The Transcription Regulation Unit applies a transcriptional approach to the study of mechanisms of signal transduction in activate T-cells. Work in this laboratory has established that the interleukin-2 (IL-2) promoter is major target of regulation by the p300/CBP nuclear co- activator proteins. A central component of the action of p300/CBP at the interleukin 2 promoter is its sequence specific recruitment to composite elements within the 300 bp proximal IL-2 promoter by the coordinate action of nuclear transcription factors. One of the key target sequences in the promoter is the CD28RE-TRE element, which mediates the assembly of a multi-protein complex at the IL-2 promoter containing c-rel/kappa B and ATF/CREB transcription factors. Recently we have defined this assembled complex as a central target for the integration of molecular signaling events during T-cell activation. Moreover we have established that this complex is targeted for down- regulation by the p53 tumor suppressor gene and the immunosuppreseve action of the glucocorticoid receptor. In addition, we have shown the this complex is also the major target for upregulation by the HTLV-1 oncoprotein, Tax, and the NPM-ALK fusion oncoprotein of the Anaplastic lymphoma kinase. Thus the kappa-B/ATF/p300 complex at the CD28RE-TRE is a major downstream target of events that regulate T-cell proliferation in response to both immune activation and the action of lymphomagenic agents. Through detailed studies of the biochemistry of p300 in activated T-cells and its functional interaction at the interleukin-2 promoter we have demonstrated that p300 is undergoes significant post- translational modification in mitogen activated T-cells. Phospopeptide map analysis of p300/CBP indicate that there are changes in both the level of phosphorylation and a, as yet undefined, covalent modifications of p300/CBP during T-cell activation. Current efforts to study the influence of these modification on p300/CBP histone acetyl- transferase activity, and it interaction with other nuclear components, including , basal transcription factors, gene specific transcription factors, histone acetylases and deacetylases are currently under way.
