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FOXO-regulated transcription restricts overgrowth of Tsc mutant organs

Kieran F Harvey1, Jaakko Mattila, Avi Sofer

  • 1Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. kieran.harvey@petermac.org

The Journal of Cell Biology
|February 27, 2008
PubMed

Insights

Forkhead box O (FOXO) transcription factors suppress growth, particularly when the target of rapamycin (TOR) pathway is active. This study shows FOXO antagonizes TOR-driven growth across species, including mammals.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cellular Biology

Background:

  • The role of FOXO (Forkhead box O) transcription factors in growth regulation is debated, as FOXO mutations in Drosophila do not affect fly size.
  • A previous study indicated FOXO suppresses growth under conditions of heightened target of rapamycin (TOR) pathway activity.

Purpose of the Study:

  • To further investigate the growth-suppressive role of FOXO, particularly in relation to the TOR pathway.
  • To determine if FOXO antagonizes TOR-driven growth in a conserved manner across species.

Main Methods:

  • Utilizing Drosophila melanogaster models with mutations in tuberous sclerosis complex 1 (TSC1).
  • Analyzing FOXO levels and the expression of FOXO-regulated genes in response to TSC1 mutations.
  • Comparing transcriptional changes in Drosophila with those in mammalian cell lines.

Main Results:

  • Mutations in TSC1 led to increased FOXO levels in Drosophila.
  • Elevated FOXO levels resulted in increased expression of genes that counteract growth-promoting pathways.
  • Similar transcriptional alterations were observed in mammalian cells, indicating conserved mechanisms.

Conclusions:

  • FOXO acts as a suppressor of growth, specifically counteracting growth promoted by the TOR pathway.
  • This growth-attenuating function of FOXO is conserved in both insects and mammals, highlighting its fundamental role in metabolic and growth control.

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