# Epigenetic regulation by tumor suppressor p53

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $374,728

## Abstract

ABSTRACT
p53 is remarkable in that wild type (WT) p53 is a crucial sentinel against cancer, but single amino acid
substitutions within its DNA binding domain can cause loss of protective function and can transform p53, via
gain-of-function (GOF) alterations, into a cancer-driving oncogene. Additionally, given that p53 inactivation is
an essential step of oncogenesis, it is striking that many cancers maintain high levels of WT p53. Mechanisms
underlying these complex functions of p53 have been investigated for decades, and yet mysteries persist
about how a relatively small protein can encompass many distinct mechanisms and functions.
 Our previous epigenomic studies have begun to uncover modes of p53 interaction with chromatin, to
explain WT and mtp53 activation of gene pathways. We helped to further define functional classes of the
numerous p53 missense mutations. One mutant class loses direct DNA-binding activity, and instead is
indirectly recruited to chromatin to drive expression of epigenetic genes. Another mutant class retains 50% of
WT p53 DNA-binding affinity, however, whether these mtp53 retain binding in vivo, and how they drive cancer,
is not understood. Finally, our previous findings showed that, in certain cancer cells bearing WT p53,
methylation of the p53 protein (p53me) represses its normal tumor suppressive function, and preliminary
findings point to a potential dominant oncogenic function of p53me.
 In the proposed studies we will address new mechanisms, gene targets, and potential therapeutics that
are represented in these three major epigenetic pathways of p53 regulation. First, we will explore the
oncogenic and genomic functions of ETS-dependent p53 GOF mutants. We will inhibit the interaction of mtp53
with ETS2, hypothesizing that that blocking the ETS2 interaction with GOF p53 is a promising strategy to
selectively treat cancers harboring GOF p53 without disrupting WT p53. We will investigate the immediate
transcriptional and chromatin consequences of mtp53 disruption, using a temperature-sensitive p53 mutant as
well as rapid protein degradation systems. These approaches will advance fundamental understanding of
mtp53’s molecular functions in the nucleus. Second, we will determine the oncogenic mechanisms of a direct-
DNA binding class of p53 mutants. We propose a novel model of p53-mediated oncogenesis, whereby p53
mutants that retain intrinsic DNA-binding function at canonical p53 REs, also aberrantly activate cancer-
related genes that neighbor tumor suppressor genes. We hypothesize that this “gene target switching”
involves mtp53 interacting with HMGA1 to facilitate new enhancer-promoter looping to cancer genes. Third,
we will define roles of WT p53 in cancer. Our published results show p53me represses WT p53’s tumor
suppressor activity, but the underlying mechanism mediating this repression is poorly understood. Further, we
have evidence to suggest WT p53me may impart new oncogenic functions. We will test the hypothesis...

## Key facts

- **NIH application ID:** 10360465
- **Project number:** 5R01CA078831-23
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** SHELLEY L BERGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $374,728
- **Award type:** 5
- **Project period:** 1999-04-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360465

## Citation

> US National Institutes of Health, RePORTER application 10360465, Epigenetic regulation by tumor suppressor p53 (5R01CA078831-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10360465. Licensed CC0.

---

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