CONTROL OF P53 TUMOR SUPPRESSOR BY CBP/P300

Duke University, Durham NC

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Abstract

DESCRIPTION (from the application): The long-term objective of this proposal is to elucidate the function of CBP and its family member p300 in cellular growth and oncogenesis. CBP and p300 are transcriptional co-activators that modulate transcriptional output from multiple signal transduction pathways. Biochemical evidence indicates that CBP/p300 are acetyltransferases that acetylate and activate the p53 tumor suppressor protein, indicating a role of CBP/p300 in growth regulation. Consistent with this idea, the inactivation of CBP/p300 by viral oncoprotein E1A contributes to cellular immortalization and transformation. Mono-allelic loss of CBP in humans (i.e. Rubinstein Taybi syndrome) and in mice leads to an increased risk of cancers, supporting a specific role for CBP in oncogenesis. To begin to address the molecular basis for the tumor susceptibility in RTS patients and to examine how CBP and p300 function in growth regulation and oncogenesis, we propose to characterize their functional interaction with p53. Two specific aims are proposed to capitalize on previously generated CBP and p300 deficient mice and cells: 1. To establish the role of CBP and/or p300 in modulating the activity of p53 and to analyze the functional impact of CBP/p300 mediated acetylation on p53 activity in vitro. 2. To establish the functional significance of p53-CBP or p53-p300 interaction in cellular immortalization, transformation control in vitro, and tumor formation in mice. The proposed research not only will provide critical insights into the role of CBP and p300 in modulating the tumor suppressor activity of p53, but also elucidate molecular basis for the tumor susceptibility in RTS patients. By uncovering the significance of a specific acetylation event in this process, this work may also open a new avenue of therapeutic approach to modulate p53 activity by manipulating the acetyltransferase activity of CBP and/or p300. Using p53 as a model system, we may also uncover the functional distinction between CBP and p300. Such a finding may provide the basis that CBP mutation but not p300 mutation, leads to tumor susceptibility.