ERK5/KLF4 SIGNALING IS A SHARED PATHWAY UNDERLYING THE NEUROPROTECTIVE EFFECTS OF H2O2 PRECONDITIONING AND NGF
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Purpose: Oxidative stress has long been implicated in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. While high levels of oxidative stress is generally associated with neuronal death, a slight rise of reactive oxygen species (ROS) levels can be protective by "preconditioning" cells to develop a resistance against subsequent challenges. However, the mechanisms underlying such a preconditioning (PC)-induced protection are still poorly understood. One clue stems from the observation that the mitogen-activated protein (MAP) kinase ERK5 is recruited both under conditions of H2O2 - induced neuronal preconditioning (PC) as well as following application of the application of the neuroprotectant, Nerve Growth Factor (NGF). This project tests the hypothesis that the ERK5-dependent signaling cascade may function as a convergence point for various protective signals to counteract oxidative stress-induced neuronal death. Methods: We used PC12 cells as our model to study the effect of oxidative stress. Activity of the ERK5 signaling pathway was enhanced by over-expression of active upstream kinease, or blocked by pharmacological inhibitors or RNAi. Cell viability was determined by Calcein Assay. Results: Over-expression of a constitutively active form of MEK5, the upstream activator of ERK5, partially rescued PC12 cells from H2O2-caused death, while inhibition of ERK5 by pharmacological inhibitors or RNAi abolished NGF or PC-induced protection.Furthermore, both NGF and PC increased the expression of the transcription factor, KLF4, which can initiate an anti-apoptotic response in various cell types. Induction of KLF4 by NGF or PC in PC12 cells is blocked by siERK5, suggesting that ERK5 is required in this process. Finally, siKLF4 can also attenuate NGF- or PC-induced neuroprotection. Conclusions: Taken together, our data suggest that ERK5/KLF4 cascade is a common signaling pathway shared by multiple mechanisms to protect neurons from oxidative stress-induced cell death. Since oxidative stress is thought to be a major player in many aging-associated diseases, KLF4 may serve as a therapeutic target, that when activated, counteracts oxidative stress under such conditions.