A LIFETIME GAME: MUTANT P53 PHASE SEPARATION AND TRANSITION IN CANCER

P53 is a transcriptional factor preventing cells from undergoing malignance  transformation. When destabilized p53 mutations hijack its tumor suppressor activities,  and p53 becomes an oncogene. Because TP53 is the ‘top 1’ gene harboring mutations in  human cancer, and cancer phenotypes are diverse, much effort has been developed to  target oncogenic p53 mutations. The significant consequences of p53 mutations include  (i) loss of function in which it loses the ability to bind DNA-responsive elements, (ii) the  regulation of novel genes through a gain of function phenotype, and (iii) the negative  dominance in which some monoallelic mutations sequester the protein’s wild type activity.  In the last 20 years, our group has provided evidence that mutant p53 undergoes amyloid  aggregation in cancer and, more recently, liquid-liquid phase separation. We are devoted  to understanding why aggregation-prone p53 conformations are formed and the  molecular mechanisms that trigger the process. Next, we aim to show how mutant p53  perpetrates cancer through a gain-of-function phenotype. Finally, we seek to determine  how to target these species to avoid cancer. 

We have shown that most hotspot p53  mutations are destabilized and more hydrated than the wild type, leading to aggregation.  Further, the mutant p53 phase separates in vitro and inside cells, forming membrane-less  organelles that sequester the p53 family members p63 and p73. Some p53 mutants may  also undergo dual gain-of-function activities, including chemoresistance and triggering  migration and invasiveness. 

This work was supported by Conselho Nacional Desenvolvimento Científico e  Tecnológico (CNPq, #313137) and by Fundação Carlos Chagas Filho de Amparo à  Pesquisa do Estado do Rio de Janeiro (FAPERJ, #201.296/2021 and #210.294/2022)We have shown that most hotspot p53  mutations are destabilized and more hydrated than the wild type, leading to aggregation.  Further, the mutant p53 phase separates in vitro and inside cells, forming membrane-less  organelles that sequester the p53 family members p63 and p73. Some p53 mutants may  also undergo dual gain-of-function activities, including chemoresistance and triggering  migration and invasiveness. 

This work was supported by Conselho Nacional Desenvolvimento Científico e  Tecnológico (CNPq, #313137) and by Fundação Carlos Chagas Filho de Amparo à  Pesquisa do Estado do Rio de Janeiro (FAPERJ, #201.296/2021 and #210.294/2022)