Year: 2023
Type: dissertation
Abstract: The p53 tumor suppressor gene has a common single nucleotide polymorphism (SNP) at codon 72, resulting in either proline (P72) or arginine (R72) encoding, which leads to a modification in its functionality. Several groups have linked this polymorphism to an increased risk of cancer, diabetes, and metabolic diseases. However, there hasn't been an extensive exploration of how this polymorphism affects the regulation of the immune system. To investigate the effects of this polymorphism on immune function, we used a humanized p53 mouse model. These mice were either homozygous for P72 or R72, and we utilized healthy human monocytes derived macrophage in conjunction with plasma from COVID-19 patients and a toxemia mouse model for sepsis study. Here, we present evidence that this polymorphism impacts the immune function of p53 via activation of macrophages, which is critically involved in the immune responses to infections and cancers, inflammation, and regulation of several vital hemostatic processes. We also showed that this SNP contributes to the aggravated inflammatory response in COVID-19 patients resulting from biased macrophage activation. During lipopolysaccharide (LPS)-induced endotoxic shock, P72 mice showed markedly enhanced response to inflammatory challenge compared to R72. Our studies revealed that R72-P53 inhibits mitochondrial manganese superoxide dismutase, leading to impaired reactive oxygen species scavenging, oxidation of tensin homolog deleted on chromosome 10 (PTEN), and, consequently, its inhibition. Reduced PTEN activity causes constitutive activation of the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway, which restricts proinflammatory (M1) and promotes anti-inflammatory (M2) phenotypes through NF-kB and p53 inhibition. In contrast, PTEN-reduced PI3K/Akt activity in P72-carrying cells favors M1 phenotypes. Moreover, we show that lipopolysaccharide (LPS) stimulated R72 macrophages fail to reduce tumor growth in a mouse cancer model, in contrast to P72 macrophages, which preserve M1 phenotype in vivo and reduce tumor growth by enhancing antitumor T cell responses. These results demonstrate that cell signaling alterations driven by codon 72 of TP53 SNP may potentially contribute to differences in clinical outcomes and health disparities in common diseases associated with dysregulated macrophage activation.
Author: Silwal, Ashok
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7082093434