Modulation of Nuclear Factor E2-related Factor-2 (Nrf2) Activation by the Stress Response Gene Immediate Early Response-3 (IER3) in Colonic Epithelial Cells

• DOI: 10.1074/jbc.m113.490920
• Publication Date: 2013-12-06T01:14:01Z
• Authors: Imke Stachel; Claudia Geismann; Konrad Aden; Florian Deisinger; Philip Rosenstiel; Stefan Schreiber; Susanne Sebens; Alexander Arlt; Heiner Schäfer
• Keywords: FYN; LY294002

Although nuclear factor E2-related factor-2 (Nrf2) protects from carcinogen-induced tumorigenesis, underlying the rationale for using Nrf2 inducers in chemoprevention, this antioxidative transcription may also act as a proto-oncogene. Thus, an enhanced activity promotes formation and chemoresistance of colon cancer. One mechanism causing persistent activation is adaptation epithelial cells to oxidative stress during chronic inflammation, e.g. colonocytes inflammatory bowel diseases, multifunctional response gene immediate early response-3 (IER3) has crucial role under these conditions. We now demonstrate that colonic tissue Ier3−/− mice subject dextran sodium sulfate colitis exhibit greater than Ier3+/+ mice, manifesting increased protein level target expression. Likewise, human NCM460 subjected shRNA-mediated IER3 knockdown compared with control cells, whereas overexpression attenuated activation. IER3-deficient exhibited reduced reactive oxygen species levels, indicating protection, well lower sensitivity TRAIL or anticancer drug-induced apoptosis clonogenicity. Knockdown expression reversed IER3-dependent effects. Further, enhancing effect deficiency on relates inhibitory tyrosine kinase Fyn by PI3K/Akt pathway. PI3K inhibitor LY294002 Akt abrogated impact activity. In conclusion, interference PI3K/Akt-Fyn pathway represents novel regulation get lost tumors which exerts its stress-adaptive tumor-suppressive