# The impact of p53 variants on liver disease

> **NIH NIH P20** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $224,249

## Abstract

The TP53 tumor suppressor is arguably one of the most important genes in cancer, given that it is inactivated 
by somatic mutations in about 50% of human tumors. p53 serves to protect cells in response to numerous 
biological and environmental stresses, such as DNA damage, reactive oxygen species (ROS), and oncogene 
activation. Upon insult, p53 responds rapidly by activating a plethora of cellular responses that inhibit the 
growth of damaged cells, including cell cycle arrest, senescence, and apoptosis. In addition to mutations, 
single nucleotide polymorphisms (SNPs) in the TP53 gene can also have a significant impact on p53 function. 
We have shown that a coding region polymorphism at amino acid 47 of p53 (Pro47Ser, hereafter S47), 
causes this protein to have markedly impaired tumor suppressor function. The S47 polymorphism of p53 
(rs1800371) is found in approximately 2% of African Americans. Genetically engineered p53 “S47 mice” are 
prone to spontaneous tumors. Over 30% of these mice developed hepatocellular carcinoma (HCC), the most 
common type of liver cancer. We found that S47 cells and mice were defective for their ability to induce 
ferroptosis, an iron and lipid-mediated form of cell death. This ferroptotic defect leads to an increase in iron 
accumulation in cells and tissues. Consistent with these findings, we recently reported that the S47 variant 
of p53 is significantly associated with Iron Overload in African Americans (OR 1.7, p=0.023), a disorder that 
causes iron accumulation and an increased predisposition to liver fibrosis and cancer. Collectively, our data 
suggest that the S47 variant of p53 may be a significant risk factor for liver disease in African Americans. 
The broad, long-term objective of this proposal is to test the hypothesis that the S47 variant is impaired for 
p53-mediated tumor suppression in the liver and has a reduced ability to suppress HCC. In Aim 1, we will 
use genetically engineered mouse models and cell lines to determine the impact of the S47 variant of p53 
on the initiation and progression of HCC. In Aim 2, we will use our human WT and S47 CRISPR knock-in 
liver cancer cell lines, and the S47 mouse, to identify personalized therapeutic approaches for S47 individuals 
with HCC. To achieve these goals, we have put in place a strong and collaborative Mentoring Team: (1) Dr. 
Don Rockey, MD; (2) Dr. Paul Monga, MD; and (3) Dr. Natalie Saini, PhD. Each laboratory has unique and 
complementary expertise in fibrosis/cirrhosis, mouse models of HCC, and bioinformatics. We expect to 
reveal the underlying mechanisms by which the S47 variant of p53 leads to increased liver disease risk. We 
also expect to uncover more efficacious therapies for HCC in this population.

## Key facts

- **NIH application ID:** 11084587
- **Project number:** 5P20GM130457-05
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Thibaut Barnoud
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $224,249
- **Award type:** 5
- **Project period:** 2024-04-04 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11084587

## Citation

> US National Institutes of Health, RePORTER application 11084587, The impact of p53 variants on liver disease (5P20GM130457-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11084587. Licensed CC0.

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