title: Keap1-Independent Regulation of Nrf2 Activity by Protein Acetylation and a BET Bromodomain Protein.
abstract: Mammalian BET proteins comprise a family of bromodomain-containing epigenetic regulators with complex functions in chromatin organization and gene regulation. We identified the sole member of the BET protein family in Drosophila, Fs(1)h, as an inhibitor of the stress responsive transcription factor CncC, the fly ortholog of Nrf2. Fs(1)h physically interacts 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 fs(1)h RNAi or with the BET protein inhibitor JQ1 de-represses CncC transcriptional activity and engages protective gene expression programs. The mechanism by which Fs(1)h inhibits CncC function is distinct from the canonical mechanism that stimulates Nrf2 function by abrogating Keap1-dependent proteasomal degradation. Consistent with the independent modes of CncC regulation by Keap1 and Fs(1)h, combinations of drugs that can specifically target these pathways cause a strong synergistic and specific activation of protective CncC- dependent gene expression and boosts oxidative stress resistance. This synergism might be exploitable for the design of combinatorial therapies to target diseases associated with oxidative stress or inflammation.
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Nirmalya
authors.initials: N
authors.lastname: Chatterjee
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Tian
authors.affiliation: Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ) and Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Spirohn
authors.affiliation: Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ) and Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Boutros
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bohmann
mesh_terms: D000107:Acetylation; D000818:Animals; D001381:Azepines / Q000008:administration & dosage; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics*; D059748:Proteolysis / Q000187:drug effects; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D029721:Drosophila Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D014230:Triazoles; C116463:cnc protein, Drosophila; C109569:fs(1)h protein, Drosophila