Molecular Activities of Angiogenin in the Nucleus


Principal Investigator: KIMBERLY ANNE DICKSON
Abstract: DESCRIPTION (provided by applicant): Although the pathologies of cancer and neurodegenerative diseases differ markedly, the molecular basis for these broad classes of disease share many common players and pathways. Often, gene products or entire pathways that are hyperactive in cancer are non-functional or suppressed in neurodegenerative disease. The striking connections between cancer and neurodegeneration have gained the attention of experts in both fields;the first international meeting on the topic occurred in Paris, France during the summer of 2010, and was called "The two faces of evil". To effectively combat either of these diseases, we must gain a more complete understanding of the complex molecular interactions that define normal and diseased states of cells and tissues. Human angiogenin (ANG) is a small, secreted ribonuclease that is central to both cancer and amyotrophic lateral sclerosis (ALS). Discovered by Bert Vallee and colleagues in 1988, ANG has long been known to stimulate blood vessel growth and aid in the growth and metastasis of tumors. However, the biological activity of ANG is not limited to the vasculature. In 2006, Prehn and colleagues reported that mutations in ANG are a cause of both familial and sporadic ALS. Recently, ANG has been shown to cleave RNA in mouse tissues exposed to stress (starvation or g-irradiation), indicating ANG has a general role in cell maintenance and survival. ANG is considered an ideal therapeutic target due to its roles in cancer and ALS, yet our meager knowledge of the molecular interactions of ANG is a critical barrier to drug design. The overarching goal of this research is to understand the specific molecular activities of human angiogenin (ANG), including its interactions with nuclear proteins, DNA, and RNA. Our experiments will be conducted using two human cell lines - human umbilical vein endothelial and HeLa - that are known to take up ANG and deliver it to the nucleus. Our preliminary results indicate that ANG effects the levels of cellular micro RNA - small non-coding RNAs that play a major role in many aspects of cell growth and function. In addition, we have determined that ANG binds non-specifically to DNA. To further investigate the nuclear activities of ANG, we will use biochemical and next-generation sequencing techniques to thoroughly characterize the interactions of ANG in the nucleus. Models of ANG action based on this research will aid in the development of ANG-directed therapies for ALS, cancer, and non-neoplastic diseases. PUBLIC HEALTH RELEVANCE: Angiogenin (ANG) is best known for its ability to stimulate blood vessel growth and, in particular, for its role in supporting the growth and metastasis of tumors. Recent studies have demonstrated that mutations in ANG can lead to amyotrophic lateral sclerosis (ALS), and that ANG is a central player in a cell's response to environmental stress. The proposed research will impart a better understanding of the molecular actions of ANG in diseased and normal cells, laying the scientific groundwork for future development of drugs designed to target ANG.
Funding Period: 2012-04-01 - 2015-03-31
more information: NIH RePORT