# Project 4: Mechanisms of wild-type and mutant p53 action in vivo

> **NIH NIH P01** · COLUMBIA UNIV NEW YORK MORNINGSIDE · 2020 · $355,831

## Abstract

Summary
Mutational data from human cancer imply that the p53 tumor suppressor gene is crucial for limiting
tumorigenesis. p53 is a sequences specific DNA binding protein that is induced by DNA damage or oncogenic
stress leading to induction of genes that trigger a series of anti-proliferative responses whose contribution to
tumor suppression remains controversial. Additionally, p53 can directly or indirectly repress gene expression,
though the impact of p53 repressed genes on tumor progression and maintenance is poorly understood.
Adding to this complexity, p53 mutations typically involve a point mutation in one allele and a large deletion
targeting the other, with emerging data indicating that both of these events promote cancer beyond p53 loss.
Our project previously established that apoptosis and cellular senescence an be major modes of p53 action in
tumor suppression, and most recently identified a key role for p53 in limiting aberrant self renewal and
restricting cellular plasticity during tumorigenesis. Using key technologies developed in our group, we showed
that reactivation of endogenous p53 in advanced tumors produces potent anti-tumor effects, and explored
mechanisms whereby p53 lesions promote tumorigenesis independent of their effects on wild-type p53, for
example, identifying therapeutically actionable effectors of p53 mutant action in pancreas cancer and additional
haploinsufficient tumor suppressors encompassed within 17p deletions that cooperate with p53 suppress
tumorigenesis. In the current proposal, Project 4 will continue to use innovative genetic and animal modeling
technologies to address significant unanswered questions in the p53 field. For example, it embraces and
studies the notion that p53 action depends on context, and combines powerful uses novel mosaic mouse
models to interrogate mechanisms of p53 mediated tumor suppression in different tissue and genetic settings.
Using potent and inducible shRNA technology optimized in the group, it tests the novel hypothesis that genes
normally repressed by p53 and aberrantly increased in mutant tumors contribute to tumor maintenance and
may include targets that are synthetically lethal to mutant p53. In doing so, it implements unique inducible
shRNA transgenic technology to explore the impact of target inhibition in tumor and normal tissues. Finally,
the project will develop a streamlined method for producing p53 mutant alleles in mice, and use this to explore
the biology of highly frequent but understudied p53 truncating alleles to determine whether they produce have
gain of function properties. Each of our proposed Aims is supported by substantial preliminary data and will
benefit from interactions with all other projects and cores. Successful completion of the proposed work will
substantially understand how p53 suppresses tumorigenesis in vivo, and may point to therapeutic opportunities
relevant to a large fraction of human cancers.

## Key facts

- **NIH application ID:** 9905344
- **Project number:** 5P01CA087497-19
- **Recipient organization:** COLUMBIA UNIV NEW YORK MORNINGSIDE
- **Principal Investigator:** SCOTT W. LOWE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,831
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905344

## Citation

> US National Institutes of Health, RePORTER application 9905344, Project 4: Mechanisms of wild-type and mutant p53 action in vivo (5P01CA087497-19). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9905344. Licensed CC0.

---

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