The p53 gene is mutated in at least half of all human cancers but how this gene acts to suppress tumor formation is not well understood. Since p53 genes are broadly conserved, ancestral properties of these genes offer promising routes towards understanding functions that become deranged in human diseases. Using the Drosophila and zebrafish model systems, I discovered that p53 restricts transposons, and showed how p53 loss leads to an eruption of these mobile elements in mouse and human cancers (Wylie et al., Genes & Dev, 2016). Building on these observations, I showed that certain p53 isoforms act as constitutive repressors, operating continuously in unstressed cells through the same canonic...
Read More
The p53 gene is mutated in at least half of all human cancers but how this gene acts to suppress tumor formation is not well understood. Since p53 genes are broadly conserved, ancestral properties of these genes offer promising routes towards understanding functions that become deranged in human diseases. Using the Drosophila and zebrafish model systems, I discovered that p53 restricts transposons, and showed how p53 loss leads to an eruption of these mobile elements in mouse and human cancers (Wylie et al., Genes & Dev, 2016). Building on these observations, I showed that certain p53 isoforms act as constitutive repressors, operating continuously in unstressed cells through the same canonical DNA binding sites that specified p53 gene induction in earlier stages (Wylie, et al. Dev. Cell, 2022). This is surprising because conventional ‘text-book’ models argue that p53 is solely a transcriptional activator. Together, these discoveries raise the possibility that p53 may mitigate oncogenic disease, in part, by restricting transposon activity and offer a novel hypothesis for p53-mediated cancer prevention. Research Goal 1: Determine how opposing transcriptional outputs by p53 are specified. This research goal will use rigorous genetic and biochemical approaches in the Drosophila system to examine how p53 repression and activation are specified. Objective 1: Determine how p53 isoform occupancy instructs distinct outcomes. Objective 2: Examine what factors specify transcriptional repression p53. Objective 3. Determine how p53 senses transposon dysregulation. Research Goal 2: Understanding the role of p53 and transposon repression in tumor suppression. This research goal will use the zebrafish model system to test whether p53 prevents oncogenic disease by repressing retrotransposons. Objective 1. Determine how p53 isoforms promote tumor suppression. Objective 2. Examine whether inhibition of retrotransposons mitigates tumor formation.
Read Less
|
