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The ERK-RSK1 activation by growth factors at G2 phase delays cell cycle progression and reduces mitotic aberrations

Hyun-Ja Nam1, Sujeong Kim, Min-Woo Lee

  • 1Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, South Korea.

Cellular Signalling
|May 3, 2008
PubMed

Insights

Growth factors like HGF can delay the G2/M cell cycle transition, mediated by ERK-RSK1 signaling. This delay may be crucial for maintaining genomic integrity during growth factor stimulation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Growth factors typically accelerate cell cycle progression from G0 to S phase.
  • The specific roles of growth factors in other cell cycle phases, particularly G2/M, remain largely unexplored.

Purpose of the Study:

  • To investigate the impact of growth factors, specifically hepatocyte growth factor (HGF), on the G2/M transition in HeLa cells.
  • To elucidate the molecular mechanisms underlying HGF-induced G2/M delay and its potential role in maintaining genomic stability.

Main Methods:

  • HeLa cells were treated with HGF, epidermal growth factor (EGF), and fibroblast growth factor (FGF).
  • Cell cycle progression was analyzed using Fluorescence-Activated Cell Sorting (FACS), mitotic index counts, and time-lapse microscopy.
  • Key molecular players including cyclin B1, MAPK kinase (MEK), ribosomal S6 kinase (RSK), and extracellular-regulated protein kinase (ERK) were assessed.
  • RNA interference (siRNA) was used to knockdown RSK1 and RSK2.
  • Chromosomal segregation and aberrations were analyzed.

Main Results:

  • HGF treatment at G2 phase induced a delay in G2/M transition, a phenomenon also observed with EGF and FGF.
  • HGF treatment delayed cyclin B1-associated kinase activation and diminished its nuclear translocation.
  • The G2/M delay was abolished by a MEK inhibitor (U0126) or a kinase-dead RSK mutant.
  • Knockdown of RSK1, but not RSK2, abrogated the HGF-induced G2/M delay, implicating the ERK-RSK1 pathway.
  • Cells expressing an oncogenic HGF receptor showed abolished G2/M delay upon RSK1 knockdown.
  • HGF induced chromosomal segregation defects, which were exacerbated by RSK1 depletion.

Conclusions:

  • Growth factor stimulation, via the ERK-RSK1 pathway, can delay G2/M cell cycle transition.
  • This delay appears to be a protective mechanism to maintain genomic integrity during active growth factor signaling.
  • The findings highlight a novel role for growth factors in regulating cell cycle checkpoints beyond the G0/S transition.

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