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.

日本語要旨:

ヒト大腸癌サンプルを解析し、癌抑制タンパク質ARFの発現と腫瘍内血管密度に逆相関があることを報告した。