): This is an application by Dr. Beni B. Wolf to work with Dr. Douglas R. Green at the La Jolla Institute for Allergy and Immunology under the Mentored Clinical Scientist Development Award. This project will provide Dr. Wolf with advanced research training in apoptosis and cancer biology and therefore enhance his background in proteinase biochemistry and internal medicine. The long term objective is for Dr. Wolf to acquire the skills necessary to function as an independent investigator. The research plan is outlined below. Cellular resistance to apoptosis can promote oncogenesis by allowing cell accumulation. Interleukin-1beta-converting enzyme (ICE) and related proteinases (apoptotic proteinases) likely execute the final common mechanism of apoptosis; however, whether proteinase inactivation promotes oncogenesis is unknown. The applicants propose to test this possibility. First, they will inactivate apoptotic proteinases in situ and examine the effects on cell viability, proliferation, and malignant transformation. They will next determine if activation of the myc oncogene is cotransforming with apoptotic proteinase inactivation. The third major aim is to identify mutations in apoptotic proteinase genes in tumor samples and to ask whether the incidence and nature of these mutations correlates with malignant transformation. F i nally, they will establish if tumor progression involves apoptotic proteinase inactivation. These studies may delineate apoptotic proteinase inactivation as a novel mechanism of oncogenesis and may therefore define these proteinase as a new class of anti-oncogenes.
| Wolf, B B; Green, D R (1999) Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem 274:20049-52 |
| Wolf, B B; Goldstein, J C; Stennicke, H R et al. (1999) Calpain functions in a caspase-independent manner to promote apoptosis-like events during platelet activation. Blood 94:1683-92 |
| Wolf, B B; Schuler, M; Echeverri, F et al. (1999) Caspase-3 is the primary activator of apoptotic DNA fragmentation via DNA fragmentation factor-45/inhibitor of caspase-activated DNase inactivation. J Biol Chem 274:30651-6 |
