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Inhibition of ERK oscillations by ionizing radiation and reactive oxygen species

Harish Shankaran1, William B Chrisler, Ryan L Sontag

  • 1Computational Biology and Bioinformatics, Pacific Northwest National Laboratory, Richland, Washington 99354, USA.

Molecular Carcinogenesis
|May 11, 2011
PubMed

Insights

Transforming growth factor alpha (TGFα) triggers oscillating protein kinase movements in human cells. Ionizing radiation and reactive oxygen species (ROS) inhibit these TGFα-induced oscillations, while a carcinogen alters their characteristics.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Radiation Biology

Background:

  • Protein kinase shuttling between cytoplasm and nucleus is crucial for growth factor signaling.
  • Transforming growth factor alpha (TGFα) signaling involves extracellular signal-regulated kinase (ERK) cytoplasmic-nuclear translocations.

Purpose of the Study:

  • To investigate the effect of TGFα on ERK oscillations in human keratinocytes.
  • To determine how X-irradiation and reactive oxygen species (ROS) impact TGFα-induced ERK oscillations.
  • To assess the influence of 12-O-tetradecanoyl phorbol-13-acetate (TPA), an epigenetic carcinogen, on these oscillations.

Main Methods:

  • Utilized human keratinocytes to study TGFα-induced ERK cytoplasmic-nuclear translocations.
  • Employed low-dose X-irradiation and hydrogen peroxide (H2O2) to model ROS exposure.
  • Measured cellular ROS levels using the fluorescent indicator dye H2-DCFDA.
  • Assessed TPA's effect on epidermal growth factor receptor (EGFR) transactivation and ERK oscillations.

Main Results:

  • TGFα induced oscillations in ERK cytoplasmic-nuclear translocations mediated by EGFR.
  • Low-dose X-irradiation and low concentrations of H2O2 inhibited TGFα-dependent ERK oscillations.
  • X-irradiation did not significantly increase ROS, while H2O2 and TPA did, with H2O2 > TPA.
  • TPA alone transactivated EGFR but did not induce ERK oscillations; TPA co-treatment altered TGFα-induced oscillation characteristics.

Conclusions:

  • TGFα-induced ERK oscillations in human keratinocytes are sensitive to inhibition by ionizing radiation and ROS.
  • Epigenetic carcinogen TPA perturbs the characteristics of TGFα-dependent ERK oscillations.
  • These findings highlight the interplay between signaling pathways, radiation, ROS, and cellular responses in keratinocytes.

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