TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth

Abstract

Tuberous sclerosis is a human disease caused by mutations in theTSC1 or the TSC2 tumor suppressor gene. Previous studies of a Drosophila TSC2 homolog suggested a role for the TSC genes in maintaining DNA content, with loss ofTSC2 leading to polyploidy and increased cell size. We have isolated mutations in the Drosophila homolog of theTSC1 gene. We show that TSC1 and TSC2 form a complex and function in a common pathway to control cellular growth. Unlike previous studies, our work shows that TSC1– orTSC2– cells are diploid. We find that, strikingly, the heterozygosity of TSC1 or TSC2 is sufficient to rescue the lethality of loss-of-function insulin receptor mutants. Further genetic analyses suggest that the TSC genes act in a parallel pathway that converges on the insulin pathway downstream fromAkt. Taken together, our studies identified the TSCtumor suppressors as novel negative regulators of insulin signaling.