WWOX Enzyme function is a target for treatment of metabolic diseases including cancer
This genetics research project will explore the WWOX Enzyme function as a target for the treatment of metabolic diseases including cancer.
Genetic variation in WWOX is associated with multiple major human diseases and conditions, all of which exhibit altered metabolism.
These associations include low HDL-C, a major risk-factor in coronary heart disease, Type 2 Diabetes, forced vital capacity in lung function, hypertension susceptibility, coronary artery calcification, obesity, left ventricular thickness and predisposition to lung cancer.
Rare inherited homozygous loss-of-function WWOX mutations cause severe CNS pathology including epilepsy, ataxia and mental retardation. Both spontaneous rat and mouse gene knock-out.
Wwox mutants exhibit tonic-clonic seizures. Consistent with a role in metabolism, Wwox KO mice exhibit growth retardation and early death, with hypoglycaemia, hypocalcemia, metabolic acidosis and kidney failure. Also consistent with these associations our functional studies in Drosophila define WWOX protein as having an integral role in metabolism (O’Keefe et al., 2011, 2015; Dayan et al., 2013; Shaukat et al., 2014; Choo et al., 2015; Lee et al., 2016).
Our experiments show that the enzyme function of WWOX is necessary for its role in metabolism, yet the substrate and product of WWOX are yet to be defined.
We hypothesise that the region C-terminal to the canonical SDR enzyme and an internal SDR ‘loop’ – both uniquely conserved among the WWOX ortholog subfamily of SDRs - constitute the enzyme substrate-binding domain and specify the WWOX ligand.
We are testing this hypothesis by mutagenesis and functional assays in Drosophila and the Honours project in 2017 will be part of this approach.