The Myb gene family was first discovered because the v-Myb oncogene of the avian myeloblastosis virus (AMV) causes a rapidly fatal leukemia in chickens. The v-Myb protein is a doubly truncated and mutated version of the normal c-Myb protein. The c-Myb proto-oncogene has also been activated by retroviral insertional mutagenesis in avian B lymphoid and murine myeloid malignancies. The common theme of these activation events is the truncation of the amino and/or carboxyl termini of c-Myb. The long-term goal of this research project is to understand in detail the molecular mechanisms by which cellular Myb proteins regulate normal and malignant hematopoiesis. Previous studies have suggested that the carboxyl terminus of c-Myb can negatively regulate the central transcriptional activation domain of c-Myb and/or inhibit DNA-binding by the amino terminus of c-Myb. However, negative regulation by the carboxyl terminus of c-Myb does not occur in budding yeast. This result implies that this regulation requires additional protein(s) present in animal cells but not in yeast. In this regard, we have recently shown that the vertebrate BS69 protein can bind to the carboxy-terminal regulatory region of c-Myb and thereby inhibit transcriptional activation. BS69 is of particular interest because it was initially identified as a transcriptional inhibitor that binds directly to the adenovirus E1A-binding protein. Amino terminal truncation of c-Myb can also result in oncogenic activation. Previous studies have shown that deletion of the first of the three Myb repeats (as occurs in v-Myb) strongly activates c-Myb for the transformation of myelomonocytic cells in culture. Recently others have reported that deletion of only 20 amino-terminal residues of c-Myb occurs following retroviral insertional mutagenesis in chicken B cell lymphomas. Despite retaining all three Myb repeats, such a deleted protein causes lymphomas, carcinomas, and sarcomas, but not myeloid malignancies in chickens. We propose to develop a cell culture assay for transformation by this activated form of c-Myb and to investigate its biochemical and biological properties.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA056509-06A1
Application #
2909188
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Program Officer
Shen, Grace L
Project Start
1994-01-01
Project End
2004-04-30
Budget Start
1999-07-01
Budget End
2000-04-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Davidson, Colin J; Tirouvanziam, Rabindra; Herzenberg, Leonard A et al. (2005) Functional evolution of the vertebrate Myb gene family: B-Myb, but neither A-Myb nor c-Myb, complements Drosophila Myb in hemocytes. Genetics 169:215-29
Tirouvanziam, Rabindra; Davidson, Colin J; Lipsick, Joseph S et al. (2004) Fluorescence-activated cell sorting (FACS) of Drosophila hemocytes reveals important functional similarities to mammalian leukocytes. Proc Natl Acad Sci U S A 101:2912-7
Wang, D M; Dubendorff, J W; Woo, C H et al. (1999) Functional analysis of carboxy-terminal deletion mutants of c-Myb. J Virol 73:5875-86
Dubendorff, J W; Lipsick, J S (1999) Transcriptional regulation by the carboxyl terminus of c-Myb depends upon both the Myb DNA-binding domain and the DNA recognition site. Oncogene 18:3452-60
Woo, C H; Sopchak, L; Lipsick, J S (1998) Overexpression of an alternatively spliced form of c-Myb results in increases in transactivation and transforms avian myelomonoblasts. J Virol 72:6813-21
Ganter, B; Fu, S l; Lipsick, J S (1998) D-type cyclins repress transcriptional activation by the v-Myb but not the c-Myb DNA-binding domain. EMBO J 17:255-68
Fu, S L; Lipsick, J S (1997) Constitutive expression of full-length c-Myb transforms avian cells characteristic of both the monocytic and granulocytic lineages. Cell Growth Differ 8:35-45
Dini, P W; Eltman, J T; Lipsick, J S (1995) Mutations in the DNA-binding and transcriptional activation domains of v-Myb cooperate in transformation. J Virol 69:2515-24