The tumor supressor protein p53 regulates the expression of genes that control the cellular response to various forms of stress. In the absence of p53, cells fail to initiate transcriptional programs that result in cell cycle arrest or apoptosis,thus generating a defect in the cancer surveillance mechanism. The long-term goal of our research is to understand how these genes are transcriptionally regulated by p53 and other factors in order to produce the most appropiate cellular response to stress and prevent tumor growth. Based on our previous work, we propose that the set of transcriptional co-factors utilized by p53 varies among distinct types of stress and different target genes. The goal of this proposal is to elucidate the molecular basis of this combinatorial regulation.
Our specific aims are: 1. To elucidate the stress-specific mechanism of p53-dependent transcriptional activation of the p21/Waf1/Cip1 gene. p21 mediates the cell cycle arrest response and its levels of expression vary greatly depending on the source of stress. We will identify stress-specific co-factors that influence its activation. 2. To determine how p53 activates transcription in the absence of stress-dependent signaling upon activation by nutlin. Nutlin is a small molecule capable of activating p53 without stressing the cells, thus allowing us to dissect the role of stress-dependent signaling in the p53 transcriptional response. 3. To identify promoter-specific co-factors used by p53 to activate the apoptotic genes PUMA and Fas/APO1. p53 target genes involved in diverse cellular pathways are differentially regulated. This suggest that different co-factors may be important for activation of distinct subsets of genes. To achieve our aims we will use high-throughput Chromatin Immunoprecipitation assays to examine the interaction of p53 and several co-factors with p53 target genes during activation by different forms of stress. The role of putative co-factors in the cellular response to stress will be tested by interfering with its expression using RNAi technology. Because most anti-cancer therapies rely on p53 activity to trigger the death of tumor cells, our research may provide new insights in the mode of p53 action and yield new targets for pharmacological intervention in human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA117907-05
Application #
7764740
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mietz, Judy
Project Start
2006-05-26
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$205,444
Indirect Cost
Name
University of Colorado at Boulder
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Espinosa, Joaquín M (2017) On the Origin of lncRNAs: Missing Link Found. Trends Genet 33:660-662
Liang, Kaiwei; Volk, Andrew G; Haug, Jeffrey S et al. (2017) Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia. Cell 168:59-72.e13
Audetat, K Audrey; Galbraith, Matthew D; Odell, Aaron T et al. (2017) A Kinase-Independent Role for Cyclin-Dependent Kinase 19 in p53 Response. Mol Cell Biol 37:
Nichol, Jessica N; Galbraith, Matthew D; Kleinman, Claudia L et al. (2016) NPM and BRG1 Mediate Transcriptional Resistance to Retinoic Acid in Acute Promyelocytic Leukemia. Cell Rep 14:2938-49
Espinosa, Joaquín M (2016) Revisiting lncRNAs: How Do You Know Yours Is Not an eRNA? Mol Cell 62:1-2
Andrews, Forest H; Tong, Qiong; Sullivan, Kelly D et al. (2016) Multivalent Chromatin Engagement and Inter-domain Crosstalk Regulate MORC3 ATPase. Cell Rep 16:3195-3207
Perez-Perri, Joel I; Dengler, Veronica L; Audetat, K Audrey et al. (2016) The TIP60 Complex Is a Conserved Coactivator of HIF1A. Cell Rep 16:37-47
Ferreyra Solari, Nazarena E; Belforte, Fiorella S; Canedo, Lucía et al. (2016) The NSL Chromatin-Modifying Complex Subunit KANSL2 Regulates Cancer Stem-like Properties in Glioblastoma That Contribute to Tumorigenesis. Cancer Res 76:5383-94
Abraham, Christopher G; Espinosa, Joaquín M (2015) The Crusade against Mutant p53: Does the COMPASS Point to the Holy Grail? Cancer Cell 28:407-408
Tentler, John J; Ionkina, Anastasia A; Tan, Aik Choon et al. (2015) p53 Family Members Regulate Phenotypic Response to Aurora Kinase A Inhibition in Triple-Negative Breast Cancer. Mol Cancer Ther 14:1117-29

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