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Ornithine decarboxylase mRNA is stabilized in an mTORC1-dependent manner in Ras-transformed cells

Sofia Origanti1, Shannon L Nowotarski, Theresa D Carr

  • 1Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA.

The Biochemical Journal
|November 11, 2011
PubMed

Insights

Ras activation stabilizes ornithine decarboxylase (ODC) mRNA by 8-fold, primarily through mTORC1 pathway regulation of HuR binding. This discovery offers new strategies for targeting Ras-driven tumors by controlling ODC mRNA decay.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Ras activation significantly induces ornithine decarboxylase (ODC), a key enzyme in polyamine synthesis.
  • ODC is implicated in the development and progression of Ras-driven tumors, making it a potential therapeutic target.

Purpose of the Study:

  • To investigate the mechanisms controlling ODC mRNA translation and stability in normal versus Ras12V-transformed cells.
  • To elucidate the role of the mTORC1 pathway and HuR protein in regulating ODC mRNA stability.

Main Methods:

  • Comparison of ODC mRNA translation profiles and stability in normal and Ras12V-transformed RIE-1 cells.
  • Treatment with the mTORC1 inhibitor rapamycin and siRNA knockdown of mTOR.
  • Analysis of HuR protein association with ODC mRNA and ODC 3'UTR deletion constructs.

Main Results:

  • Ras12V transformation led to an 8-fold stabilization of ODC mRNA, with only a modest increase in translation initiation.
  • Inhibition of mTORC1 (using rapamycin or siRNA) destabilized ODC mRNA and reduced HuR binding to the ODC transcript.
  • Specific regions within the ODC 3'UTR (bases 1969-2141) were identified as critical for mRNA stabilization.

Conclusions:

  • A novel mechanism for ODC synthesis control involves the regulation of ODC mRNA decay via the mTORC1 pathway and HuR.
  • Targeting ODC mRNA stability presents a potential therapeutic strategy for preventing polyamine accumulation in Ras-driven cancers.

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