A protein discovered in the late 1970s has been shown to defend human cells from becoming cancerous. Researchers have been trying to stabilise p53 for decades, because it is a large protein that breaks down easily. Have they finally succeeded?
The p53 protein is a key player in the human body’s defence against cancer, as it helps to discover and prevent genetic mutations which can, in turn, create cancerous cells. A news release notes that if a cell is lacking functional p53, it quickly becomes a cancer cell that starts to proliferate, dividing uncontrollably.
That is why scientists around the world are working on cancer treatments that aim at affecting the way the tumour suppressor p53 protein works. A study published in the journal Structure, called “A ‘spindle and thread’-mechanism unblocks translation of N-terminally disordered proteins”, lays bare the issues surrounding the protein.
“The problem is that cells only make small amounts of p53 and then quickly break it down as it is a very large and disordered protein,” says the study’s last author Michael Landreh, researcher at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.
Landreh adds that the team has been “inspired by how nature creates stable proteins and [has] used spider silk protein to stabilise p53. Spider silk consists of long chains of highly stable proteins, and is one of nature’s strongest polymers.”
In a joint effort with, amongst others, Jan Johansson and Anna Rising at Sweden’s KI Department of Biosciences and Nutrition, who research spider silk in their laboratories, the team attached a small section of synthetic spider silk protein onto the human p53 protein.
When the researchers added the fusion protein into human cells, they discovered that cells began producing it in large quantities. The new protein also turned out to be more stable than regular p53 and capable of killing cancer cells.
The researchers made use of electron microscopy, computer simulations and mass spectrometry in order to assess and indicate that the possible reason for the qualities of the fusion protein was that the spider silk part “gave structure” to p53’s disordered sections.
The next step for the researchers is a study of the new protein’s structure so that they can identify its parts in detail and how they interact to prevent cancer. The team also wishes to learn how the cells are affected by the new fusion p53 protein and how well they deal with its spider-silk ingredient.
“Creating a more stable variant of p53 in cells is a promising approach to cancer therapy, and now we have a tool for this that’s worth exploring,” says co-author and senior professor Sir David Lane at Karolinska Institutet. “We eventually hope to develop an mRNA-based cancer vaccine, but before we do so we need to know how the protein is handled in the cells and if large amounts of it can be toxic.”
One of the discoverers of p53 protein in the late 1970s, Sir David Lane has also said “Understanding more about p53 and trying to clinically exploit this property of tumours has been the theme of my research. If we understand what p53 does, we can also understand the fundamentals of cancer.”
Because p53 can prevent cells with DNA damage from turning into cancer cells, it has been called ‘the guardian of the genome’. According to the authors, “Mutations that inactivate p53 can be found in up to 60% of all human cancers, and consequently, restoring its function is an attractive therapeutic strategy.”
The study was a collaboration between researchers at Karolinska Institutet, KTH Royal Institute of Technology and Stockholm University in Sweden and A*STAR (Agency for Science, Technology and Research) in Singapore. It was supported by grants from several bodies, including the Swedish Foundation for Strategic Research, Karolinska Institutet, the Swedish Cancer Society, the Swedish Research Council, Vinnova, the Olle Engkvist Foundation, the Swedish Society for Medical Research (SSMF), Formas and the Ake Wiberg Foundation.