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Analysis of Translation Initiation During Stress Conditions by Polysome Profiling
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A RNA interference screen identifies the protein phosphatase 2A subunit PR55gamma as a stress-sensitive inhibitor of

Pieter J A Eichhorn1, Menno P Creyghton, Kevin Wilhelmsen

  • 1Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Plos Genetics
|December 12, 2007
PubMed

Insights

Protein Phosphatase type 2A (PP2A) regulatory subunits PR55gamma and PR55delta inhibit c-Jun NH(2)-terminal kinase (JNK) activation. UV irradiation disrupts the PR55gamma and c-SRC interaction, regulating c-SRC activity.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Biochemistry

Background:

  • Protein Phosphatase type 2A (PP2A) holoenzymes are crucial for diverse biological activities.
  • Deregulation of specific PP2A holoenzymes is implicated in oncogenic transformation and signaling.
  • Previous research using generic PP2A inhibitors limits understanding of individual holoenzyme contributions.

Purpose of the Study:

  • To investigate the roles of individual PP2A holoenzyme complexes in cellular signaling pathways.
  • To elucidate the specific functions of PP2A regulatory subunits in JNK activation.
  • To uncover novel mechanisms of c-SRC regulation.

Main Methods:

  • Construction of shRNA vectors targeting individual PP2A regulatory subunits for RNA interference.
  • Analysis of c-Jun NH(2)-terminal kinase (JNK) activation.
  • Co-immunoprecipitation assays to study protein-protein interactions.
  • Site-directed mutagenesis to investigate phosphorylation sites.

Main Results:

  • PR55gamma and PR55delta were identified as inhibitors of JNK activation induced by UV irradiation.
  • PR55gamma directly binds to c-SRC and modulates the phosphorylation of serine 12.
  • Phosphorylation at serine 12 of c-SRC is essential for JNK activation mediated by c-SRC.
  • The interaction between PR55gamma and c-SRC is sensitive to UV irradiation, decreasing upon stress.

Conclusions:

  • PR55gamma and PR55delta act as negative regulators of UV-induced JNK activation.
  • A novel mechanism reveals stress-induced regulation of c-SRC activity via disruption of its interaction with the inhibitor PR55gamma.
  • This study provides insights into the specific roles of PP2A holoenzymes in stress response and signaling pathways.

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