# A Pathway of Tumor Suppression

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $366,000

## Abstract

The p53 tumor suppressor is a DNA damage/stress response protein that functions as a transcription factor to
regulate a large number 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 which are potent tumor suppressive
mechanisms. Disruption of the pathway occurs most often through mutation or deletion of the p53 gene itself,
but elevated levels of two important p53 inhibitors, MDM2 and MDM4, also contribute to tumor development in
specific cancers. MDM2 encodes an E3 ubiquitin ligase that targets p53 for degradation and both MDM2 and
MDM4 inhibit p53 activity by masking its transcriptional activation domain. In mice, overexpression of Mdm2 or
Mdm4 is sufficient to drive tumorigenesis, while deletion of either Mdm2 or Mdm4 results in p53-dependent lethal
phenotypes. These and other studies provide compelling data for the relationship between Mdm proteins and
p53 and have led to the development of MDM2 inhibitors (MDM2i) for the treatment of human cancers. Recently
published Phase I clinical trials using one such MDM2i show promise as several patients achieved complete or
partial responses or had stable disease following treatment and tumors exhibited activation of downstream p53
target genes. Unfortunately, these studies also highlighted serious adverse effects including hematological,
gastrointestinal and kidney toxicities, phenotypes that were predicted from studies in mouse models. In addition,
activation of known p53 targets did not always correlate with p53-mediated cellular events and implies tissue
specificity of response. We have developed in vivo mouse models that allow us to probe the specificity of the
p53 response at the molecular and organismal levels. Global loss of Mdm2 results in tissue-specific activation
of p53 targets and apoptosis/senescence phenotypes which also vary by tissue type. In another model, deletion
of the p53 target Puma but not p21 rescued some of the defects due to reduced MDM2 levels. These tissue
specific differences need to be better defined to understand the toxicities of Mdm2i in humans and to develop
potential biomarkers for toxicity. Thus the first aim will be to determine and functionally examine the p53
transcriptional program and the downstream pathways (senescence/apoptosis) that are activated in vivo upon
depletion of Mdm2 in bone marrow, intestine and kidney. High MDM2 levels as occur in some human cancers
are not tolerated by normal cells. We have completed a CRISPR/Cas9 screen to identify factors that allow normal
cells to survive despite elevated levels of MDM2 to identify and characterize synthetic lethal relationships with
high MDM2 in tumors (aim 2). Lastly, we plan to determine the mechanisms and factors that cause increased
MDM2 levels in tumors that lack amplification of the Mdm2 locus since small differences in MDM2 levels (and
therefore p53) impact tumorigenesis (aim 3). Our stu...

## Key facts

- **NIH application ID:** 10053320
- **Project number:** 5R01CA047296-33
- **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:** 2021
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 1988-07-01 → 2022-06-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10053320

## Citation

> US National Institutes of Health, RePORTER application 10053320, A Pathway of Tumor Suppression (5R01CA047296-33). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10053320. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*