amanitins and angiogenin

Angiogenin is a potent angiogenic protein whose inhibition is known to prevent human tumor growth in athymic mice. It is secreted by both tumor and normal cells; and interacts with endothelial and smooth muscle cells to induce a wide range of cellular responses including cell migration and invasion, proliferation, and formation of tubular structures. Angiogenin is rapidly endocytosed and translocated to the cell nucleus where it accumulates in the nucleolus and binds to DNA. Although nuclear translocation is necessary for its angiogenic activity, the nuclear function of angiogenin is unclear. Here we report that exogenous angiogenin enhances the production of 45S rRNA in endothelial cells, and reduction of endogenous angiogenin inhibits its transcription. In a nuclear run-on assay, angiogenin stimulates RNA synthesis including that containing the initiation site sequences of 45S rRNA. This suggests that the nuclear function of angiogenin relates to its capacity to induce rRNA synthesis. Because rRNA transcription is essential for the synthesis of new ribosomes that are necessary for protein translation and cell growth, inhibition of angiogenin-stimulated transcription of rRNA may inhibit angiogenesis and therefore, would serve as a molecular target for therapeutic intervention.

Topics: Amanitins; Cell Line; Cell Nucleus; Endothelium, Vascular; Muscle, Smooth, Vascular; Neovascularization, Physiologic; Nucleic Acid Synthesis Inhibitors; Oligonucleotides, Antisense; Ribonuclease, Pancreatic; RNA, Ribosomal; Transcription, Genetic