A 5′ untranslated region containing the IRES element in the Runx1 gene is required for angiogenesis, hematopoiesis and leukemogenesis in a knock-in mouse model
A 5′ untranslated region containing the IRES element in the Runx1 gene is required for angiogenesis, hematopoiesis and leukemogenesis in a knock-in mouse model
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DOI：
10.1016/j.ydbio.2010.07.015
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发表时间：
2010-09-15
影响因子：
2.7
通讯作者：
Honda, Hiroaki
中科院分区：
文献类型：
--
作者：
Nagamachi, Akiko;Htun, Phyo Wai;Honda, Hiroaki
虽然内部核糖体进入位点（IRES）介导的翻译被认为对正常的细胞功能很重要，但其确切的生物学作用尚未完全了解。Runx 1基因编码与造血、血管生成和白血病发生有关的转录因子，在5'非翻译区含有IRES序列。为了阐明IRES元件在Runx 1功能中的作用，我们产生了野生型Runx 1或Runx 1/Evi 1（一种在人类白血病中鉴定的Runx 1融合蛋白）的敲入小鼠。在这两种情况下，天然启动子依赖的转录被保留，而IRES介导的。翻译被删除了。有趣的是，表达野生型Runx 1缺失IRES元件（Runx 1（Delta IRES/Delta IRES））的纯合子在子宫内死亡，由于周细胞发育受损，外周血管显著扩张。此外，Runx 1（Delta IRES/Delta IRES）胎肝中的造血细胞显著减少，并表现出分化模式改变、增殖活性降低和重建能力受损。另一方面，表达缺失IRES元件的Runx 1/Evi 1的杂合子（Runx 1（+/RE Delta IRES））正常出生并且没有显示任何血液学异常，相比之下，常规Runx 1/Evi 1杂合子在子宫内死于中枢神经系统出血并且Runx 1/Evi 1嵌合小鼠发展急性白血病。本文报道的研究结果证明了IRES元件在生理和病理条件下Runx 1功能中的重要作用。(C)2010年爱思唯尔公司All rights reserved.
Although internal ribosome entry site (IRES)-mediated translation is considered important for proper cellular function, its precise biological role is not fully understood. Runx1 gene, which encodes a transcription factor implicated in hematopoiesis, angiogenesis, and leukemogenesis, contains IRES sequences in the 5' untranslated region. To clarify the roles of the IRES element in Runx1 function, we generated knock-in mice for either wild-type Runx1 or Runx1/Evi1, a Runx1 fusion protein identified in human leukemia. In both cases, native promoter-dependent transcription was retained, whereas IRES-mediated. translation was eliminated. Interestingly, homozygotes expressing wild-type Runx1 deleted for the IRES element (Runx1(Delta IRES/Delta IRES)) died in utero with prominent dilatation of peripheral blood vessels due to impaired pericyte development. In addition, hematopoietic cells in the Runx1(Delta IRES/Delta IRES) fetal liver were significantly decreased, and exhibited an altered differentiation pattern, a reduced proliferative activity, and an impaired reconstitution ability. On the other hand, heterozygotes expressing Runx1/Evi1 deleted for the IRES element (Runx1(+/RE Delta IRES)) were born normally and did not show any hematological abnormalities, in contrast that conventional Runx1/Evi1 heterozygotes die in utero with central nervous system hemorrhage and Runx1/Evi1 chimeric mice develop acute leukemia. The findings reported here demonstrate the essential roles of the IRES element in Runx1 function under physiological and pathological conditions. (C) 2010 Elsevier Inc. All rights reserved.