The broad goal of this proposal is to understand the oncogenicity of transcriptional regulators. The work will focus on Jun and proteins that interact with Jun. The general working hypothesis is that Jun induces oncogenic transformation by virtue of its ability to control the transcription of specific genes. An alternative hypotheses is that the stimulation of DNA synthesis induced by Jun is the critical function for oncogenesis. These hypothesis will be tested by seeking a correlation between oncogenicity and transactivation or stimulation of DNA synthesis using Jun constructs of differing oncogenic potential. A mutational analysis of structural and functional changes affecting oncogenicity of Jun will be carried out to define domains and molecular activities important in transformation. In order to learn more about the regulatory functions of Jun, proteins that interact with Jun will be identified by genetic complementation, anti-idiotype antibodies and screening of expression libraries with labeled fragments of Jun. The regulation of Jun itself will be studied at the transcriptional, translational and posttranslational levels: one of the major aims in this direction is to understand the cell cycle dependence of the nuclear translocation of Jun. Target genes that are controlled by Jun and play an important role in oncogenesis will be identified with regulatable Jun constructs. Cooperation of Jun with additional oncogenic events will be studied in the transgenic mouse model. The interference of Jun with the MyoD induced transcriptional program will be analyzed at the molecular level. Recently isolated highly oncogenic retroviruses will be examined for novel oncogenes.
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