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The nuclear function of angiogenin in endothelial cells is related to rRNA production
Zheng-ping Xu1, Takanori Tsuji, James F Riordan
1Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, One Kendall Square, Building 600, 3rd Floor, Cambridge, MA 02139, USA.
Abstract:
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.
Insights
Angiogenin, a protein promoting blood vessel growth, stimulates ribosomal RNA (rRNA) synthesis in cells. Inhibiting this nuclear function may offer a new therapeutic strategy against tumor growth.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Angiogenin is a protein that promotes angiogenesis, crucial for tumor growth.
- Its nuclear function, despite being necessary for angiogenic activity, remains largely unknown.
- Angiogenin interacts with various cells, inducing migration, proliferation, and tube formation.
Purpose of the Study:
- To elucidate the nuclear function of angiogenin.
- To investigate angiogenin's role in ribosomal RNA (rRNA) synthesis.
- To explore the potential of targeting angiogenin's nuclear function for therapeutic intervention.
Main Methods:
- Utilized endothelial cells to study angiogenin's effects.
- Employed nuclear run-on assays to measure RNA synthesis.
- Manipulated exogenous and endogenous angiogenin levels.
Main Results:
- Exogenous angiogenin was found to enhance 45S rRNA production in endothelial cells.
- Reduction of endogenous angiogenin led to decreased rRNA transcription.
- Angiogenin was shown to stimulate RNA synthesis, specifically targeting 45S rRNA initiation sites.
Conclusions:
- Angiogenin's nuclear function is linked to its ability to induce rRNA synthesis.
- rRNA transcription is vital for ribosome biogenesis, protein translation, and cell growth.
- Inhibiting angiogenin-stimulated rRNA transcription presents a potential therapeutic target for anti-angiogenesis strategies.