title: Ets family members induce lymphangiogenesis through physical and functional interaction with Prox1.
abstract: Prox1 plays pivotal roles during embryonic lymphatic development and maintenance of adult lymphatic systems by modulating the expression of various lymphatic endothelial cell (LEC) markers, such as vascular endothelial growth factor receptor 3 (VEGFR3). However, the molecular mechanisms by which Prox1 transactivates its target genes remain largely unknown. Here, we identified Ets-2 as a candidate molecule that regulates the functions of Prox1. Whereas Ets-2 has been implicated in angiogenesis, its roles during lymphangiogenesis have not yet been elucidated. We found that endogenous Ets-2 interacts with Prox1 in LECs. Using an in vivo model of chronic aseptic peritonitis, we found that Ets-2 enhanced inflammatory lymphangiogenesis, whereas a dominant-negative mutant of Ets-1 suppressed it. Ets-2 also enhanced endothelial migration towards VEGF-C through induction of expression of VEGFR3 in collaboration with Prox1. Furthermore, we found that both Prox1 and Ets-2 bind to the VEGFR3 promoter in intact chromatin. These findings suggest that Ets family members function as transcriptional cofactors that enhance Prox1-induced lymphangiogenesis.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yoshimatsu
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Hajime
authors.initials: H
authors.lastname: Mihira
authors.forename: Taichi
authors.initials: T
authors.lastname: Itoh
authors.forename: Junichi
authors.initials: J
authors.lastname: Suehiro
authors.forename: Keiko
authors.initials: K
authors.lastname: Yuki
authors.forename: Kaori
authors.initials: K
authors.lastname: Harada
authors.forename: Masato
authors.initials: M
authors.lastname: Morikawa
authors.forename: Caname
authors.initials: C
authors.lastname: Iwata
authors.forename: Takashi
authors.initials: T
authors.lastname: Minami
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Morishita
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Watabe
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D042583:Lymphangiogenesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation / Q000235:genetics; D010538:Peritonitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013864:Thioglycolates / Q000008:administration & dosage; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: C494041:ETS1 protein, human; D018398:Homeodomain Proteins; D050784:Proto-Oncogene Protein c-ets-1; D050787:Proto-Oncogene Protein c-ets-2; D034741:RNA, Small Interfering; D013864:Thioglycolates; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D040321:Vascular Endothelial Growth Factor Receptor-3