4-Hydroxynonenal Induces G2/M Phase Cell Cycle Arrest by Activation of the Ataxia Telangiectasia Mutated and Rad3-related Protein (ATR)/Checkpoint Kinase 1 (Chk1) Signaling Pathway

摘要: 4-Hydroxynonenal (HNE) has been widely implicated in the mechanisms of oxidant-induced toxicity, but detrimental effects HNE associated with DNA damage or cell cycle arrest have not thoroughly studied. Here we demonstrate for first time that caused G2/M hepatocellular carcinoma HepG2 (p53 wild type) and Hep3B null) cells was accompanied decreased expression CDK1 cyclin B1 activation p21 a p53-independent manner. treatment suppressed Cdc25C level, which led to inactivation CDK1. HNE-induced phosphorylation at Ser-216 resulted its translocation from nucleus cytoplasm, thereby facilitating degradation via ubiquitin-mediated proteasomal pathway. This regulated by ataxia telangiectasia Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) The role double strand break strongly suggested remarkable increase comet tail formation H2A.X HNE-treated vitro. supported increased vivo mGsta4 null mice impaired metabolism levels tissues. HNE-mediated ATR/Chk1 signaling inhibited ATR inhibitor (caffeine). Additionally, most on were attenuated hGSTA4 transfected cells, indicating involvement these events. A novel GSTA4-4 maintenance genomic integrity is also suggested. Background: an important molecule. Results: induces H2A.X. ATR/Chk1-mediated regulation predominant mechanism arrest. overexpression inhibits Conclusion: causes Significance: play integrity.