CREB binding protein (CBP) and p300 are modular transcriptional coactivators that integrate numerous signal transduction pathways in eukaryotic cells. They are essential for such basic cellular functions as growth, differentiation, apoptosis, and DNA repair. CBP/p300 play critical roles in embryonic development and are the targets of numerous oncogemc events. They also function as tumor suppressors and are required for the transcriptional activities of many cellular oncogenes and tumor virus oncoproteins. The molecular mechanisms by which CBP and p300 recognize and bind transcription factors, transcriptional coactivators, viral oncoproteins, and tumor suppressors such as p53 are poorly understood. There is an urgent need for structural characterization of the various CBP/p300 domains and their complexes in order to elucidate the mechanisms by which they recognize and discriminate between their many cellular and viral targets. The goals of the present proposal are to address these issues by determining the solution structures of several key CBP/p300 domains in complex with target proteins of central relevance to their role in cell growth and transformation. The structure of the complex formed between the CH1 region of CBP and hypoxia-inducible factor-l (HIF- I alpha) will be determined. This interaction is essential for activation of genes that ensure cell survival under hypoxic conditions and is a potential target for antitumor agents. The structure of complexes of the CH3 domain of CBP/p300 with adenoviral E1A oncoproteins will be determined to elucidate mechanisms of molecular recognition. The mechanisms by which CBP/p300 regulate p53 turnover and activate p53-mediated transcription will be investigated through structural analysis of complexes formed with the p53 transactivation domain and with MDM2. Finally, structures of the complexes formed between the KIX domain of CBP, the cellular proto-oncogene c-Myb, and MLL (mixed lineage leukemia protein) will be determined to elucidate mechanisms by which cooperative interactions modulate binding interactions and transcriptional activity. This research will provide fundamental insights into the mechanisms of molecular recognition by CBP/p300, and the molecular basis by which they mediate critical interactions involved in tumor growth and progression.
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