Angiogenin is an angiogenic ribonuclease that is upregulated in a variety of cancer cells. It undergoes nuclear translocation in endothelial cells and in various cancer cells but not in normal fibroblasts and epithelial cells. Nuclear angiogenin has been shown to stimulate rRNA transcription, a rate-limiting step for ribosome biogenesis. Preliminary studies have shown that knocking-down angiogenin expression in endothelial cells decreases rRNA transcription and abolishes cell proliferation stimulated by a number of angiogenic proteins including aFGF, bFGF, EGF, and VEGF. Down-regulating angiogenin in cancer cells reduces rRNA transcription, cell proliferation, and tumorigenicity. Blockade of nuclear translocation of angiogenin inhibits angiogenesis and xenografic growth of human tumor cells on nude mice. Therefore, angiogenin seems to play an important role in modulating rRNA transcription and may be a general requirement for angiogenesis and tumor growth regardless of the nature of the growth stimuli. The objective of this proposal is to characterize this unconventional mechanism of rRNA transcription regulation mediated by angiogenin in the process of angiogenesis and tumor growth. This proposal has four specific aims. First, the role of angiogenin in VEGF-dependent tumor angiogenesis and tumor growth will be characterized in a xenografic mouse model. Second, the role of angiogenin in Akt-induced prostate cancer development will be examined in the transgenic mice that over-express Akt in the prostate. Third, binding of angiogenin to rDNA will be characterized in vivo by ChIP to determine whether and how this interaction enhances promoter occupancy and rRNA transcription. Fourth, angiogenin-mediated inhibition of histone H3 methylation will be analyzed and the effect of angiogenin on nucleosomal structure and chromatin remodeling will be characterized. Based on the compelling preliminary results, the proposed studies are likely to reveal a novel mechanism by which angiogenin regulates rRNA transcription in the orchestrated event of ribosome biogenesis during angiogenesis and tumor growth.
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