Whilst all scientists like to claim that the protein that they work on is the most important, when it comes to cancer progression, there is one that is arguably the most important, known as p53. Discovered in 1979 by many scientists independently, p53 primarily acts as a transcription factor that binds to DNA to induce gene expression. It was the first known tumour suppressor, which is a protein that acts to prevent tumour formation. The importance of p53 in cancer prevention is illustrated by Li-Fraumeni syndrome patients, who have p53 mutations in their DNA from birth. This syndrome increases the probability of developing cancer; approximately 41% of patients with p53 mutations will develop cancer by the age of 18, and 90% by age 60(1). Due to its crucial role as a tumour suppressor, p53 is often referred to as the ‘guardian of the genome’. Think of p53 as a bouncer in a nightclub: at the first sign of trouble, it will throw that cell out!
In response to DNA damage in a cell, p53 will immediately trigger a fight or flight response, depending on the extent of the damage. In fight mode, p53 acts to trigger cell cycle arrest, preventing the cell from dividing, and then can initiate a state of permanent arrest, known as senescence. Following this, p53 will initiate a DNA repair response in order to repair the damage and return the cell to regular function. If the DNA damage is extensive, p53 instead kicks into its flight response, activating genes to initiate cell death, known as apoptosis. This process is crucial to remove damaged cells, as they often go on to become cancerous — growing uncontrollably to form tumours.
Due to p53’s crucial role in preventing cancer growth, it is unsurprising that it's one of the most mutated proteins across all cancer types. In one study looking at mutations across 12 major cancer types, researchers determined that p53 is mutated in 42% of all cancers, which was the highest percentage mutation rate across all proteins(2). Different cancer types can have very variable levels of p53 mutation rates and in some cancers it almost seems necessary for their progression. For example, in ovarian cancer p53 mutations were seen in 95% of cases(2). Sometimes these mutations lead to complete loss of p53 in the cell, meaning that DNA damage goes unchecked and cells can grow uncontrollably. However, more interestingly, the majority of p53 mutations allow p53 to still be expressed, but as a mutant protein that promotes cancer development. Due to their new found ability to promote cancer development, these mutants have been dubbed "gain of function" p53 mutants(3). I like to call them p53's evil twins. These mutants may only have one single change in their 3D structure, but such changes have dramatic consequences. They have been shown to have detrimental affects for patient health, including faster cancer growth increased metastatic spread and resistance to chemotherapy(4).
Curiously, despite p53’s important role as a tumour suppressor, there are no current therapies specifically targeting the p53 protein that have been approved as standard treatments for cancer. Luckily for scientific researchers, p53’s evil twin provides a possible avenue to explore, as we can target it in order to restore normal p53 function. Many methods of doing this have shown success in early trials, but have yet to be approved for use in standard cancer treatment. Many researchers around the world are dedicated to studying p53, and all its mutants, in the hopes that one day we can utilise our guardian of the genome correctly to protect us from cancer.
References
Bougeard G et al. 2015. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. Journal of Clinical Oncology 33: 2345–2352.
Kandoth C et al. 2013. Mutational landscape and significance across 12 major cancer types. Nature 502: 333–339.
Freed-Pastor WA, Prives C. 2012. Mutant p53: One name, many proteins. Genes and Development 26: 1268–1286.
Dolma L, Muller PAJ. 2022. GOF Mutant p53 in Cancers: A Therapeutic Challenge. Cancers 14.
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