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

作者：Nagamachi Akiko; Htun Phyo Wai; Ma Feng; Miyazaki Kazuko; Yamasaki Norimasa; Kanno Masamoto; Inaba Toshiya; Honda Zen ichiro; Okuda Tsukasa; Oda Hideaki; Tsuji Kohichiro; Honda Hiroaki^*

来源：Developmental Biology, 2010, 345(2): 226-236.

DOI：10.1016/j.ydbio.2010.07.015

• Internal ribosome entry site (IRES)
• Runx1
• Runx1/Evi1
• Angiogenesis
• Hematopoiesis
• Leukemogenesis

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.

• 出版日期2010-9-15
• 单位河北医科大学