Principal Investigator Ronald Raines
How can enzyme-catalyzed RNA cleavage promote the growth of new blood vessels? The responsible enzyme—angiogenin—was the first substance shown to promote organogenesis (here, neovascularization). Its 1985 discovery at Harvard Medical School was lauded on the front page of the New York Times. Despite its importance, the mechanism by which a ribonuclease promotes cell proliferation was a mystery until we discovered that angiogenin catalyzes the cleavage of a particular phosphodiester bond in a nucleolar substrate: promoter-associated RNA (pRNA). That cleavage prevents the silencing of ribosomal DNA transcription by the nucleolar remodeling complex (NoRC). We also found that angiogenin is phosphorylated on key serine residues, enabling evasion of the ribonuclease inhibitor protein and passage to the nucleus. Thus, unlike canonical growth factors that deliver epigenetic information to DNA indirectly via receptor-mediated signal-transduction pathways, angiogenin is unique in conveying its proliferative signal from outside of the cell directly to a nucleic acid in an autonomous manner. We are now exploring the broad implications of these findings. For example, kinase inhibitors used in the clinic can keep angiogenin susceptible to its potent cytosolic inhibitor. Thus, some cancer chemotherapeutic agents could act, in part, by an unappreciated mechanism—decreasing the angiogenic activity of endogenous angiogenin.
Amyotrophic lateral sclerosis (ALS or “Lou Gehrig’s Disease”) is a notorious disease for which there is no cure and but one (ineffective) drug. The disease has been linked to mutations that alter the activity of two enzymes: ↑superoxide dismutase and ↓angiogenin (which is a secretory ribonuclease). Realizing these links, we have generated a “masked” angiogenin that is activated by hydrogen peroxide, which is a product of catalysis by superoxide dismutase. We found that the masked angiogenin, unlike the wild-type enzyme, does not promote the proliferation of human endothelial cells, which would be undesirable. The masked enzyme does, however, protect human astroglia from oxidative stress, which is highly desirable. These findings validate an unprecedented attack at the core of ALS.