ARF suppresses tumor angiogenesis through translational control of VEGFA mRNA.

Abstract

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.

• Authors: Hiroyuki Kawagishi, Hideaki Nakamura, Mitsuo Maruyama, Shuki Mizutani, Kazushi Sugimoto, Masatoshi Takagi, Masataka Sugimoto
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 11 Pg. 4749-58 (Jun 01 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20501856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 AACR.

Chemical References

• NPM1 protein, human
• Npm1 protein, mouse
• Nuclear Proteins
• RNA, Messenger
• Tumor Suppressor Protein p14ARF
• Vascular Endothelial Growth Factor A
• Nucleophosmin

Topics

• Animals
• Cell Nucleolus (genetics, metabolism)
• Cell Transformation, Neoplastic (genetics, pathology)
• Colonic Neoplasms (blood supply, genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• NIH 3T3 Cells
• Neovascularization, Pathologic (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Nucleophosmin
• Protein Biosynthesis
• RNA, Messenger (genetics, metabolism)
• Tumor Suppressor Protein p14ARF (genetics, metabolism)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, biosynthesis, genetics)