Functional Analysis of Nova Proteins: Gene Regulation and Breast Tumor Immunity
Abstract
The paraneoplastic neurological disorders (PNDs) are a group of autoimmune diseases in which neuron-specific proteins are expressed ectopically in tumors. Because PND patients have high-titer antibodies to these proteins, and display significant immunological suppression of tumors expressing these proteins, the PNDs are a model system in which to study tumor immunity. Paraneoplastic opsoclonus-myoclonus ataxia (POMA) is a PND in which the neuron specific Nova-1 protein is expressed in tumors, particularly in breast cancer. Nova-1 is an RNA binding protein, and POMA patient antisera can block Nova-1's RNA binding activity. The action of POMA patient antisera suggests that the understanding of Nova-i's functional role in cellular RNA metabolism may provide insight into both breast tumor biology and in the elucidation of the effective anti-tumor immune response seen in POMA patients. We have determined the sequence-specific RNA binding activity of Nova-1, and show that the protein interacts with tetranucleotide RNA sequence UCAY. We have demonstrated that Nova-1 can function as an alternative splicing factor, which is dependent upon an intronic UCAY element. Furthermore, we have obtained a high-resolution crystal structure of the Nova-1 KH3 domain and a UCAY-containing RNA target. We have also generated Nova-1 null mice, which display specific alternative splicing defects as predicted by our in vitro studies. The Nova-1 null mice display severe motor dysfunction, suggestive of the human POMA disorder, and further characterization of these mice should aid in the elucidation of additional aspects of Nova-1 biology.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1999
- Accession Number
- ADA385942
Entities
People
- Kirk B. Jensen
Organizations
- The Rockefeller University