Study reveals how mutant p53 protein converts other proteins into cancer drivers

Research from the Federal University of Rio de Janeiro (UFRJ) and the National Institute of Science and Technology for Structural Biology and Bioimaging (INBEB) in Brazil has uncovered a critical mechanism by which mutations in the p53 protein—a key tumor suppressor known as the “guardian of the genome”—turn other proteins into cancer-promoting agents.

The study, led by Dr. Jerson Lima Silva, offers fresh insights into a process that plays a pivotal role in the development and progression of many cancers. The findings were recently published in Communications Chemistry.

p53 is central to the body’s defense against cancer, tasked with regulating the cell cycle and triggering the death of damaged cells before they can become malignant. However, in more than 50% of all tumors, mutations in p53 undermine its protective role, converting it into a driver of cancer. In this study, the research team demonstrated that mutant p53 not only loses its tumor-suppressing abilities but also gains the capacity to corrupt other anti-tumor proteins, including p63 and p73.

Through a mechanism known as aberrant phase transition, mutant p53 induces amyloid aggregation in p63 and p73, forming harmful protein clumps known as amyloid structures. These aggregates drive the oncogenic transformation of these proteins, leading to uncontrolled tumor growth. The study also suggests that other proteins could be similarly affected, though further research is needed to identify them.

These findings provide critical new insights into why some tumors, such as glioblastoma, are so aggressive. They also open up avenues for developing targeted cancer treatments that could disrupt or reverse the harmful interactions caused by mutant p53.

“This discovery could be key to designing therapies for aggressive cancers, including glioblastoma, where mutant p53 plays a dominant role,” said Dr. Silva.

Using advanced biophysical techniques and fluorescence microscopy, the team investigated three specific p53 mutations: M237I, commonly found in glioblastoma; R249S, which is prevalent in liver cancer; and R248Q, associated with breast cancer. They found that each of these mutants not only altered the behavior of p53 but also triggered p63 and p73 to form amyloid-like structures, further driving cancer progression.

“While normal p53 can form functional biomolecular condensates,” Silva explained, “these mutants significantly speed up the transition to solid, amyloid-like states. This shift operates through a prion-like mechanism, converting p63 and p73 condensates into aggregates. This process may be crucial for understanding how p53 mutations contribute to cancer development.”

Excitingly, the research also revealed that heparin, a widely used anticoagulant, can inhibit the formation of these harmful aggregates. This suggests a potential therapeutic approach to either prevent or reverse the malignancy-enhancing effects of mutant p53.

“This discovery opens a new frontier for targeting cancer at its roots, by intervening in the phase transitions and aggregation of p53, p63 and p73,” added Dr. Silva.

Provided by
Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem (INBEB)