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Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1

Issam Ben-Sahra1, Jessica J Howell, John M Asara

  • 1Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.

Science (New York, N.Y.)
|February 23, 2013
PubMed

Insights

Growth signals activate mTORC1, stimulating pyrimidine synthesis for cell growth. This involves S6K1 phosphorylating the CAD enzyme, boosting nucleotide production for RNA and DNA synthesis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Metabolism

Background:

  • Cellular growth requires anabolic processes, regulated by signaling pathways.
  • The mechanistic target of rapamycin complex 1 (mTORC1) is a key kinase sensing growth signals.
  • mTORC1 controls anabolic growth and proliferation by integrating nutrient and growth factor cues.

Purpose of the Study:

  • To investigate the role of mTORC1 signaling in regulating metabolic flux.
  • To identify how mTORC1 influences de novo pyrimidine synthesis.
  • To elucidate the downstream effectors of mTORC1 in metabolic regulation.

Main Methods:

  • Analysis of metabolic flux through the de novo pyrimidine synthesis pathway.
  • Investigating the phosphorylation status of the CAD enzyme.
  • Utilizing biochemical assays to determine enzyme activity and protein interactions.

Main Results:

  • Activation of mTORC1 acutely stimulates metabolic flux through the de novo pyrimidine synthesis pathway.
  • mTORC1 signaling, via S6K1, directly phosphorylates the CAD enzyme at S1859.
  • This phosphorylation enhances the activity of CAD, the rate-limiting enzyme in pyrimidine synthesis.

Conclusions:

  • mTORC1 signaling is a critical regulator of nucleotide biosynthesis.
  • The mTORC1-S6K1-CAD axis provides essential nucleotides for RNA and DNA synthesis during growth.
  • This pathway supports ribosome biogenesis and overall anabolic growth.

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