# A Pathway of Tumor Suppression

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $466,560

## Abstract

Abstract
The p53 tumor suppressor is a DNA damage/stress response protein that functions as a transcription factor
to regulate a large repertoire of genes that prevent proliferation of damaged cells via initiation of cell cycle
arrest and senescent programs or via apoptosis and other mechanisms of cell death. However, the
molecular, morphological, and physiological consequences of this transcriptional program remain poorly
understood in vivo. We have defined the physiological p53 transcriptional program using the mouse as a
model system. Global p53 activation causes anomalies in the pancreas (an acinar to ductal metaplasia),
intestine (crypt atrophy) and kidney (dilated tubules), and directly activates hundreds of genes many in a
tissue-specific manner. Seven genes, however, are universally expressed in the five tissues (pancreas,
intestine, kidney, ovary, heart) examined and represent a pan-tissue p53 transcriptional signature which
includes Mdm2 (which encodes a potent p53 inhibitor) but not p21 (a cell cycle inhibitor and first identified p53
target gene). The pan-tissue p53 transcriptional signature includes three other genes with central functions in
cell survival or cell death for which little is known. Eda2r is a transmembrane receptor and member of the TNF
family with the ability to induce apoptosis. Significantly reduced expression of EDA2R is observed in mutant
p53 breast, colorectal, and lung cancers and in pancreatic ductal adenocarcinoma and glioblastoma. Gtse1
encodes a cytoplasmic protein that migrates to the nucleus upon DNA damage, and binds and inhibits p53
activity in cells in culture. A review of cancer sequencing data indicates that amplification of GTSE1 is
mutually exclusive with TP53 alterations in angiosarcomas further implicating it as an inhibitor of p53
function. Polκ is an error prone DNA polymerase that allows replication of damaged DNA and ensures cell
survival, but contributes to an increased mutation burden. We hypothesize that these three transcriptional
targets are key effectors of the p53 pathway and functionally contribute to ensure cell survival (via cell cycle
arrest or senescence) or initiate cell death. In addition, two of these effectors have opposing properties: Eda2r
induces apoptosis, while Gtse1 inhibits p53 activity and ensures cell survival. Single cell analysis in the
pancreas upon p53 activation, either by deletion of Mdm2 or inflammation, will be performed to understand
the cell-specific and dynamic nature of the p53 transcriptional program. The specific aims are: 1) to
determine the roles of Eda2r in p53-dependent processes in vivo; 2) To determine the importance of Gtse1
in inhibiting p53 activity in vivo; 3) To determine the functional significance of p53 regulation of Polκ in
homeostasis, inflammation and cancer; and 4) To determine the specificity of the p53 response using single
cell analyses of the pancreas. A deep fundamental knowledge of the physiological p53 transcriptional
program and ...

## Key facts

- **NIH application ID:** 10442016
- **Project number:** 2R01CA047296-34
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** GUILLERMINA LOZANO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $466,560
- **Award type:** 2
- **Project period:** 1988-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442016

## Citation

> US National Institutes of Health, RePORTER application 10442016, A Pathway of Tumor Suppression (2R01CA047296-34). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10442016. Licensed CC0.

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