This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: A tumor suppressor gene known as p53 is mutated in more than half of all cancers, but how it acts to prevent cancer formation is largely unknown. A study by UT Southwestern Medical Center researchers sheds light on this phenomenon by showing what happens when p53 becomes disabled, revealing the gene's diverse roles in maintaining healthy metabolic activity, repressing mobile genes called retrotransposons and preventing cells from adopting features of sperm and eggs.
"The p53 gene is widely recognized as the most commonly mutated cancer gene. Our work is the first to examine the immediate consequences of p53 loss at the single-cell level in real time," said John Abrams, Ph.D., professor of cell biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, and corresponding author of the study published in Genes & Development.
Described as the "guardian of the genome," p53 helps protect cells by activating tumor-suppressing genes and turning off tumor-driving genes when DNA is damaged by factors such as genotoxic chemicals or ionizing radiation. But research led by Abrams and others indicates p53 may have a "steady-state" function when cells aren't stressed, which could also contribute to cancer suppression. Studying this potential function in unstressed cells has been difficult because there hasn't been a reliable way to turn off p53 and investigate the immediate effects in real time.
In conventional platforms used to study p53 deficiency—such as p53-mutated tumor cells from patients or genetically engineered mouse models or cell lines in which the gene has been deleted—there's a significant lag between p53 loss and the appearance of the resulting cancerous changes. Thus, what happens right after p53 turns off is unclear and obscured by other changes that appear in the aftermath. To elucidate the more immediate changes, mouse cells were genetically engineered so that p53 turned off after the cells were exposed to a drug called tamoxifen.
One change Abrams and his colleagues noticed within 48 hours was that cells without working p53 switched from the metabolic pathway known as oxidative phosphorylation to a metabolic pathway characteristic of cancer cells called Warburg metabolism. Rather than oxidizing nutrients to release chemical energy as healthy cells do, Warburg metabolism causes cells to derive energy by consuming large amounts of glucose through fermentation that produces lactic acid. This finding suggests the switch to Warburg metabolism is relatively immediate once p53 is disabled, rather than a long-term consequence of tumor development as some researchers have hypothesized, Abrams explained.
Similarly, previous research had shown that retrotransposons—"jumping genes" that can change their places in the genome but that largely remain dormant in healthy cells—can become reactivated in p53-mutant cells, but the timeline of this derepression has been unclear. The new study showed that this change happens immediately following p53 elimination, causing widespread effects throughout the genome. Another important change the researchers saw in the altered cells was a fast shift to genetic programs seen exclusively in sperm and egg cells, including activation of the genes necessary for meiosis, a type of cell division that produces cells with only one copy of each chromosome.
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