aomori 036, Japan
[5] Hirosaki Univ, Sch Med, Dept Biomed Chem, Hirosaki, Aomori 036, Japan
[6] Jichi Med Sch, Dept Hematol, Tochigi, Japan
关键词
D O I
10.1182/blood-2004-07-2826
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Both nuclear factor erythroid 2 45 kDa subunit (p45) and BTB and CNC homolog 1 (Bach) transcription factors can form dimers with one of the small Maf proteins, and these heterodimers bind to the musculoaponeurotic fibrosarcoma oncogene (Maf) recognition element (MARE). MARE is known to act as a critical cis-regulatory element of erythroid and megalkaryocytic genes. Although detailed analyses of p45-null mutant mice and small maf compound mutant mice revealed that these factors are both critical for platelet production, the functional contributions of Bachl and the relationship or redundancy between Bachl and p45 in megakaryocytes remain to be clarified. To address these issues, we generated transgenic lines of mice bearing human BACH1 cDNA under the control of the GATA-1 locus hematopoietic regulatory domain. The transgenic mouse lines showed significant thrombocytopenia associated with impaired maturation of the megalkaryocytes, and they developed myelofibrosis. The megakaryocytes in the transgenic mice exhibited reduced proplatelet formation, and the modal ploidy class of megakaryocytes was 2N, indicating the impairment of endomitosis. Transcription of the p45 target genes was down-regulated and we indeed found that BACH1 binds to the thromboxane synthase gene, one of the target genes for p45 in megalkaryocytes. These findings thus provide evidence that BACH1 acts as a transcriptional repressor in the regulation of MARE-dependent genes in megalkaryocytes. (c) 2005 by The American Society of Hematology.
引用
收藏
页码:3100 / 3108
页数:9
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