Resolving the tumour suppressor function of the E3 ubiquitin ligase Parkin
Worldwide Cancer Research
Walter and Eliza Hall Institute of Medical Research
The E3 ubiquitin ligase Parkin is critical for maintaining mitochondrial quality control as it is the key effector in damage-induced mitophagy. As well as a have key role in early onset Parkinson’s disease, Parkin is emerging as an important tumour suppressor, with mounting evidence indicating that the gene encoding Parkin (PRKN/PARK2) is one of the most frequently deleted or mutated genes in a wide variety of cancers including glioblastoma, colorectal, breast cancer. We have also identified links between Parkin loss and neuroblastoma, a common childhood cancer with poor prognosis and limited treatment options. How Parkin limits the growth of such diverse tumours is unclear. We hypothesise that the ability of Parkin to limit inflammation promoted by damaged mitochondria underpins its tumour suppressor function. We will use complementary cell and new mouse models coupled with innovative proteomics analyses to resolve how the E3 ubiquitin ligase Parkin controls inflammation as well as critical processes including apoptosis, cell cycle regulation and metabolism to define how Parkin activity limits the development of neuroblastoma. This proposal will identify Parkin or its specific substrates as new targets to treat neuroblastoma and potentially other cancers.
2.1 Biological and endogenous factors