MECHANISM OF TRANSFORMATION BY THE V-MYB ONCOGENE

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The v-myb oncogene causes acute monoblastic leukemia in chickens and induces the leukemic transformation of normal myelomonocytic cells in culture. During the previous funding period, we demonstrated that the ability of the v-Myb protein to activate transcription of a model reporter gene correlated well with its ability to cause leukemic transformation. We also established a number of assays for transcriptional activation and sequence-specific DNA binding by v-Myb and used them to map several functional domains within the v-Myb protein by a combination of biochemical and genetic analyses. c- myb, the normal cellular gene from which v-myb arose, is essential for vertebrate hematopoiesis. Genes related to myb have also been identified in insects, plants, cellular slime molds, and yeasts. Recently, it has been shown that cdc5, a cell division cycle gene of the fission yeast Schizosaccharomyces pombe, encodes a protein with significant similarity to c-Myb. These results suggest that a better understanding of transformation by v-Myb may have broader implications in understanding the basic cell cycle machinery common to all eukaryotes. We have three major goals for the next five years of research on this project. First, we would like to understand in greater molecular detail which features of the v-Myb protein are essential for leukemic transformation. Second, we would like to identify and characterize the other cellular components with which v-Myb interacts. Third, we have developed a model of how the function of the Cdc5 protein in S. pombe relates to tissue-specific transformation by v-Myb and would like to test it experimentally. Therefore, our specific aims for the next funding period are as follows; 1.) To determine which residues of v-Myb are essential for DNA-binding, transcriptional activation, and leukemic transformation. 2.) To identify host cell proteins and DNA sequences which interact directly with v-Myb. 3.) To test the ability of v-Myb to regulate the cell cycle in leukemic cells and in fission yeast.