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.
© 2011. Published by The Company of Biologists Ltd
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Chromatin Immunoprecipitation
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Endothelial Cells / immunology
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Endothelial Cells / metabolism*
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Endothelial Cells / pathology
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Gene Expression Regulation, Developmental
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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Inflammation
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Lymphangiogenesis / genetics
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Lymphangiogenesis / immunology
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Mice
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Mice, Inbred BALB C
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Mutation / genetics
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Peritonitis / chemically induced
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Peritonitis / genetics
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Peritonitis / metabolism*
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Peritonitis / physiopathology
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Proto-Oncogene Protein c-ets-1 / genetics
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Proto-Oncogene Protein c-ets-1 / metabolism*
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Proto-Oncogene Protein c-ets-2 / genetics
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Proto-Oncogene Protein c-ets-2 / metabolism*
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RNA, Small Interfering / genetics
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Thioglycolates / administration & dosage
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Vascular Endothelial Growth Factor Receptor-3 / genetics
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Vascular Endothelial Growth Factor Receptor-3 / metabolism
Substances
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ETS1 protein, human
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Homeodomain Proteins
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Protein c-ets-2
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RNA, Small Interfering
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Thioglycolates
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Tumor Suppressor Proteins
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prospero-related homeobox 1 protein
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Vascular Endothelial Growth Factor Receptor-3