CREB binding protein (CBP) and p300 are general transcriptional regulators that integrate numerous signal transduction pathways in eukaryotic cells, functioning both as coactivators and repressors of gene expression. They are essential for such basic cellular functions as growth, differentiation, apoptosis, and embryonic development. They also function as tumor suppressors and regulate key genes that control cellular proliferation, tumorigenesis, and cancer progression. Because of their function at the nexus of critical cell signaling networks, CBP and p300 are targeted by many cellular and viral oncoproteins. The goals of the present proposal are to elucidate the structural and molecular basis by which CBP and p300 perform their central regulatory roles to protect against or promote oncogenic transformation. The research will focus on elucidation of the molecular determinants by which CBP and p300 interact with the tumor suppressor p53 and with transforming oncoproteins from human papillomavirus. p53 is activated by a complex phosphorylation cascade that results in enhanced interactions between the p53 transcriptional activation domain and CBP/p300. The E6 and E7 oncoproteins from high risk human papillomavirus recognize and bind CBP/p300 to repress p53-mediated transcriptional pathways, prevent apoptosis, and transform the host cell. State-of-the-art structural, biophysical, and proteomics tools will be utilized to elucidate the molecular basis for key CBP/p300 interactions responsible for activation of the p53 response to DNA damage, immortalization and transformation of the host cell by high risk human papillomavirus strains, and regulation and repression of damage response genes. This research will provide novel insights into the mechanism of activation of p53-regulated genes in response to genotoxic stress, into the molecular interactions through which high risk human papillomavirus oncoproteins subvert the cellular regulatory machinery to immortalize and transform the cell, and into the function of CBP as a transcriptional repressor.

Public Health Relevance

The proposed research will address the mechanisms by which CREB binding protein (CBP) and p300 function as tumor suppressors and regulate key genes that control cell proliferation, tumor formation, and tumor progression. This research will provide new molecular level understanding of the role of CBP and p300 in stabilization and activation of the tumor suppressor p53, and in the cancerous transformation of human cells by high risk papillomaviruses. It will provide new knowledge of the key molecular interactions by which CBP and p300 guard against or promote cancer, interactions which are of direct interest as potential targets for design of novel therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA096865-15
Application #
9026569
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Knowlton, John R
Project Start
2002-06-10
Project End
2017-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
15
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Park, Sangho; Stanfield, Robyn L; Martinez-Yamout, Maria A et al. (2017) Role of the CBP catalytic core in intramolecular SUMOylation and control of histone H3 acetylation. Proc Natl Acad Sci U S A 114:E5335-E5342
Bhowmick, Asmit; Brookes, David H; Yost, Shane R et al. (2016) Finding Our Way in the Dark Proteome. J Am Chem Soc 138:9730-42
Dyson, H Jane; Wright, Peter E (2016) Role of Intrinsic Protein Disorder in the Function and Interactions of the Transcriptional Coactivators CREB-binding Protein (CBP) and p300. J Biol Chem 291:6714-22
Krois, Alexander S; Ferreon, Josephine C; Martinez-Yamout, Maria A et al. (2016) Recognition of the disordered p53 transactivation domain by the transcriptional adapter zinc finger domains of CREB-binding protein. Proc Natl Acad Sci U S A 113:E1853-62
Haberz, Peter; Arai, Munehito; Martinez-Yamout, Maria A et al. (2016) Mapping the interactions of adenoviral E1A proteins with the p160 nuclear receptor coactivator binding domain of CBP. Protein Sci 25:2256-2267
Arai, Munehito; Sugase, Kenji; Dyson, H Jane et al. (2015) Conformational propensities of intrinsically disordered proteins influence the mechanism of binding and folding. Proc Natl Acad Sci U S A 112:9614-9
Wright, Peter E; Dyson, H Jane (2015) Intrinsically disordered proteins in cellular signalling and regulation. Nat Rev Mol Cell Biol 16:18-29
Berlow, Rebecca B; Dyson, H Jane; Wright, Peter E (2015) Functional advantages of dynamic protein disorder. FEBS Lett 589:2433-40
Toretsky, Jeffrey A; Wright, Peter E (2014) Assemblages: functional units formed by cellular phase separation. J Cell Biol 206:579-88

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