The Impact of p53 Variants on Liver Disease

Research Project 3 – 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, 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. Antonis Kourtidis, PhD. Each laboratory has unique and complementary expertise in fibrosis/cirrhosis, mouse models of HCC, and targeted therapy. 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.