Abstract
Simple SummaryTP53 is one of the most well-known and intensively studied tumor-suppressor genes. TP53 is also the most commonly mutated gene in cancer. Many TP53 mutations are missense mutations and are located in several hotspots. Increasing evidence has shown that these hotspot mutations both lose the wild-type function and gain oncogenic functions to promote cancer progression. Among these hotspot mutations, p53-R175H has the highest occurrence in diverse cancers. In this review, we summarize studies associated with p53-R175H gain of function, and outline the current situation of the development of small molecules or immunotherapies that target p53-R175H.Wild-type p53 is known as “the guardian of the genome” because of its function of inducing DNA repair, cell-cycle arrest, and apoptosis, preventing the accumulation of gene mutations. TP53 is highly mutated in cancer cells and most TP53 hotspot mutations are missense mutations. Mutant p53 proteins, encoded by these hotspot mutations, lose canonical wild-type p53 functions and gain functions that promote cancer development, including promoting cancer cell proliferation, migration, invasion, initiation, metabolic reprogramming, angiogenesis, and conferring drug resistance to cancer cells. Among these hotspot mutations, p53-R175H has the highest occurrence. Although losing the transactivating function of the wild-type p53 and prone to aggregation, p53-R175H gains oncogenic functions by interacting with many proteins. In this review, we summarize the gain of functions of p53-R175H in different cancer types, the interacting proteins of p53-R175H, and the downstream signaling pathways affected by p53-R175H to depict a comprehensive role of p53-R175H in cancer development. We also summarize treatments that target p53-R175H, including reactivating p53-R175H with small molecules that can bind to p53-R175H and alter it into a wild-type-like structure, promoting the degradation of p53-R175H by targeting heat-shock proteins that maintain the stability of p53-R175H, and developing immunotherapies that target the p53-R175H–HLA complex presented by tumor cells.
Highlights
Cancer is a set of diseases characterized by abnormal cell growth with the potential to invade other parts of the body
In 2004, Olive et al reported that p53R172H/− and p53R270H/− mice developed novel tumors compared to p53−/− mice, including a variety of carcinomas and more frequent endothelial tumors [15]
By summarizing the p53-R175H gain-of-functions reported by different groups, p53R175H and other p53 hotspot mutations were found to contribute to tumor development by promoting cancer cell proliferation, migration, invasion, initiation, metabolic reprogramming, angiogenesis, and conferring drug resistance to cancer cells (Table 2)
Summary
Cancer is a set of diseases characterized by abnormal cell growth with the potential to invade other parts of the body. Different mutations might have different levels of impact on the function of p53, either by altering the global protein structure or disrupting the p53–DNA interface, and there is a selection for cancer cells that express p53 mutants, losing its wild-type function [7]. Missense mutations located at these hotspots encode mutant p53 oncoproteins that lose canonical tumor-suppressor functions and gain oncogenic functions to promote cancer progression. Among these hotspot mutations, p53-R175H has the highest occurrence in cancer patients in both the TCGA database and IARC TP53 somatic mutations database (Table 1).
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