Identification of novel oncogenes is an important aspect of cancer research. Potential oncogenes are being identified based on their genetic alterations or abnormal gene expression patterns. It is hypothesized that some signal transducing proteins are only transiently required in tumorigenesis, their expression patterns return to normal in tumor cells, and therefore, their oncogenicity is unrecognized. This hypothesis is consistent with a notion that oncogenes generally function through transient activation mechanisms in normal differentiation process. The hypothesis is also supported by the investigator's recent observations made on CD3 transgenic mice: Although high levels of CD3 transgene expression in early thymocytes were necessary to induce lymphomas, this transgene expression was not detected in the tumor cells. It is apparent that the oncogenicity of CD3 would be unrecognized if only the tumor cells were analyzed. It is proposed to test the hypothesis that transient overexpression of oncogenic signal transducing proteins can induce tumor. The strategy is to control the timing of oncogene expression in transgenic mice: To start oncogene expression using a tetracycline-inducible system and to stop oncogene expression by deletion of the oncogene using an interferon-inducible, Cre-loxP-mediated deletion system. Three genes, CD3 , lck, and Shc, will be induced for transient overexpression in transgenic mice which will then be monitored for lymphomagenesis. These genes are chosen based on following reasons: 1) They are transiently activated in signal transduction cascades in normal cells; 2) Both CD3 and lck can rapidly induce T cell lymphomas when overexpressed early in thymocyte development; 3) Shc is a part of the CD3 and lck involved signal pathway, and its overexpression in vitro can induce cell transformation; 4) They represent three types of signal transducing molecules: docking sites, kinases, and adapters, respectively.
| Wang, B; Wang, N; Whitehurst, C E et al. (1999) T lymphocyte development in the absence of CD3 epsilon or CD3 gamma delta epsilon zeta. J Immunol 162:88-94 |
| Wang, B; Wang, N; Salio, M et al. (1998) Essential and partially overlapping role of CD3gamma and CD3delta for development of alphabeta and gammadelta T lymphocytes. J Exp Med 188:1375-80 |
| Wang, N; Wang, B; Salio, M et al. (1998) Expression of a CD3 epsilon transgene in CD3 epsilon(null) mice does not restore CD3 gamma and delta expression but efficiently rescues T cell development from a subpopulation of prothymocytes. Int Immunol 10:1777-88 |
