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Research Description:
The focus of the Graves laboratory is the transcriptional regulation of gene expression. This central process in biology is often disrupted in a cancer cell as evidenced by the large number of oncogenes and tumor suppressor loci that encode transcription factors. Dr. Graves investigates the regulatory pathways that provide specificity for transcription factors that belong to multi-gene families. The investigations are currently focused on the ets gene family. The ets family dramatically illustrates the specificity problem. The ETS domain, a highly conserved 85-amino acid region, defines the family and directs DNA binding. There are over 25 homologs in the human genome, many of which are co-expressed in the same cell types. In the simpler eukaryote C. elegans there are 10 family members. From these facts an important question emerges: how is specificity programmed into the family? Modulation of DNA binding by auto-inhibitory mechanisms, protein partnerships and post-translational modifications provide routes to specificity. Regulation of transcriptional activity by a Ras/MAPK-dependent signaling also contributes to specificity. The Graves’ laboratory uses a combination of biochemical, structural and genetic approaches to investigate these strategies at a mechanistic level. The issue of transcription factor specificity is central to the control of cell growth and differentiation in normal development and the dysregulation of these processes during oncogenesis. Current project use both cancer cells and the model organism C. elegans to address these questions.
Research Keywords:
DNA-protein interactions, Transcription, Signaling, Ets family