Decreased levels of cell cycle inhibitor p27Kip1 due to excessive degradation occur in a variety of aggressive human tumors. Since reduced p27 expression has been associated with a poor prognosis in many human cancers and resistance to certain anti-tumor therapies, it has been postulated that elevation of p27 expression could improve prognosis and perhaps even provide a cure for malignant cancers. However, this concept has not been proven or rigorously tested largely due to the absence of specific small molecule inhibitors that perturb abnormal reduction in p27 levels. The abundance of p27 is primarily controlled by the ATP-dependent ubiquitin-proteasome pathway. SCFSkp2 is the major ubiquitin E3 ligase responsible for degradation of p27. Therefore inhibition of SCFSkp2 E3 ligase activity is expected to enhance p27 accumulation. The overall goals of this application are to investigate unique enzymatic mechanisms of SCFSkp2 E3 ligase that are amenable to chemical perturbation and develop specific reagents for chemical genetic dissection of the function of SCFSkp2 in cancer biology. Understanding the detailed and unique mechanism by which SCFSkp2 promotes ubiquitination of p27 is essential for developing highly selective therapeutic strategies to increase p27 levels with minimal side effects. Identifying specific small molecule inhibitors of p27 degradation is a first step towards evaluating whether inhibition of p27 degradation would be an effective anti-cancer therapy approach and translating what we have learned about the basic mechanisms of p27 degradation into potential new drug leads in cancer biology.

Public Health Relevance

Excessive degradation tumor suppressing protein p27 in primary cancer tissue correlates with poor survival as well as poor response to chemotherapies. The goal of this proposal is to understand the molecular processes associated with abnormal degradation and search for drug-like molecules to prevent this degradation. Our studies could lead to novel therapy for malignant cancers and improve prognosis of patient with aggressive tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107098-09
Application #
8247820
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Hildesheim, Jeffrey
Project Start
2004-04-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$232,440
Indirect Cost
$77,078
Name
University of Colorado at Boulder
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Nardini, John T; Chapnick, Douglas A; Liu, Xuedong et al. (2016) Modeling keratinocyte wound healing dynamics: Cell-cell adhesion promotes sustained collective migration. J Theor Biol 400:103-17
Chapnick, Douglas A; Bunker, Eric; Liu, Xuedong (2015) A biosensor for the activity of the "sheddase" TACE (ADAM17) reveals novel and cell type-specific mechanisms of TACE activation. Sci Signal 8:rs1
Zhang, Conggang; Lee, Schuyler; Peng, Yinghua et al. (2015) A chemical genetic approach to probe the function of PINK1 in regulating mitochondrial dynamics. Cell Res 25:394-7
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Zhang, Conggang; Lee, Schuyler; Peng, Yinghua et al. (2014) PINK1 triggers autocatalytic activation of Parkin to specify cell fate decisions. Curr Biol 24:1854-65
Chapnick, Douglas A; Liu, Xuedong (2014) Leader cell positioning drives wound-directed collective migration in TGFβ-stimulated epithelial sheets. Mol Biol Cell 25:1586-93
Chapnick, Douglas A; Jacobsen, Jeremy; Liu, Xuedong (2013) The development of a novel high throughput computational tool for studying individual and collective cellular migration. PLoS One 8:e82444
Ungermannova, Dana; Lee, Junglim; Zhang, Gan et al. (2013) High-throughput screening AlphaScreen assay for identification of small-molecule inhibitors of ubiquitin E3 ligase SCFSkp2-Cks1. J Biomol Screen 18:910-20
Lee, Junglim; Sammond, Deanne W; Fiorini, Zeno et al. (2013) Computationally designed peptide inhibitors of the ubiquitin E3 ligase SCF(Fbx4). Chembiochem 14:445-51
Ungermannova, Dana; Parker, Seth J; Nasveschuk, Christopher G et al. (2012) Identification and mechanistic studies of a novel ubiquitin E1 inhibitor. J Biomol Screen 17:421-34

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