(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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085676-03
Application #
6626753
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Blair, Donald G
Project Start
2001-01-05
Project End
2005-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
3
Fiscal Year
2003
Total Cost
$227,728
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Kawaguchi, Yoshiharu; Ito, Akihiro; Appella, Ettore et al. (2006) Charge modification at multiple C-terminal lysine residues regulates p53 oligomerization and its nucleus-cytoplasm trafficking. J Biol Chem 281:1394-400
Ito, Akihiro; Kawaguchi, Yoshiharu; Lai, Chun-Hsiang et al. (2002) MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J 21:6236-45
Ito, A; Lai, C H; Zhao, X et al. (2001) p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J 20:1331-40