DNA binding proteins play an important role in processes such as replication and repair of DNA, as well as transcription activation and termination. Many transcription factors bind to a specific DNA site (or sites) and as a result of this specific binding the factors regulate important metabolic functions such as cell growth development and differentiation. There is great interest in understanding the function of those regulatory proteins, especially when the role of the transcription factors is linked to oncogenesis. The PU.1 transcription factor is a member of the ets gene family and is identical to the spi.1 oncogene. The PU.I gene, as well as other members of the ets family have been implicated in oncogenic processes such as the development of erythroid leukemia. Recent studies suggest that ets proteins contribute to tumorigenesis in breast cancers. The ets proteins share a conserved region of approximately 85 amino acids (the ETS domain) that serves as a DNA binding domain and recognizes a purine-rich sequence-with the core sequence: 5-GGAA/T-3. The sequence of the ETS domain represents a new, yet uncharacterized DNA-binding motif, with no homology to other DNA- binding structures. The goals of this project are to use a combination of molecular biology, nuclear magnetic resonance (NMR) and x-ray crystallography to examine sites in the PU.I protein that mediate specific DNA recognition. Atomic models will be used to understand the molecular basis for the function of ets-related transcription factors and to evaluate the role of these regulatory elements in the development of leukemia, breast cancer, and other cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA063489-01A1
Application #
2105370
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1995-09-22
Project End
1998-06-30
Budget Start
1995-09-22
Budget End
1996-06-30
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
009214214
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Jia, X; Lee, L K; Light, J et al. (1999) Backbone dynamics of a short PU.1 ETS domain. J Mol Biol 292:1083-93
Pio, F; Kodandapani, R; Ni, C Z et al. (1996) New insights on DNA recognition by ets proteins from the crystal structure of the PU.1 ETS domain-DNA complex. J Biol Chem 271:23329-37