ARF suppresses tumor angiogenesis through translational control of VEGFA mRNA.
Vascular endothelial growth factor A (VEGFA) is a specific mitogen for vascular endothelial cells that plays a critical role in cancer neoangiogenesis. Here, we report that the nucleolar tumor suppressor p19(ARF) suppresses VEGFA expression, acting at the level of mRNA translation without affecting the transcription of the VEGFA gene. Translational repression of VEGFA mRNA by p19(ARF) does not require p53, a major target of the ARF tumor suppressor pathway, but instead correlates with binding to nucleophosmin/B23. Maintaining VEGFA expression relies on nucleophosmin/B23, and downregulating this protein by RNAi or p19(ARF) leads to translational repression of VEGFA. p19(ARF) inhibits VEGFA-dependent tumor angiogenesis in nude mice. Additionally, p14(ARF) expression and microvessel density are inversely correlated in human colon carcinomas. Taken together, our results define a mechanism by which the ARF tumor suppressor targets the translational repression of specific oncogenes during neoplastic transformation.
Kawagishi
Hiroyuki
H
Department of Mechanism of Aging, National Center for Geriatrics and Gerontology, Aichi, Japan. msugimot@ncgg.go.jp
Nakamura
Hideaki
H
Maruyama
Mitsuo
M
Mizutani
Shuki
S
Sugimoto
Kazushi
K
Takagi
Masatoshi
M
Sugimoto
Masataka
M
D000818:Animals; D002466:Cell Nucleolus / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D003110:Colonic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*
C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF; D042461:Vascular Endothelial Growth Factor A; D000090243:Nucleophosmin