The goal of this project is to understand the mechanism by which the v-myb oncogene of avian myeloblastosis virus (AMV) induces acute myeloid leukemia. This system provides a valuable model for human leukemogenesis for several reasons. First, progenitor of this oncogene, c-myb, is highly conserved in humans, mice and chickens. Second, alterations in c-myb cause myeloid, erythroid, and lymphoid leukemias in mice and birds. Third, c-myb has been shown to amplified and/or rearranged in various human malignancies. The proteins encoded by both v-myb and c-myb are present within the cell nucleus and bind to DNA. Recent work in our laboratory strongly suggests that these myb-encoded nuclear proteins act by regulating the expression of other cellular genes. The studies outlined in this proposal will accomplish the following: (1)Determine if gene regulation by p48v-myb is required for transformation; (2)Define the DNA sequences required for a gene to be regulated by p48v-myb; (3)Determine which domains of p48v-myb are required for gene regulation; (4)Determine the role of phosphorylation and protein-protein interactions in transformation and gene regulation by p48v-myb; (5)Determine the structural and functional conservation of the DNA-binding domains of myb-related proteins from vertebrates, invertebrates, and green plants; (6)Identify and characterize the cellular genes which are controlled by p48v-myb.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA043592-08
Application #
3185823
Study Section
Virology Study Section (VR)
Project Start
1993-08-01
Project End
1995-01-31
Budget Start
1993-08-01
Budget End
1994-01-31
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
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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