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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

3'UTR-directed, kinase-proximal mRNA decay inhibits C/EBPβ phosphorylation/activation to suppress senescence in tumor

Jacqueline Salotti1, Nida Asif1, Srikanta Basu1

  • 1Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.

Iscience
|August 14, 2026
PubMed

Insights

Cancer cells suppress C/EBPβ activity using perinuclear mRNA decay. Disrupting this pathway restores C/EBPβ function, inducing senescence and impairing tumor growth by blocking oncogene-induced senescence (OIS).

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cellular Senescence

Background:

  • C/EBPβ is crucial for oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP).
  • Tumor cells suppress C/EBPβ activity via 3'UTR regulation of protein activity (UPA), sequestering transcripts away from activating kinases.

Purpose of the Study:

  • To elucidate the mechanism of 3'UTR-mediated suppression of C/EBPβ activity.
  • To investigate the role of perinuclear mRNA decay in regulating C/EBPβ and cancer progression.

Main Methods:

  • Investigated mRNA decay factors UPF1 and STAU1/2 localization and function.
  • Analyzed the impact of a G/U-rich regulatory element (GRE) deletion in the 3'UTR of CEBPB on tumor progression in vivo.
  • Assessed OIS and differentiation states in RAS-expressing fibroblasts with GRE deletion.

Main Results:

  • Identified kinase-proximal mRNA decay as the mechanism suppressing C/EBPβ activation.
  • UPF1 and STAU1/2 promote CEBPB transcript degradation at perinuclear endosomes, preventing C/EBPβ phosphorylation.
  • Deletion of the 3'UTR GRE in Kras-driven lung tumors impaired progression and promoted AT2-like differentiation.
  • GRE Δ/Δ fibroblasts exhibited enhanced OIS dependent on S100a9 upregulation.

Conclusions:

  • Perinuclear mRNA decay is a novel mechanism that suppresses C/EBPβ activity and prevents senescence in cancer.
  • Targeting this decay pathway holds potential for cancer therapy by restoring senescence.
  • The 3'UTR GRE is a critical regulator of C/EBPβ activity and tumor cell fate.
Keywords:
3′UTR3′UTR regulation of protein activityRAS signalingSASP cytokinescanceroncogene-induced senescence

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