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Tuberous sclerosis complex proteins 1 and 2 control serum-dependent translation in a TOP-dependent and -independent

Benoit Bilanges1, Rhoda Argonza-Barrett, Marina Kolesnichenko

  • 1Cancer Research Institute, University of California, San Francisco, California, USA.

Molecular and Cellular Biology
|June 15, 2007
PubMed

Insights

The tuberous sclerosis complex (TSC) proteins TSC1 and TSC2 regulate protein translation via mTORC1 signaling. Loss of TSC1/TSC2 impairs mRNA translation control, impacting specific mRNAs crucial for tuberous sclerosis pathology.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Tuberous sclerosis complex (TSC) proteins TSC1 and TSC2 are known regulators of the mTORC1 pathway.
  • The precise mechanisms by which TSC1/TSC2 control global protein synthesis and specific mRNA translation under varying stimuli remain unclear.

Purpose of the Study:

  • To investigate how TSC1 and TSC2 regulate protein translation in response to serum withdrawal.
  • To identify specific mRNAs translationally controlled by TSC1/TSC2 and the mTORC1 pathway.

Main Methods:

  • Utilized wild-type and Tsc1/Tsc2-deficient mouse embryo fibroblasts (MEFs).
  • Analyzed mTORC1 signaling, translation initiation complex assembly, and mRNA distribution between polysomes and subpolysomes.
  • Performed microarray analysis on polysome- and subpolysome-associated mRNAs.
  • Investigated the effect of the mTORC1 inhibitor rapamycin.

Main Results:

  • Serum withdrawal inhibited mTORC1 signaling and altered translation complexes in wild-type MEFs, but not in Tsc1/Tsc2-deficient MEFs.
  • 90% of serum-regulated mRNAs were dependent on TSC1 and TSC2 for their translational control.
  • Rapamycin affected only 40% of serum-regulated mRNAs, indicating TSC1/TSC2-dependent regulation beyond mTORC1 inhibition.
  • Re-expression of TSC1/TSC2 restored serum-dependent signaling and mRNA redistribution.
  • Rapamycin-sensitive, serum-responsive mRNAs were enriched for specific untranslated regions (UTRs).

Conclusions:

  • The TSC1/TSC2 complex is a major regulator of protein translation, primarily through mTORC1-dependent mechanisms.
  • Specific mRNA translation profiles are deregulated in TSC, implicating altered translation in the pathology.
  • TSC1/TSC2 control mRNA translation in response to mitogenic and nutritional cues, with implications for tuberous sclerosis.

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