Departments: Oncological Sciences - Professor
Academic Office Information
- ETS Family
- DNA-Protein Interactions
- Signal Transduction
We have set as a long-term goal to understand how a family of highly related DNA binding factors is utilized in biological regulation using the ETS family as a model system. Do individual ETS proteins have unique roles or are there redundancies of function within the family? Specificity would require both a divergence of functionality of individual family members as well as pathways to direct different family members to different gene promoter targets. There is extensive co-expression of ETS family members in a diverse sampling of human cell types. Genome-wide analysis of promoter targets in several of the cell types shows that, in some cases, there is specific matching between specific ETS proteins and specific targets. In other cases, there is co-occupancy by multiple ETS proteins at a specific promoter. We are currently investigating mechanisms of specificity for multiple family members including Ets-1, ETV6, ETV1, ETV4 and ETV5.
Fred Hutchinson Cancer Research Center
University of Washington
- Simon L Currie, Desmond K Lau, Jedediah J Doane, Frank G Whitby, Mark Okon, Lawrence P McIntosh, and Barbara J Graves (In Press). Structured and disordered regions cooperatively mediate DNA-binding autoinhibition of ETS factors ETV1, ETV4, and ETV5. (Epub ahead of print) Nucleic Acids Res.
- Perez-Borrajero C, Lin CS, Okon M, Scheu K, Graves BJ, Murphy MEP, McIntosh LP (2018). The Biophysical Basis for Phosphorylation-Enhanced DNA-Binding Autoinhibition of the ETS1 Transcription Factor. J Mol Biol, 431(3), 593-614.
- Currie SL, Warner SL, Vankayalapati H, Liu X, Sharma S, Bearss DJ, Graves BJ (2018). Development of High-Throughput Screening Assays for Inhibitors of ETS Transcription Factors. SLAS Discov, 24(1), 77-85.
- Madison BJ, Clark KA, Bhachech N, Hollenhorst PC, Graves BJ, Currie SL (2018). Electrostatic repulsion causes anticooperative DNA binding between tumor suppressor ETS transcription factors and JUN-FOS at composite DNA sites. J Biol Chem, 293(48), 18624-18635.
- Currie SL, Doane JJ, Evans KS, Bhachech N, Madison BJ, Lau DKW, McIntosh LP, Skalicky JJ, Clark KA, Graves BJ (2017). ETV4 and AP1 Transcription Factors Form Multivalent Interactions with three Sites on the MED25 Activator-Interacting Domain. J Mol Biol, 429(20), 2975-2995.
- Currie SL, Lau DKW, Doane JJ, Whitby FG, Okon M, McIntosh LP, Graves BJ (2016). Structured and disordered regions cooperatively mediate DNA-binding autoinhibition of ETS factors ETV1, ETV4 and ETV5. Nucleic Acids Res, 45(5), 2223-2241.
- Desjardins G, Okon M, Graves BJ, McIntosh LP (2016). Conformational Dynamics and the Binding of Specific and Nonspecific DNA by the Autoinhibited Transcription Factor Ets-1. Biochemistry, 55(29), 4105-18.
- De S, Okon M, Graves BJ, McIntosh LP (2016). Autoinhibition of ETV6 DNA Binding Is Established by the Stability of Its Inhibitory Helix. J Mol Biol, 428(8), 1515-30.
- Desjardins G, Meeker CA, Bhachech N, Currie SL, Okon M, Graves BJ, McIntosh LP (2014). Synergy of aromatic residues and phosphoserines within the intrinsically disordered DNA-binding inhibitory elements of the Ets-1 transcription factor. Proc Natl Acad Sci U S A, 111(30), 11019-24.
- Coyne HJ 3rd, De S, Okon M, Green SM, Bhachech N, Graves BJ, McIntosh LP (2012). Autoinhibition of ETV6 (TEL) DNA binding: appended helices sterically block the ETS domain. J Mol Biol, 421(1), 67-84.
- Hollenhorst PC, Ferris MW, Hull MA, Chae H, Kim S, Graves BJ (2011). Oncogenic ETS proteins mimic activated RAS/MAPK signaling in prostate cells. Genes Dev, 25(20), 2147-57.
- Hollenhorst PC, McIntosh LP, Graves BJ (2011). Genomic and biochemical insights into the specificity of ETS transcription factors. [Review]. Annu Rev Biochem, 80, 437-71.
- Green SM, Coyne HJ 3rd, McIntosh LP, Graves BJ (2010). DNA binding by the ETS protein TEL (ETV6) is regulated by autoinhibition and self-association. J Biol Chem, 285(24), 18496-504.
- Seidel JJ, Graves BJ (2002). An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors. Genes Dev, 16(1), 127-37.