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Up-regulation of a cellular protein at the translational level by a retrovirus

Fayth K Yoshimura1, Xixia Luo, Xiaoqing Zhao

  • 1Department of Immunology and Microbiology and the Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA. fyoshi@med.wayne.edu

Proceedings of the National Academy of Sciences of the United States of America
|April 2, 2008
PubMed

Insights

Mink cell focus-forming (MCF) murine leukemia viruses (MLVs) induce endoplasmic reticulum (ER) stress, leading to increased cellular inhibitor of apoptosis protein 1 (c-IAP1) via translational regulation. This retroviral mechanism may contribute to thymic lymphoma pathogenesis.

Area of Science:

  • Virology
  • Molecular Biology
  • Oncology

Background:

  • Mink cell focus-forming (MCF) murine leukemia viruses (MLVs) are linked to thymic lymphoma in mice.
  • MCF13 MLV infection causes endoplasmic reticulum (ER) stress due to viral envelope precursor polyprotein accumulation.
  • ER stress is observed in preleukemic thymic lymphocytes and cultured mink epithelial cells.

Purpose of the Study:

  • To investigate the molecular mechanisms linking MCF13 MLV-induced ER stress to cellular responses.
  • To determine the effect of ER stress on eukaryotic initiation factor 2 (eIF2) phosphorylation and apoptosis-related proteins.
  • To elucidate the translational regulation of cellular inhibitor of apoptosis protein 1 (c-IAP1) during retroviral infection.

Main Methods:

  • Real-time RT-PCR for gene expression analysis.
  • Protein turnover assays to assess protein stability and synthesis.
  • Analysis of eIF2 alpha-subunit phosphorylation.
  • Detection of c-IAP1 levels in infected cells and lymphomas.

Main Results:

  • MCF13 MLV infection induces ER stress, leading to increased phosphorylation of eIF2 alpha-subunit.
  • ER stress correlates with the up-regulation of cellular inhibitor of apoptosis protein 1 (c-IAP1).
  • c-IAP1 up-regulation occurs at the translational level, confirmed by message levels and protein turnover assays.
  • Elevated c-IAP1 levels are observed in both experimental models and naturally occurring thymic lymphomas.

Conclusions:

  • MCF13 MLV infection triggers ER stress and modulates cellular pathways involved in apoptosis.
  • Retroviral regulation of c-IAP1 occurs at the translational level, independent of transcriptional changes.
  • This translational control mechanism by a simple retrovirus may be crucial for pathogenesis, contributing to thymic lymphoma development.

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