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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Virology Study Section (VR)
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Cole, John S
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Stanford University
Schools of Medicine
United States
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Navratilova, Jarmila; Horvath, Viktor; Kozubik, Alois et al. (2007) p53 arrests growth and induces differentiation of v-Myb-transformed monoblasts. Differentiation 75:592-604
Wang, D-M; Sevcikova, S; Wen, H et al. (2007) v-Myb represses the transcription of Ets-2. Oncogene 26:1238-44
Fu, Shu-Ling; Ganter, Brigitte; Lipsick, Joseph S (2006) Myb proteins inhibit fibroblast transformation by v-Rel. Mol Cancer 5:54
Wang, Duen-Mei; Lipsick, Joseph S (2002) Mutational analysis of the transcriptional activation domains of v-Myb. Oncogene 21:1611-5
Ganter, B; Chao, S T; Lipsick, J S (1999) Transcriptional activation by the myb proteins requires a specific local promoter structure. FEBS Lett 460:401-10
Ohi, R; Feoktistova, A; McCann, S et al. (1998) Myb-related Schizosaccharomyces pombe cdc5p is structurally and functionally conserved in eukaryotes. Mol Cell Biol 18:4097-108
Engelke, U; Wang, D M; Lipsick, J S (1997) Cells transformed by a v-Myb-estrogen receptor fusion differentiate into multinucleated giant cells. J Virol 71:3760-6
Ganter, B; Lipsick, J S (1997) Myb binding sites within the N-ras promoter repress transcription. Oncogene 15:193-202
Fu, S L; Lipsick, J S (1996) FAETL motif required for leukemic transformation by v-Myb. J Virol 70:5600-10
Engelke, U; Whittaker, L; Lipsick, J S (1995) Weak transcriptional activation is sufficient for transformation by v-Myb. Virology 208:467-77

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