Transcriptional downregulation of microRNA-19a by ROS production and NF-κB deactivation governs resistance to oxidative stress-initiated apoptosis

Cell apoptosis is one of the main pathological alterations during oxidative stress (OS) injury. Previously, we corroborated that nuclear factor-kappa B (NF-kappa B) transactivation confers apoptosis resistance against OS in mammalian cells, yet the underlying mechanisms remain enigmatic. Here we report that microRNA-19a (miR-19a) transcriptionally regulated by reactive oxygen species (ROS) production and NF-kappa B deactivation prevents OS-initiated cell apoptosis through cylindromatosis (CYLD) repression. CYLD contributes to OS-initiated cell apoptosis, for which NF-kappa B deactivation is essential. MiR-19a directly represses CYLD via targeting 3' UTR of CYLD, thereby antagonizing OS-initiated apoptosis. CYLD repression by miR-19a restores the IKK beta phosphorylation, RelA disassociation from I kappa B alpha, I kappa B alpha polyubiquitination and degradation, RelA recruitment at VEGF gene promoter as well as VEGF secretion in the context of OS. Either pharmacological deactivation of NF-kappa B or genetic upregulation of CYLD compromises the apoptosis-resistant phenotypes of miR-19a. Furthermore, miR-19a is transcriptionally downregulated upon OS in two distinct processes that require ROS production and NF-kappa B deactivation. VEGF potentiates the ability of miR-19a to activate NF-kappa B and render apoptosis resistance. Our findings underscore a putative mechanism whereby CYLD repression-mediated and NF-kappa B transactivation-dependent miR-19a regulatory feedback loop prevents cell apoptosis in response to OS microenvironment.