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Phosphorylation by Akt disables the anti-oncogenic activity of YB-1

A G Bader1, P K Vogt

  • 1Department of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA 78744, USA.

Oncogene
|August 21, 2007
PubMed

Insights

Phosphorylation by Akt disables the inhibitory activity of Y-box binding protein 1 (YB-1), enhancing oncogenic translation. Overexpressing wild-type YB-1 overrides this inactivation, maintaining protein synthesis inhibition and resistance to transformation.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Oncogenesis

Background:

  • Y-box binding protein 1 (YB-1) is a DNA/RNA-binding protein regulating mRNA translation.
  • YB-1 inhibits protein synthesis at higher concentrations and confers resistance to oncogenic transformation.
  • YB-1 is a direct substrate of Akt, but the functional significance of its phosphorylation is unknown.

Purpose of the Study:

  • To investigate the functional significance of Akt-mediated YB-1 phosphorylation in PI3K-induced transformation.
  • To explore the effect of phosphorylated YB-1 on cellular transformation by generating YB-1 mutants.

Main Methods:

  • Generated YB-1 mutants in the Akt phosphorylation consensus sequence.
  • Assessed the effect of wild-type and mutant YB-1 on PI3K-induced transformation in chicken embryo fibroblasts.
  • Analyzed YB-1's affinity for mRNA caps and its effect on cap-dependent translation.

Main Results:

  • The phosphomimetic YB-1 S99E mutant did not interfere with cellular transformation, unlike wild-type YB-1.
  • The S99E mutant showed reduced affinity for mRNA caps and failed to inhibit cap-dependent translation.
  • Phosphorylation by Akt appears to disable YB-1's inhibitory activity, promoting oncogenic translation.

Conclusions:

  • Akt-mediated phosphorylation inactivates YB-1's translational inhibitory function, thereby promoting oncogenesis.
  • Overexpression of wild-type YB-1 can overcome Akt-mediated inactivation, preserving protein synthesis inhibition and transformation resistance.

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