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A study of the effects of hamartin and tuberin on cell growth suggests that tuberin acts as a tumour suppressor gene—but not by regulating the cell cycle. The researchers induced transient overexpression of hamartin and tuberin in cell cultures from a human kidney (HEK293) cell line by transfection. They used constructs of the TSC1 gene for hamartin and TSC2 gene for tuberin to transfect the cultures, separately and together, and constructs for three common TSC2 mutants They measured cell growth with two colour fluorescence activated cell sorting to analyse the percentage of cells in each growth phase.
TSC2, alone or with TSC1, produced a significant increase in G1 phase cells (41%, 39%) over the vector control (32%). So did a TSC2 mutation in exon 16 or 38 but not a C-terminus truncation mutation (41%, 40%, and 33%, respectively). TSC1 did not alter the percentage of G1 phase cells.
When the cultures were grown with nocodazole to block the cell cycle at phase G2/M, those with TSC2, with or without TSC1, still showed a significant increase in cells in G1 (14%, 17%, respectively). Cultures with a TSC2 exon mutation behaved similarly (17%, 13%), but with TSC1 and the C-terminus TSC2 mutation G1 phase cells remained low.
TSC1 and TSC2 mutations cause tuberous sclerosis complex (TSC), with widespread tumours, including kidney tumours, and seizures and autism. Until now, both wild type genes were believed to act together as tumour suppressors, but the mechanism is unknown.