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Erk1/2 MAP kinases are required for epidermal G2/M progression

Phillip A Dumesic1, Florence A Scholl, Deborah I Barragan

  • 1Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.

The Journal of Cell Biology
|May 6, 2009
PubMed

Insights

Extracellular signal-regulated kinase (Erk)1/2 are crucial for normal epithelial tissue renewal. Simultaneous depletion of Erk1/2 inhibits cell division, leading to G2/M arrest, highlighting their essential role in epithelial self-renewal.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Mitogen-activated protein kinases (MAPKs), specifically Erk1/2, are frequently hyperactivated in human cancers.
  • The role of Erk1/2 in normal epithelial tissue, where most Erk-associated cancers originate, remains largely unknown.
  • Previous studies focused on Erk1/2 function in fibroblasts, revealing distinct cell cycle regulation compared to epithelial cells.

Purpose of the Study:

  • To investigate the function of Erk1/2 in normal epithelial tissue self-renewal.
  • To determine the specific cell cycle phase regulated by Erk1/2 in epithelial cells.
  • To elucidate the molecular mechanisms underlying Erk1/2-dependent cell cycle progression in epidermis.

Main Methods:

  • Simultaneous depletion of Erk1 and Erk2 in mouse epidermis using genetic approaches.
  • Analysis of cell division, proliferation, and cell cycle progression following Erk1/2 loss.
  • Rescue experiments involving reintroduction of Erk2 or activation of downstream effectors.
  • Gene expression analysis, focusing on cell cycle regulators like cyclin B1 and c-Fos.

Main Results:

  • Individual loss of Erk1 or Erk2 had no discernible effect on epidermal tissue.
  • Simultaneous depletion of Erk1/2 significantly inhibited cell division and tissue self-renewal.
  • Growth inhibition was rescued by Erk2 reintroduction but not by activating G1 progression effectors.
  • Erk1/2 loss in epithelial cells led to reduced cyclin B1 and c-Fos expression, causing G2/M arrest.
  • A disruption of the cyclin B1-Cdc2 gene regulatory network was observed.

Conclusions:

  • Erk1/2 are essential for the self-renewal of normal epithelial tissues.
  • Unlike fibroblasts, Erk1/2 in epithelial cells are required for progression through the G2/M phase of the cell cycle.
  • Erk1/2 signaling plays a critical role in maintaining epithelial tissue homeostasis by regulating the G2/M transition.

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