Download or read book Identification and Characterization of Proteins with Novel Functions in Nrf2 Signaling written by Nirmalya Chatterjee and published by . This book was released on 2015 with total page 124 pages. Available in PDF, EPUB and Kindle. Book excerpt: "Oxidative stress causes widespread damage to biomolecules, leads to different pathological conditions and contributes to aging. The Nrf2 transcription factor, a major mediator of oxidative stress responses, controls gene expression programs that protect multiple organs from oxidative damage, delay the onset of some age-associated diseases and promote longevity at least in some organisms. In an unstressed condition, Nrf2 interacts with its cytoplasmic inhibitor Keap1, which targets it for proteasomal degradation. Oxidative stress prevents Keap1-mediated degradation of Nrf2, resulting in its accumulation and nuclear translocation. In the nucleus, Nrf2 dimerizes with a small Maf protein, binds to ?Antioxidant Response Elements' and induces multiple antioxidant and detoxification genes. Complete understanding of the molecular mechanisms of Nrf2 regulation is important to assess its role in normal physiology and disease. The key components of Nrf2 signaling are conserved in Drosophila where CncC is the homolog of mammalian Nrf2. In order to study mechanisms of Nrf2 function in Drosophila, cell-based and in vivo transcriptional reporters for Nrf2 were developed. A cell-based dsRNA library screen was carried out to find novel regulators of Nrf2 signaling. Among others we identified Cdk12 and Fs(1)h. Cdk12, a RNA PolII-CTD kinase, was found to be required for CncC target gene expression in a cell-autonomous manner and to be important for oxidative stress resistance. In contrast, Fs(1)h, the sole member of the BET protein family in Drosophila, was identified as an inhibitor of CncC. Bromodomain-containing BET proteins have complex functions in chromosome organization and the control of gene expression. Fs(1)h was found to physically interact with CncC in a manner that requires the function of its bromodomains and the acetylation of CncC. Treatment of cultured Drosophila cells or adult flies with the BET protein inhibitor JQ1 de-represses CncC transcriptional activity and induces protective gene expression programs. The mechanism by which Fs(1)h inhibits CncC function is distinct from that of Keap1. Consistent with this, combinations of drugs that can specifically target Keap1 and Fs(1)h cause a synergistic and specific activation of CncC dependent gene expression. This synergism might be exploitable for the design of combinatorial therapeutic approaches, targeting Nrf2 in various diseases."--Pages vi-vii.