A number of the cellular genes which upon mutation are capable of inducing cellular transformation (proto-oncogenes) have recently been identified as components involved in the normal cellular growth pathways. Recently, the oncogene responsible for avian erythroblastosis, erb B, has been shown to represent a truncated version of the epidermal growth factor receptor (EGF-R). This oncogene offers a unique opportunity to study the relationship between growth factor receptors and leukemia, and the process of oncogenic conversion of a normal cellular gene. It has been demonstrated that the c-erb B gene is mutated consistently in leukemia induced by a non-acute retrovirus. The mutation by viral DNA insertion is very specific and reproducible results in the production of a truncated c-erb B/EGF-R gene product that contains only the protein kinase domain. Presumably, this process constitutively activates the EGF-R receptor function leading to the uncontrolled growth of the target cell. In an effort to better understand the molecular basis for this process, the c-DNA clones corresponding to the activated c-erb B/EGF-R gene have been isolated from leukemic cells. Using these clones, we have constructed an avian leukemia model by inserting an activated c- erb B gene into a competent retroviral vector. The Rous/erb B virus (REB) is leukemogenic in chickens and appears to have tissue specificity. In this study we plan to: 1) Further characterize the REB virus and define the oncogenic determinants of its c-erb B gene product using site specific in vitro mutagenesis techniques; 2) Characterize the biochemical properties of the c-erb B gene product in its activated form and in its proto-oncogene form; 3) Determine the effect of activated c-erb B expression on the abrogation of growth factor dependence of hematopoietic cells.
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| Pelley, R J; Maihle, N J; Boerkoel, C et al. (1989) Disease tropism of c-erbB: effects of carboxyl-terminal tyrosine and internal mutations on tissue-specific transformation. Proc Natl Acad Sci U S A 86:7164-8 |
