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Inhibition of protein synthesis by Y box-binding protein 1 blocks oncogenic cell transformation

Andreas G Bader1, Peter K Vogt

  • 1Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Rd., BCC239, La Jolla, CA 92037, USA. andreas@scripps.edu

Molecular and Cellular Biology
|March 4, 2005
PubMed

Insights

Y box-binding protein 1 (YB-1) inhibits cancer cell growth by blocking translation, independent of its nuclear localization. This RNA-binding protein requires specific domains to interfere with oncogenic signaling pathways.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • Y box-binding protein 1 (YB-1) is a multifunctional protein known to be repressed by the phosphoinositide 3-kinase (PI3K) pathway.
  • YB-1 can interfere with oncogenic transformation when reexpressed, suggesting a role in cancer regulation.

Purpose of the Study:

  • To elucidate the molecular requirements for YB-1's inhibitory function in PI3K-induced cell transformation.
  • To determine the specific domains and mechanisms by which YB-1 exerts its anti-transformational effects.

Main Methods:

  • Mutational analysis of YB-1 to assess its impact on transformation, localization, RNA binding, and translation inhibition.
  • Utilized retroviral vectors (RCAS) for protein expression in chicken embryo fibroblasts.
  • Investigated cap binding, mRNA binding, homodimerization, and translation inhibition capabilities of YB-1 mutants.

Main Results:

  • YB-1's interference with transformation necessitates RNA binding and a distinct C-terminal domain, separate from the cytoplasmic retention domain.
  • A strong correlation exists between YB-1's ability to interfere with transformation and its inhibition of translation.
  • A noncanonical nuclear localization signal (NLS) was identified, but its absence did not impair YB-1's anti-transformational activity, indicating a non-nuclear function.

Conclusions:

  • YB-1 inhibits PI3K-induced transformation through specific translation inhibition, mediated by its RNA-binding and C-terminal domains.
  • The anti-transformational function of YB-1 is independent of its nuclear localization.
  • These findings highlight YB-1 as a potential therapeutic target in cancers driven by the PI3K pathway.

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