Notch receptors and their ligands are evolutionarily conserved transmembrane polypeptides that regulate cell fate determination and are associated with physiological and pathological processes such as angiogenesis and tumorigenesis. In order to understand the role of Jagged 1/Notch signaling in these processes, the phenotype of NIH 3T3 cells stably transfected with a non-transmembrane and secreted form of human Jagged 1 (sJ1) found to be upregulated during angiogenesis was examined. sJ1 transfectants exhibit a transformed phenotype that includes changes in cell morphology, increased survival at clonal density, anchorage-independent growth in soft agar in the presence of FGF1 and alterations in migratory behavior. sJ1 cells are also able to elicit an angiogenic response in the chorioallantoic membrane assay (CAM) and implantation of sJ1 transfected cells into athymic mice yielded highly angiogenic masses. The mechanisms by which sJ1 induces these phenotypic changes are unknown and are addressed by the two specific aims of this proposal 1) to determine if the NIH 3T3 sJ1 phenotype results from activation or inhibition of specific Notch receptor signaling pathways and 2) to determine the minimal domain of sJ1 sufficient to induce the sJ1 phenotype in NIH 3T3 cells. These objectives will be met by characterizing NIH 3T3 cells stably transfected with J 1 and Notch deletion mutants using a novel biological assay based on the laboratory?s characterization of sJ1 transfectants. Elucidation of the mechanisms by which sJ1 regulates cellular phenotype may aid in the development of therapeutic agents used for the treatment of pathological conditions such as cancer.
| Urs, Sumithra; Roudabush, Alice; O'Neill, Christine F et al. (2008) Soluble forms of the Notch ligands Delta1 and Jagged1 promote in vivo tumorigenicity in NIH3T3 fibroblasts with distinct phenotypes. Am J Pathol 173:865-78 |
| Small, Deena; Kovalenko, Dmitry; Soldi, Raffaella et al. (2003) Notch activation suppresses fibroblast growth factor-dependent cellular transformation. J Biol Chem 278:16405-13 |
