title: 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.
abstract: 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.
authors.affiliation: Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Nagamachi
authors.forename: Phyo Wai
authors.initials: PW
authors.lastname: Htun
authors.forename: Feng
authors.initials: F
authors.lastname: Ma
authors.forename: Kazuko
authors.initials: K
authors.lastname: Miyazaki
authors.forename: Norimasa
authors.initials: N
authors.lastname: Yamasaki
authors.forename: Masamoto
authors.initials: M
authors.lastname: Kanno
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inaba
authors.forename: Zen-ichiro
authors.initials: Z
authors.lastname: Honda
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Okuda
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oda
authors.forename: Kohichiro
authors.initials: K
authors.lastname: Tsuji
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D002454:Cell Differentiation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D055879:Gene Knock-In Techniques; D006410:Hematopoiesis / Q000235:genetics*; D006579:Heterozygote; D007938:Leukemia / Q000235:genetics*; D008099:Liver / Q000473:pathology; D051379:Mice; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000235:genetics*; D012270:Ribosomes / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D050676:Core Binding Factor Alpha 2 Subunit; C493726:Runx1 protein, mouse