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Tuberous sclerosis complex (TSC) is a tumour suppressor gene syndrome whose manifestations include seizures, mental retardation, autism, and tumours of the brain, retina, kidney, heart, and skin.1 Mutations in two tumour suppressor genes, TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13, cause TSC. TSC2 encodes tuberin, a 190 kDa protein with homology to the catalytic domain of a GTPase activating protein (GAP) for Rap1.2TSC1 encodes hamartin, a 130 kDa protein.3 Tuberin and hamartin have been shown to directly interact, both in mammalian cells4,5 and in Drosophila.6,7 This is consistent with the nearly identical spectrum of disease seen in humans with TSC1 and TSC2 germline mutations, and with the identical phenotypes of Drosophila TSC16–8 and TSC29 homologue mutants. The mouse models of TSC1 and TSC2 also have similar phenotypes; renal carcinoma and renal cysts develop in heterozygous animals of the Eker rat model of TSC210,11 and in the knock out mouse models of both TSC112 and TSC2, 13,14 all of which are embryonically lethal in the homozygous form.
The cellular pathways through which germline TSC1 or TSC2 mutations result in tumorigenesis are not completely understood. Mammalian tuberin and hamartin have been shown to suppress cell growth, accompanied by an increase in cells in the G1 phase of the cell cycle.15–17 The importance of cell cycle regulation to human TSC is not known. In this study, we used a sensitive fluorescence activated cell sorting approach to investigate the cell cycle effects of wild type hamartin and tuberin, two patient derived mutant forms of tuberin, and a carboxy-terminus construct of tuberin containing the region of GTPase activating protein homology. Similar overexpression approaches using cell sorting have been used to elucidate the cell cycle effects …