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Translational Upregulation of an Individual p21Cip1 Transcript Variant by GCN2 Regulates Cell Proliferation and

Stacey L Lehman1, George J Cerniglia1, Gregg J Johannes2

  • 1Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Plos Genetics
|June 24, 2015
PubMed

Insights

The Integrated Stress Response (ISR) kinase GCN2 selectively upregulates a specific p21 transcript variant via upstream open reading frames (uORFs). This mechanism is crucial for cell cycle regulation and survival under stress conditions.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Multiple transcripts encode the cell cycle inhibitor p21(Cip1), differing in 5' untranslated regions (UTRs).
  • The regulatory mechanisms and functional significance of these p21 transcript variants under stress are largely unknown.

Purpose of the Study:

  • To investigate the regulation and function of distinct p21 transcript variants.
  • To elucidate the role of the Integrated Stress Response (ISR) kinase GCN2 in p21 regulation.

Main Methods:

  • (35)S labeling and luciferase reporter assays to assess protein translation.
  • Polysome transcript profiling to analyze translational control.
  • Mutational analysis of p21 transcript variants.

Main Results:

  • GCN2 activation selectively upregulates a p21 transcript variant with 5' upstream open reading frames (uORFs).
  • uORFs suppress translation basally but promote it under stress via eIF2α phosphorylation.
  • Ablation of p21 ameliorates G1/S arrest and reduces cell survival upon GCN2 activation.

Conclusions:

  • Uncovers a novel post-transcriptional regulatory mechanism for p21.
  • Provides functional significance for multiple p21 transcripts.
  • Establishes a key role for GCN2 in stress-induced cell cycle control.

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