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Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway

Christophe Denoyelle1, George Abou-Rjaily, Vladimir Bezrookove

  • 1Department of Dermatology and Comprehensive Cancer Center, University of Michigan, 1500E Medical Center Drive, 4217 CCGC, Ann Arbor, MI 48109, USA.

Nature Cell Biology
|September 12, 2006
PubMed

Insights

Endoplasmic reticulum (ER) stress from oncogenes like HRAS triggers senescence via the unfolded protein response (UPR), not classical markers. This reveals the ER

Area of Science:

  • Cell Biology
  • Oncology
  • Molecular Biology

Background:

  • Endoplasmic reticulum (ER) dysfunction is implicated in various pathologies, including cancer.
  • The role of ER stress in early normal cell transformation remains largely unexplored.

Purpose of the Study:

  • To investigate the contribution of ER stress to early cell transformation.
  • To determine the mechanism of premature senescence induced by oncogenes in human melanocytes.

Main Methods:

  • Utilized primary human melanocytes and human naevi biopsies.
  • Introduced oncogenic HRAS (HRAS(G12V)) and BRAF (BRAF(V600E)) to assess cell-cycle arrest and ER morphology.
  • Analyzed senescence markers including p53, p16(INK4a), heterochromatin foci, DNA damage, and the unfolded protein response (UPR).

Main Results:

  • Oncogenic HRAS(G12V), but not BRAF(V600E), induced rapid cell-cycle arrest with significant ER vacuolization and expansion.
  • HRAS(G12V)-induced senescence was mediated by the ER-associated unfolded protein response (UPR), independent of p53, p16(INK4a), or classical senescence markers.
  • HRAS activation selectively impacted the UPR, with less induction observed for activated NRAS.

Conclusions:

  • Premature senescence is not a universal response to activating oncogenes.
  • The endoplasmic reticulum acts as a critical gatekeeper in tumor suppression.
  • The unfolded protein response plays a key role in HRAS-driven oncogene-induced senescence.

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