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Activation of extracellular signal-regulated kinase (ERK) by mitogenic stimuli is repressed in v-Src-transformed

M R Stofega1, C L Yu, J Wu

  • 1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor 48109, USA.

Cell Growth & Differentiation : the Molecular Biology Journal of the American Association for Cancer Research
|January 1, 1997
PubMed

Insights

Oncogenic transformation by viral oncoproteins represses mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) pathway activation. This repression, occurring upstream of ERK, suggests negative feedback regulation is involved in maintaining cell transformation.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Oncology

Background:

  • Mitogenic signaling pathways activate extracellular signal-regulated kinases (ERK), a subfamily of mitogen-activated protein kinases (MAPK), in normal cells.
  • Viral oncoproteins like v-Src, v-Ras, and v-Raf can lead to oncogenic transformation by chronically stimulating signaling pathways.

Purpose of the Study:

  • To investigate the effect of oncogenic transformation by viral oncoproteins on ERK/MAPK pathway activation.
  • To determine if elevated ERK activity is necessary for maintaining the transformed phenotype.

Main Methods:

  • Stable transformation of rodent fibroblast cell lines with v-Src, v-Ras, or v-Raf.
  • Stimulation with serum or phorbol ester to assess ERK/MAPK activation.
  • Treatment with the phosphatase inhibitor orthovanadate to evaluate the role of phosphatases.

Main Results:

  • ERK activation was markedly repressed in v-Src-transformed cells, with similar repression observed in v-Ras- and v-Raf-transformed cells.
  • MAPK/ERK kinase (MEK) activation was also repressed, indicating the repression occurs upstream of ERK.
  • Orthovanadate partially restored ERK activation in some cell lines, suggesting MEK-level regulation.
  • ERK activity was not constitutively elevated in transformed cells compared to normal cells.

Conclusions:

  • Oncogenic transformation by viral oncoproteins leads to negative feedback regulation of the ERK signaling pathway upstream of ERK.
  • Sustained high ERK activity is not required for maintaining cell transformation induced by these viral oncoproteins.

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