Abstract
Soon after proposing the “two‐hit” hypothesis for tumorigenesis, Knudson pursued further experimental validation of the concept by using a rat model of dominantly inherited renal tumor. Today, the Eker rat is one of the best characterized models of tuberous sclerosis complex (TSC) and has been used extensively for study of the function of the TSC2 tumor suppressor gene. Along with TSC1, these two genes behave as expected for tumor suppressor genes with evidence for loss of heterozygosity in tumors and suppression of growth when expressed in proliferating cells. Despite much experimental work, the mechanisms of these genes have remained elusive until recently. This review summarizes some of the current concepts in our understanding of the biological and biochemical function of the TSC genes.