Interferons Transcriptionally Up-Regulate MLKL Expression in Cancer Cells.

ABSTRACT: Interferons (IFNs) are key players in the tumor immune response and act by inducing the expression of IFN-stimulated genes (ISGs). Here, we identify the mixed-lineage kinase domain-like pseudokinase (MLKL) as an ISG in various cancer cell lines. Both type I and type II IFNs increase the expression of MLKL indicating that MLKL up-regulation is a general feature of IFN signaling. IFN? up-regulates mRNA as well as protein levels of MLKL demonstrating that IFN? transcriptionally regulates MLKL. This notion is further supported by Actinomycin D chase experiments showing that IFN?-stimulated up-regulation of MLKL is prevented in the presence of the transcriptional inhibitor Actinomycin D. Also, knockdown of the transcription factor IFN-regulatory factor 1 (IRF1) and signal transducer and activator of transcription (STAT) 1 as well as knockout of IRF1 significantly attenuate IFN?-mediated induction of MLKL mRNA levels. Up-regulation of MLKL by IFN? provides a valuable tool to sensitize cells towards necroptotic cell death and to overcome apoptosis resistance of cancer cells.

SUBMITTER: Knuth AK 

PROVIDER: S-EPMC6310689 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature