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September 24, 2020

Is the p53 gene truly the guardian of the genome?

By AVERY GULINO | February 14, 2019

PUBLIC DOMAIN Recently, researchers discovered that the p53 gene can both stop and accelerate cancer growth.

The p53 gene is widely known as a cancer suppressor gene that reduces the frequency of tumors – but what if that wasn’t the case? 

The highly cited statistic that p53 mutations are found in just over 50 percent of all human cancers suggests that when the gene is not functioning properly, cancer becomes more likely. 

While the proper expression of the gene seems to reduce the likelihood of cancer in most cases, the wide type (WT) p53 gene — the gene that normally occurs in nature — may sometimes actually promote cancer growth. 

In a multi-year study of liver cancer, researchers concluded that the WTp53 gene actually accelerates cancer growth once cancer has been initiated. By the same mechanism that it suppresses cancer growth in many cancers, WTp53 accelerates growth in a select few cases. 

The p53 gene normally acts in response to stress signals — one of the most common being DNA damage — and triggers some form of cell death, cell-cycle arrest or senescence. 

The difference in those cases when p53 enhances cancer, however, is due to one protein known as p53 upregulated modulator of apoptosis, otherwise known as PUMA. As the name suggests, PUMA is upregulated when p53 is active and causes mitochondria in the cell to switch energy sources from oxidative phosphorylation to glycolysis. Cancer cells, as it so happens, thrive off glycolysis. Again, PUMA is activated only in some cases after a tumor process has already begun. 

The mechanism of how p53 regulates tumor formation is still unclear and varies widely based on the cell type and environment, but it is clear that there is a high correlation of WTp53 and low cancer rates.

There are three steps of p53 expression that seem consistent across the board in stopping cancer growth. The p53 gene must first be stabilized, meaning it cannot bind to its negative regulator and become fully expressed. Then, p53 must bind to the DNA that is under stress or has been damaged. This area is a common spot for mutation, which would render the p53 unable to join the DNA. The p53 gene would then be unable to work, and the damaged DNA would not be destroyed and likely proliferate into a tumor. Finally, the target genes must be activated. The p53 gene also acts as a checkpoint for cells when undergoing the growth cycle: p53 can check if cell functions are being performed properly before moving to the next phase of the growth cycle. 

In reality, p53 is far more complex and is described as a whole network of proteins, activators, repressors and the like. Only a small amount of this network is currently understood, including its effect on aging.

Though its full effect is still unclear, p53 appears to also play a role in the aging process. Aging is often caused by increased levels of oxidative damage, which p53 helps to regulate. If a small amount of oxidation occurs, p53 expresses antioxidants to calm the system down. This way, the oxidation decreases and the cancer is stopped. But if too much oxidation occurs, the p53 gene signals for apoptosis to occur, initiating cell death to prevent spreading to other plants. 

While this all seems to support the tumor suppressing qualities of p53, it is still unclear in which cases cancer growth is enhanced due to the glycolysis stimulated by p53. 

However, since p53 is still so widely known as a cancer suppressor, drugs are being developed to enhance the effect of p53 and fix mutations that inhibit it. These drugs could end up acting as a double edged sword and accelerate the growth of cancers that may already exist. 

Overall, it is clear that p53 is an extraordinarily complex gene that controls many factors of cancer and aging. Much more research is necessary, however, before we can determine all the ways in which p53 interacts and how exactly it effects the body. 

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