In its normal form, the protein p53 suppresses tumor formation, but when its gene is mutated — as it is in about half of all human cancers — the protein no longer functions as a tumor suppressor, and it can instead negatively affect wild-type p53. In a study in the Journal of Biological Chemistry published in June, researchers in Brazil report that this dominance of mutated p53 happens in part because the protein aggregates into prion-like amyloid oligomers and fibrils. Using a combination of approaches, the team also showed that this prion-like formation can affect the function of wild-type p53. Genome Technology's Christie Rizk spoke with senior author Jerson Lima Silva from the Federal University of Rio de Janeiro about the study and its implications for cancer treatment. What follows is an excerpt of that conversation, edited for space.
Genome Technology: What made you investigate the aggregation of p53 in cancer?
Jerson Lima Silva: This started a while ago. For around 15 years or more, we have been working with the mammalian prion proteins from different sources. It seemed to us that p53 had very similar properties to prion proteins — the whole protein is a tetramer. We started studying the stability of p53 and we found that p53 had this tendency to aggregate — we published a paper in 2003 that showed that p53, depending on the conditions, would lead into aggregation — and we started to compare the wild-type protein with different hotspot mutants, and we also started to look at conditions that could stabilize the protein and at the possibility of trying to rescue the function of the protein that has no function because it aggregated in this misfolded conformation.
GT: So what comes first — the mutation or the aggregation?
JLS: What happens is that once you have a mutant form, it exerts this negative dominance effect on the good — the non-mutated — protein, and then the whole cell completely loses the tumor suppressor activity of p53. In fact, in several tumors, you have increasing concentrations of p53. In principle, once you have the mutant, the mutant [acts] like a prion and converts the wild type into this misfolded conformation.
GT: Could this finding change the way cancer is treated — treat the -aggregation instead of the mutation?
JLS: Yes, of course. There's a long road ahead, but I think that's one way to look at it. The idea is probably not to recover the function of the protein that has gone bad, but if you can neutralize that by preventing it from aggregating and prevent this effect of acting as a prion, maybe you can use that.
GT: What about other cancer-associated proteins that work like p53 — could they also show this kind of behavior? Do you have plans to study that?
JLS: We do, and in fact there are other groups doing that as well. We quote a paper that appeared last year [in Nature Chemical Biology from Frederic Rousseau and Joost Schymkowitz's lab at the Free University of Brussels] in our article that showed that in some cancer cell lines, you have aggregation of p53 with p63 and p73. And this may be even worse because if you have a mutant, it's aggregating and exerting this prion-like effect, but it might eventually take [with it] other tumor suppressors like p63 and p73 — the functions of which are not as well known as p53, but people know that they are important to suppress cancer. P53 is like a hub — it's so important to the cell for different things that it's a real mess if you lose the function of the protein. But again, I think maybe because it's a hub, any targeting strategy has to be very careful, because if you control too much, maybe it will go the other way and the cell will want to go into premature death and apoptosis. That's why it's so difficult to find therapies against different diseases, especially cancer and neurodegenerative diseases.