The tuberous sclerosis complex (TSC) pathway and mechanism of size control

C. J. Potter, L. G. Pedraza, H. Huang, T. Xu

Research output: Contribution to journalArticle

Abstract

We have identified three groups of growth-constraint genes using mosaic genetic screens in Drosophila melanogaster, including PTEN (phosphatase and tensin homologue deleted on chromosome 10), and the tuberous sclerosis complex (TSC) genes, Tsc1 and Tsc2. our studies show that all three groups of genes participate in mechanisms that regulate organ and organism size in animals. We propose that mechanisms of organ size control are critical targets for diseases, such as tumorigenesis, which require an increase in tissue size and total mass, and for evolutionary events that alter the size of organisms. Using genetic and biochemical methods, we have shown that Tsc1 and Tsc2 function in the insulin/phosphoinositide 3-kinase (PI3K)/Akt pathway. We have shown that Akt regulates the Tsc1-Tsc2 complex by directly phosphorylating Tsc2. We have shown further that S6 kinase (S6K) is a downstream component of the PI3K/Akt/TSC pathway and reduction of S6K activity can block TSC defects. Recent studies from many laboratories have now confirmed our findings in mice, rats and human patients, and have shown that drugs that antagonize S6K activities, such as rapamycin, diminish turnouts in TSC-deficient mice and rats. Clinical trials based on these findings have begun. Given that other components of the pathway, such as PTEN, are also mutated in a large number of cancer patients and that these components regulate intracellular insulin signalling, therapeutics based on the knowledge of the pathway could have effects beyond the TSC patient population.

Original languageEnglish (US)
Pages (from-to)584-586
Number of pages3
JournalBiochemical Society transactions
Volume31
Issue number3
DOIs
StatePublished - Jun 1 2003

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Keywords

  • Drosophila genetics
  • Phosphoinositide 3-kinase (PI3K)/PTEN/Akt/tuberous sclerosis complex (TSC) pathway
  • Size-control mechanisms
  • Tuberous sclerosis gene function
  • Tumourigenesis

ASJC Scopus subject areas

  • Biochemistry

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