To understand the developmental functions of tumor suppressors, we have been performing genetic screens to identify overgrowth mutations in mosaic flies. Interestingly, all the identified mutations also deregulate organ and organism size, suggesting that tumorigenesis might reflect an impairment of organ size control. Three classes of mutations have been isolated.
Mutations in the second class of genes, such as slimb, cause patterned outgrowths in mosaic animals and alter organ size by affecting signals that regulate pattern formation.
Mutations in the third class, such as the Drosophila homologs of the human tumor suppressors, PTEN, TSC1, and TSC2, cause overgrowth of mutant clones in mosaic animals largely by increasing cell size. Size control mechanisms could be critical targets for evolutionary events to alter organism size, and also for disease processes such as tumorigenesis that require increases in
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| Mutations in evolutionarily conserved genes such as Tsc1 cause an increase in cell and tissue size in Drosophila. From Potter et al. (2001). |
tissue size. Tuberous sclerosis complex (TSC) is a genetic disease characterized by hamartomas in multiple organs including brain, kidneys, lungs, heart, eyes, and skin. TSC is a common cause of epilepsy and autism and is also the cause of lymphangiomyomatosis (LAM), a rare lung disease. However, the functions of the two TSC genes are unknown. Our findings that
Drosophila Tsc1 and Tsc2 function together in the insulin/PI3K/PTEN/Akt pathway downstream of Akt and upstream of S6K, and that TSC defects can be alleviated by reducing S6K activity, have now been confirmed in other animals and human patients. This has helped lead to the initiation of clinical trials in the US, England, and Germany.
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Stimulation of Akt activity, either by activation of IR, PI(3)K or loss of PTEN, results in direct phosphorylation of Tsc2. This event disrupts binding to Tsc1 and thereby inactivates the Tsc complex. Inactivation of the Tsc1−Tsc2 complex results in increased cell growth, possibly mediated by downstream inhibition of TOR and activation of S6K (Potter et al., 2001, 2002).
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We are also working with the Rothberg Institute to develop novel therapeutics for TSC patients. Given that the pathway is mutated in a large number of cancers and is involved in insulin signaling, the therapeutic implications of results from such trials will go beyond the TSC and LAM patient population.
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