MEK/ERK pathway protects ionizing radiation-induced loss of mitochondrial membrane potential and cell death in lymphocytic leukemia cells.
MEK/ERK-mediated signals have recently been found to inhibit Fas-mediated cell death through inhibition of caspase-8 activity. It remains unknown whether MEK/ERK-mediated signals affect ionizing radiation (IR)-induced cell death. Here we demonstrate that MEK/ERK-mediated signals selectively inhibit IR-induced loss of mitochondrial membrane potential (DeltaPsi(m)) and subsequent cell death. In Jurkat cells, TPA strongly activated ERK and inhibited the IR-induced caspase-8/Bid cleavage and the loss of DeltaPsi(m). The inhibitory effect of TPA was mostly abrogated by pretreatment of a specific MEK inhibitor PD98059, indicating that the effect depends upon MEK/ERK-mediated signals. Moreover, BAF-B03 transfectants expressing IL-2 receptor (IL-2R) beta(c) chain lacking the acidic region, which is responsible for MEK/ERK-mediated signals, revealed higher sensitivity to IR than the transfectants expressing wild-type IL-2R. Interestingly, the signals could neither protect the DeltaPsi(m) loss nor cell death in UV-irradiated cells. These data imply that the anti-apoptotic effect of MEK/ERK-mediated signals appears to selectively inhibit the IR-induced cell death through protection of the DeltaPsi(m) loss. Our data enlighten an anti-apoptotic function of MEK/ERK pathway against IR-induced apoptosis, thereby implying its contribution to radioresistance.
Shonai
T
T
Department of Radiology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan.
Adachi
M
M
Sakata
K
K
Takekawa
M
M
Endo
T
T
Imai
K
K
Hareyama
M
M
D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism / Q000528:radiation effects; D016923:Cell Death / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology* / Q000528:radiation effects; D019169:Jurkat Cells / Q000187:drug effects / Q000201:enzymology* / Q000528:radiation effects; D048369:MAP Kinase Kinase 1; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000528:radiation effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology; D011839:Radiation, Ionizing; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014466:Ultraviolet Rays
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate