The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation

The inherited human disease tuberous sclerosis, characterized by hamartomat ous tumors, results from mutations in either TSC1 or TSC2. We have characte rized mutations in the Drosophila Tsc1 and Tsc2/gigas genes. Inactivating m utations in either gene cause an identical phenotype characterized by enhan ced growth and increased cell sire with no change in ploidy. Overall, mutan t cells spend less time in G1. Coexpression of both Tsc1 and Tsc2 restricts tissue growth and reduces cell size and cell proliferation. This phenotype is modulated by manipulations in cyclin levels. In postmitotic mutant cell s, levels of Cyclin E and Cyclin A are elevated. This correlates with a ten dency for these cells to reenter the cell cycle inappropriately as is obser ved in the human lesions.