C-Myc is a Nrf2-interacting protein that negatively regulates phase II genes through their electrophile responsive elements.
c-Myc is a transcription factor that is implicated in many cellular processes including proliferation, apoptosis and cancers. Recently, c-Myc was shown to be involved in regulation of glutamate cysteine ligase through E-box sequences. This investigation examined whether c-Myc also regulates phase II genes through interaction with the electrophile response element (EpRE). Experiments were conducted in human bronchial epithelial cells using si-RNA to knock down c-Myc. RT-PCR and reporter assays were used to measure transcription and promoter activity. c-Myc downregulated transcription and promoter activity of phase II genes. Chromatin immunoprecipitation verified binding of c-Myc to EpRE while coimmunoprecipitation demonstrated interaction of c-Myc with Nrf2. c-Myc also forms a ternary complex with Nrf2 and p-c-Jun. Finally, c-Myc decreased Nrf2 stability. Thus, our results suggest regulation of the EpRE/Nrf2 signaling pathway by c-Myc through both interaction with the EpRE binding complex and increased degradation of Nrf2.
Levy
Smadar
S
Department of Natural Sciences, University of California, Merced, USA.
Forman
Henry Jay
HJ
D000447:Aldehydes / Q000494:pharmacology; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D024721:E-Box Elements / Q000502:physiology; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism*; D006801:Humans; D050217:Metabolic Detoxication, Phase II / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D020218:Response Elements / Q000502:physiology*; D015533:Transcriptional Activation
D000447:Aldehydes; D051267:NF-E2-Related Factor 2; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D005721:Glutamate-Cysteine Ligase; C027576:4-hydroxy-2-nonenal