# Mechanisms of gene expression control in the p53 network

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $332,381

## Abstract

PROJECT SUMMARY.
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 des...

## Key facts

- **NIH application ID:** 9856414
- **Project number:** 5R01CA117907-14
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Joaquin M. Espinosa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $332,381
- **Award type:** 5
- **Project period:** 2006-05-26 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856414

## Citation

> US National Institutes of Health, RePORTER application 9856414, Mechanisms of gene expression control in the p53 network (5R01CA117907-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856414. Licensed CC0.

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