Programmed cell death (PCD) is a differentiative process that is required for the selective loss of cells during development. The predominant mechanism used for PCD in vertebrates is apoptosis, which is characterized by DNA degradation, chromatin margination along the nuclear envelope and membrane blebbing. While much is known about the triggers which initiate apoptosis, there is little information about the molecular mechanisms which mediate the process. This proposal takes advantage of a transgenic mouse where the majority of the T cells express the same T cell receptor. When this receptor is stimulated by the appropriate antigen in vivo, massive synchronized apoptotic cell death is induced in the T cells. Using these naturally dying thymocytes, we have generated a cDNA library. The library was screened by a plus/minus hybridization protocol, allowing us to isolate several putative cell death genes. It is proposed that cell death recombinants, which will be sequenced, expressed and used to generate antibodies which can aid in the analysis of the putative protein product.Experiments also are presented to examine how the expression of these genes are regulated during cell death in both T cells and non-immune cells.
| Nickoloff, Brian J; Osborne, Barbara A; Miele, Lucio (2003) Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents. Oncogene 22:6598-608 |
| Miele, L; Osborne, B (1999) Arbiter of differentiation and death: Notch signaling meets apoptosis. J Cell Physiol 181:393-409 |
