Contrasting actions of prolonged mitogen-activated protein kinase activation on cell survival.
Activation of the ERK mitogen-activated protein kinase pathway has been implicated in pro-survival and cellular protective mechanisms, so that chronic ERK activation may be a useful therapeutic strategy. Here, we further explored the consequences of prolonged ERK activation following expression of constitutively active form of MEK, MEK-EE, in cardiac myocytes. We confirmed that chronic MEK-EE overexpression halved myocyte death following glucose deprivation, but surprisingly this was not associated with preserved intracellular ATP levels. Whilst activities of a number of antioxidant enzymes were not altered upon MEK-EE expression, paradoxically Cu/Zn superoxide dismutase activity was almost halved upon MEK-EE expression. When we then exposed myocytes to the superoxide generator menadione, we observed significantly higher death of MEK-EE expressing myocytes. Pre-incubation with U0126 inhibited menadione-induced death. Our results are the first to show that MEK-ERK signalling can act to increase or decrease cell survival, the outcome depending on the form of stress stimulus encountered.
Badrian
Bahareh
B
Biochemistry and Molecular Biology, University of Western Australia (UWA), and Lions Eye Institute, Crawley, WA 6009, Australia.
Casey
Tammy M
TM
Lai
May C
MC
Rakoczy
P Elizabeth
PE
Arthur
Peter G
PG
Bogoyevitch
Marie A
MA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002470:Cell Survival / Q000502:physiology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D018698:Glutamic Acid / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D009570:Nitriles / Q000494:pharmacology; D017354:Point Mutation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D024483:Vitamin K 3 / Q000494:pharmacology
D000975:Antioxidants; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D018698:Glutamic Acid; D024483:Vitamin K 3; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose