Elucidating the Effects of Chimeric G-proteins in Cancer
Conducted by Associate Professor Helmut Schaider (UQ DRC) in collaboration with Associate Professor Richard Sturm (UQ DRC), Professor H. Peter Soyer (UQ DRC), Professor Brian Gabrielli (UQ DI) and Professor Meenhard Herlyn (The Wistar Institute, Philadelphia, PA, US)
Aim of the study: G-protein coupled receptors (GPCRs) are amongst the most intensively studied cell membrane bound receptors heavily involved in cell signalling eliciting a broad spectrum of cellular responses. More than half of current drug targets are GPCRs. GPCRs signal through G-proteins. We recently found that a viral GPCR encoded by human cytomegalovirus, US28, is inducing cell death in melanoma cells through Galpha13 signalling. Based on this observation we are proposing that chimeric G-proteins mimicking US28 constitutive activity might be a new alternative strategy for the treatment of solid cancers.
Methods: Cell culture, cloning, molecular biology, protein chemistry, functional assays, in vivo tumour models
Description: We have been generating a prototype of a fusion protein, which induces apoptosis and exerts anti-proliferative properties in many cell lines, including cancer cells. The fusion protein has so far been probed only in melanoma cell lines and more tailoring is necessary to increase the effectiveness. Specifically it is important to generate different constructs comprising mute sequences to test for enhanced induction of cell death. We will continue on engineering and characterizing fusion proteins and gain more insight into the nature of these fusion proteins. Cell type specific expression of fusion proteins, which might be also achieved with appropriate delivery systems, will be important for direct delivery of fusion-proteins.
Status: Currently we are studying different engineered chimeric G-proteins for their overall effects on cell proliferation and phenotypic changes in vitro and in vivo. Based on successful screening some of the fusion proteins might be followed up for refinement and further analyses.