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An activated mTOR mutant supports growth factor-independent, nutrient-dependent cell survival

Aimee L Edinger1, Craig B Thompson

  • 1Abramson Family Cancer Research Institute, University of Pennsylvania, 450 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104, USA.

Oncogene
|May 11, 2004
PubMed

Insights

Activating mutations in mTOR (mechanistic target of rapamycin) can promote cell survival independently of growth factors. This suggests mTOR activation may drive resistance to apoptosis and potentially cellular transformation.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The mechanistic target of rapamycin (mTOR) pathway regulates cell growth and metabolism in response to nutrient availability.
  • In mammals, mTOR activity is primarily controlled by growth factor signaling through the PI3K/Akt pathway.
  • Growth factor deprivation leads to dephosphorylation of key mTOR targets, indicating reduced pathway activity.

Purpose of the Study:

  • To investigate if constitutive mTOR activation can sustain cell survival independently of growth factor signaling.
  • To assess the protective effects of a growth factor-independent mTOR mutant (DeltaTOR) against growth factor deprivation.

Main Methods:

  • Expression of a constitutively active mTOR mutant (DeltaTOR) in cells.
  • Evaluation of cellular responses to growth factor deprivation in DeltaTOR-expressing cells versus wild-type mTOR-expressing cells.
  • Assessment of cell survival, metabolic rates, mitochondrial function, and apoptosis markers.

Main Results:

  • DeltaTOR-expressing cells were protected from growth factor deprivation-induced effects like amino-acid transporter degradation and reduced glycolytic rate.
  • DeltaTOR expression prevented cellular atrophy, maintained mitochondrial membrane potential, and inhibited Bax activation.
  • Constitutive mTOR activation promoted nutrient-dependent cell survival independent of growth factors and enhanced colony formation in soft agar.

Conclusions:

  • Activating mutations in mTOR can confer resistance to apoptosis by sustaining cell survival during growth factor deprivation.
  • Constitutive mTOR activation may play a role in cellular transformation and oncogenesis.

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