): The v-CBL oncogene is the transforming agent of the Cas NS-1 retrovirus that causes pre-B cell lymphomas and myeloid leukemia in mice. Mutations in CBL that activate its transforming potential result in tyrosine phosphorylation of CBL. Its cellular homolog, c-CBL, is inducibly tyrosine phosphorylated in normal cells by numerous stimuli that result in cellular growth or activation. c-CBL is also highly phosphorylated in cells transformed by activated ABL, and in these cells, tyrosine phosphorylated CBL interacts with a variety of SH2 domain-containing proteins including activated ABL, CRKL, GRB-2, and PI3-kinase. v-ABL was similarly found in an acutely transforming murine retrovirus and causes tumors which are phenotypically and histologically similar to those induced by v-CBL. These findings suggest that tyrosine kinases play a significant role in CBL-mediated tumorigenesis and suggest that CBL may have a critical role in ABL-mediated transformation. To investigate CBL function and its role in transformation, it will first be determined if CBL can transform myeloid cell lines to growth factor independence. Secondly, the role of CBL tyrosine phosphorylation in transformation will be explored. Two potential sites of CBL tyrosine phosphorylation in ABL-transformed cells have been mapped. Mutations at these sites will be created to determine their effects on CBL phosphorylation and CBL-mediated transformation. In vitro phopshotylation studies will determine if these sites are phosphorylated by the ABL kinase in vitro. Further, the CBL tyrosine phosphorylation sites that interact with SH2 domain-containing proteins will be identified. Finally, to assess the necessity of CBL for ABL-mediated myelold transformation, production of a dominant interfering CBL protein will be attempted. During the period of this career development award, the candidate will improve h e r k n owledge base by attending molecular biology courses, while simultaneously executing the proposed research project under the guidance of a mentor. This career development plan will provide the foundation for design of other studies and a transition to an independent investigative career, with an ultimate goal of elucidating mechanisms of leukemogenesis that may translate into efficacious therapies.
| Wayman, G A; Walters, M J; Kolibaba, K et al. (2000) CaM kinase IV regulates lineage commitment and survival of erythroid progenitors in a non-cell-autonomous manner. J Cell Biol 151:811-24 |
