Survival rates have not increased appreciably in the past few decades, highlighting the need for novel therapeutic strategies.  We are seeking to exploit a potential vulnerability in lung cancer cells, which may derive growth advantage through increased quantities of gene products involved in the pathway through which proteins are degraded (protein degradation is a critical component in many cellular pathways).  Our hypothesis is that cancer cells are able to increase their content of ubiquitin (the central component of this pathway) by expressing UCHL1, an enzyme that stabilizes ubiquitin.  This hypothesis predicts that tumours that have elevated UCHL1 will have elevated ubiquitin, a prediction that will be tested by analyzing tissue microarrays (microscope slides with large numbers of samples from human lung cancers).  We will determine if ubiquitin starvation blocks tumour growth by crossing mice genetically predisposed to lung cancer with mice lacking functional ubiquitin or UCHL1 genes.