Keep Harm at Bay: Oxidative Phosphorylation Induces Nrf2-Driven Antioxidant Response Via ERK5/MEF2/miR-23a Signaling to Keap-1

摘要: Nuclear factor E2-related 2 (Nrf2) is a key transcription which induces the expression of various cellular antioxidant and detoxifying enzymes through binding transcriptional activation response elements (ARE) in promoters their genes. The Nrf2/ARE pathway known to protect cells against stress stimuli, primarily oxidative associated with increased production reactive oxygen species (ROS). Nrf2 activity tightly regulated by cytoplasmic inhibitory protein Kelch-like ECH-associated protein-1 (Keap-1) acts as an adaptor between cullin-3 ubiquitin ligase promotes rapid proteasomal degradation Nrf2. Being sensor exogenous endogenous electrophilic compounds ROS, Keap-1 undergoes conformational changes upon interaction such agents this causes release from complex, thus allowing it translocate nucleus transactivate Nrf2-responsive genes [see (Harder et al., 2015, Tebay 2015) for recent reviews]. In study, Khan al. (this issue) demonstrate that there also alternative mechanism whereby can be activated human leukemia performing phosphorylation (OXPHOS). authors found while OXPHOS results generation induction “classical” encoding heme oxygenase-1 (HO-1) NAD(P)H:quinone oxidoreductase (NQO1) occur ROS-independent manner. This was decrease mRNA levels, implying lower levels may facilitate stabilization de novo synthesized protein, increasing functional pathway. data show MAPK ERK5 upregulated system. suggests kinase responsible downregulation Keap-1, mediated downstream target ERK5, MEF2C. MEF2C binds promoter microRNA miR-23a–27a–24-2 cluster miR-23a destabilizes interacting its 3′-untranslated region (3'UTR). Taken together, suggest leukemic ERK5/MEF2/miR-23a signaling resulting leads pathway, protecting deleterious effects ROS. The findings are line previously reported ability microRNAs downregulate targeting 3′-UTR several types cancer (Eades 2011, Kabaria van Jaarsveld 2013). Interestingly, MEF2A were shown positively regulate different microRNAs, including miR-23a, vascular smooth muscle undergoing stress-induced senescence (Zhao cardiac myocytes mice myotonic dystrophy (Kalsotra 2014), respectively. Therefore, ERK5/MEF2/miR-23a/Keap-1 axis represent regulatory broad range cell under pathological conditions. The importance regulation hematopoiesis aberrations has been years [e.g., (Schotte 2012)]. For instance Gocek (2011) upregulation miR-32 1,25-dihydroxyvitamin D3 myeloid pro-apoptotic Bim, inhibition cytarabine-induced apoptosis, latter frequently result excess intracellular ROS. report demonstrates important connection alleviation stress. As such, indicate one basis emergence resistance cytotoxic chemotherapy neoplastic diseases. novel, ERK5/microRNA-dependent, mode suggested study adds mechanisms related hypermethylation inactivating mutations lead hyperactivation Nrf2/ARE, tumorigenesis chemoresistance (Zhang 2010)]. In scenario, anti-sense oligonucleotides block developed therapeutic fight consequences loss function Keap-1.