. TP53 is the most frequently mutated tumor suppressor gene in human cancer. However, about half of cancers retain a wild type version of the p53 protein, which is commonly attenuated by other mechanisms, such as overexpression of the repressor MDM2. The presence of wild type p53 opens a window of opportunity for therapeutic reactivation of this transcription factor. The goal of this proposal is to elucidate the molecular mechanisms that modify the p53 network in a cell type-specific manner, affecting cell fate choice and tumor suppression downstream of p53 reactivation. The ultimate goal is to enable effective p53-based targeted therapies. Using a comprehensive multi-omics experimental and analytical pipeline we identified three major regulatory mechanisms affecting p53 signaling in a cell type-specific fashion: chromatin architecture at target loci, secondary ?amplifying? transcription factors, and cell type-specific translational regulators. We will investigate each mechanism in detail by developing the following Specific Aims: 1. To define the impact of cellular transformation on the direct p53 program. We discovered that cell type-specific variations in the direct p53 transcriptional program are associated with distinct patterns of chromatin architecture, including differences in DNA methylation. We will now test the hypothesis that the direct p53 program is attenuated during tumor evolution via chromatin-based mechanisms that restrict the number of available direct p53 targets. We will do this by applying our multi-omics pipeline to study the direct p53 program in intestinal organoids derived from normal epithelium and colorectal carcinoma explants. 2. To define the role of secondary transcription factors in the p53 response. We identified two novel direct p53 target genes, the transcription factors ETV7 and POU2F2, which are predicted to elicit the indirect transcriptional program in cells where p53 has an intact tumor suppressive activity. We will define the role of ETV7 and POU2F2 in the observed amplification of p53 effects on the global transcriptome, as well as their contribution to p53-dependent cellular responses in vitro, and tumor suppressive activity in xenograft models. 3. To identify translational regulators controlling the cellular response to p53 activation. Translation of hundreds of mRNAs is activated or repressed downstream of p53 in a cell type-specific manner. We identified 3?UTR motifs and RNA-binding proteins (RBPs) that are predicted to mediate cell type-specific translational control. We will continue to identify and characterize functional RNA motifs and interacting RBPs acting in different contexts, and define their contribution to p53-dependent cellular responses in vitro and to the ability of p53 to induce tumor regression in xenograft models. Upon completion, this proposal will significantly advance our understanding of regulatory mechanisms within the p53 network, and contribute to the future design of improved p53-based therapeutic strategies.

Public Health Relevance

. Pharmacological activation of the p53 transcription factor could benefit 11 million cancer patients worldwide that carry tumors with a wild wild-type version of this potent tumor suppressor. However, p53 is a highly pleiotropic factor that drives vastly different cellular responses depending on the context, which limits its therapeutic potential. Research described in this proposal will identify and characterize molecular mechanisms that modify the activity of this tumor suppressor in different contexts, with the ultimate goal of illuminating novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA117907-13
Application #
9640420
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Johnson, Ronald L
Project Start
2006-05-26
Project End
2023-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
13
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Fitzwalter, Brent E; Towers, Christina G; Sullivan, Kelly D et al. (2018) Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover. Dev Cell 44:555-565.e3
Abraham, Christopher G; Ludwig, Michael P; Andrysik, Zdenek et al. (2018) ?Np63? Suppresses TGFB2 Expression and RHOA Activity to Drive Cell Proliferation in Squamous Cell Carcinomas. Cell Rep 24:3224-3236
Galati, Domenico F; Sullivan, Kelly D; Pham, Andrew T et al. (2018) Trisomy 21 Represses Cilia Formation and Function. Dev Cell 46:641-650.e6
Guarnieri, A L; Towers, C G; Drasin, D J et al. (2018) The miR-106b-25 cluster mediates breast tumor initiation through activation of NOTCH1 via direct repression of NEDD4L. Oncogene 37:3879-3893
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:
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

Showing the most recent 10 out of 55 publications