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YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1

Syam Prakash Somasekharan1, Amal El-Naggar1, Gabriel Leprivier2

  • 1Department of Pathology and Laboratory Medicine and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada.

The Journal of Cell Biology
|March 25, 2015
PubMed

Insights

Cellular stress granules (SGs) sequester mRNAs. Y-box binding protein 1 (YB-1) activates G3BP1 mRNA translation, controlling SG assembly and promoting sarcoma progression and metastasis.

Area of Science:

  • Molecular biology
  • Cell biology
  • Cancer research

Background:

  • Cellular stress inhibits global protein synthesis to conserve energy.
  • Stress granules (SGs) are ribonucleoprotein complexes that sequester translationally silent mRNAs.
  • Y-box binding protein 1 (YB-1) is found in SGs, but its function is unclear.

Purpose of the Study:

  • To investigate the role of Y-box binding protein 1 (YB-1) in stress granule (SG) formation and its implications in sarcoma.
  • To determine if YB-1 influences the availability of G3BP1, a key nucleator protein for SG assembly.

Main Methods:

  • Investigated YB-1 binding to the 5' untranslated region (UTR) of G3BP1 mRNA.
  • Assessed the impact of YB-1 inactivation on G3BP1 and SG formation in human sarcoma cells.
  • Correlated YB-1 and G3BP1 expression with clinical data in human sarcomas.
  • Examined the effect of G3BP1 down-regulation on SG formation, tumor invasion, and metastasis in mouse models.

Main Results:

  • YB-1 directly binds to and translationally activates G3BP1 mRNA's 5' UTR.
  • YB-1 inactivation significantly reduces G3BP1 and SG formation in vitro.
  • YB-1 and G3BP1 expression are highly correlated in human sarcomas, with elevated G3BP1 correlating with poor survival.
  • G3BP1 down-regulation inhibits in vivo SG formation, reduces tumor invasion, and completely blocks lung metastasis in mouse models.

Conclusions:

  • YB-1 plays a critical role in SG formation by translationally activating G3BP1.
  • Stress granules have novel functions in tumor progression, invasion, and metastasis.
  • Targeting the YB-1/G3BP1 pathway may offer therapeutic strategies for sarcoma.

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