Premium
Inhibition of ERK oscillations by ionizing radiation and reactive oxygen species
Author(s) -
Shankaran Harish,
Chrisler William B.,
Sontag Ryan L.,
Weber Thomas J.
Publication year - 2011
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20724
Subject(s) - mapk/erk pathway , reactive oxygen species , biology , transactivation , kinase , microbiology and biotechnology , extracellular , epidermal growth factor , signal transduction , transforming growth factor , biochemistry , receptor , gene expression , gene
The shuttling of activated protein kinases between the cytoplasm and nucleus is an essential feature of normal growth factor signaling cascades. Here we demonstrate that transforming growth factor alpha (TGFα) induces oscillations in extracellular signal regulated kinase (ERK) cytoplasmic‐nuclear translocations in human keratinocytes. TGFα‐dependent ERK oscillations mediated through the epidermal growth factor receptor (EGFR) are inhibited by low dose X‐irradiation (10 cGy) and low concentrations of hydrogen peroxide (0.32–3.26 µM H 2 O 2 ) used as a model reactive oxygen species (ROS). A fluorescent indicator dye (H2‐DCFDA) was used to measure cellular ROS levels following X‐irradiation, 12‐O‐tetradecanoyl phorbol‐13‐acetate (TPA) and H 2 O 2 . X‐irradiation did not generate significant ROS production while 0.32 µM H 2 O 2 and TPA induced significant increases in ROS levels with H 2 O 2 > TPA. TPA alone induced transactivation of the EGFR but did not induce ERK oscillations. TPA as a cotreatment did not inhibit TGFα‐stimulated ERK oscillations but qualitatively altered TGFα‐dependent ERK oscillation characteristics (amplitude, time‐period). Collectively, these observations demonstrate that TGFα‐induced ERK oscillations are inhibited by ionizing radiation/ROS and perturbed by epigenetic carcinogen in human keratinocytes. © 2010 Wiley‐Liss, Inc.