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  1. Article: To live or let die - complexity within the E2F1 pathway.

    Poppy Roworth, A / Ghari, Fatemeh / La Thangue, Nicholas B

    Molecular & cellular oncology

    2015  Volume 2, Issue 1, Page(s) e970480

    Abstract: The E2F1 transcription factor is a recognized regulator of the cell cycle as well as a potent mediator of DNA damage-induced apoptosis and the checkpoint response. Understanding the diverse and seemingly dichotomous functions of E2F1 activity has been ... ...

    Abstract The E2F1 transcription factor is a recognized regulator of the cell cycle as well as a potent mediator of DNA damage-induced apoptosis and the checkpoint response. Understanding the diverse and seemingly dichotomous functions of E2F1 activity has been the focus of extensive ongoing research. Although the E2F pathway is frequently deregulated in cancer, the contributions of E2F1 itself to tumorigenesis, as a promoter of proliferation or cell death, are far from understood. In this review we aim to provide an update on our current understanding of E2F1, with particular insight into its novel interaction partners and post-translational modifications, as a means to explaining its diverse functional complexity.
    Language English
    Publishing date 2015-01-30
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2372-3556
    ISSN 2372-3556
    DOI 10.4161/23723548.2014.970480
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses.

    Kawalkowska, Joanna / Quirke, Anne-Marie / Ghari, Fatemeh / Davis, Simon / Subramanian, Venkataraman / Thompson, Paul R / Williams, Richard O / Fischer, Roman / La Thangue, Nicholas B / Venables, Patrick J

    Scientific reports

    2016  Volume 6, Page(s) 26430

    Abstract: Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the ... ...

    Abstract Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the therapeutic effects in collagen-induced arthritis of the second generation PAD inhibitor, BB-Cl-amidine. Treatment after disease onset resulted in the reversal of clinical and histological changes of arthritis, associated with a marked reduction in citrullinated proteins in lymph nodes. There was little overall change in antibodies to collagen or antibodies to citrullinated peptides, but a shift from pro-inflammatory Th1 and Th17-type responses to pro-resolution Th2-type responses was demonstrated by serum cytokines and antibody subtypes. In lymph node cells from the arthritic mice treated with BB-Cl-amidine, there was a decrease in total cell numbers but an increase in the proportion of Th2 cells. BB-Cl-amidine had a pro-apoptotic effect on all Th subsets in vitro with Th17 cells appearing to be the most sensitive. We suggest that these immunoregulatory effects of PAD inhibition in CIA are complex, but primarily mediated by transcriptional regulation. We suggest that targeting PADs is a promising strategy for the treatment of chronic inflammatory disease.
    MeSH term(s) Animals ; Arthritis, Experimental/drug therapy ; Arthritis, Experimental/immunology ; Collagen ; Cytokines/metabolism ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation/drug effects ; Male ; Mice ; Ornithine/analogs & derivatives ; Protein-Arginine Deiminases/antagonists & inhibitors ; Th1 Cells/drug effects ; Th1 Cells/immunology ; Th17 Cells/drug effects ; Th17 Cells/immunology ; Th2 Cells/drug effects ; Th2 Cells/immunology
    Chemical Substances Cytokines ; Enzyme Inhibitors ; Collagen (9007-34-5) ; Ornithine (E524N2IXA3) ; Protein-Arginine Deiminases (EC 3.5.3.15)
    Language English
    Publishing date 2016-05-23
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/srep26430
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response.

    Ghari, Fatemeh / Quirke, Anne-Marie / Munro, Shonagh / Kawalkowska, Joanna / Picaud, Sarah / McGouran, Joanna / Subramanian, Venkataraman / Muth, Aaron / Williams, Richard / Kessler, Benedikt / Thompson, Paul R / Fillipakopoulos, Panagis / Knapp, Stefan / Venables, Patrick J / La Thangue, Nicholas B

    Science advances

    2016  Volume 2, Issue 2, Page(s) e1501257

    Abstract: Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains ... ...

    Abstract Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to an acetylated domain in E2F-1, and PAD4 and BRD4 coexist with E2F-1 on cytokine gene promoters. Accordingly, the combined inhibition of PAD4 and BRD4 disrupts the chromatin-bound complex and suppresses cytokine gene expression. In the murine collagen-induced arthritis model, chromatin-bound E2F-1 in inflammatory cells and consequent cytokine expression are diminished upon small-molecule inhibition of PAD4 and BRD4, and the combined treatment is clinically efficacious in preventing disease progression. Our results shed light on a new transcription-based mechanism that mediates the inflammatory effect of PAD4 and establish the interplay between citrullination and acetylation in the control of E2F-1 as a regulatory interface for driving inflammatory gene expression.
    MeSH term(s) Acetylation ; Animals ; Arthritis, Experimental/genetics ; Arthritis, Experimental/immunology ; Arthritis, Experimental/metabolism ; Cell Cycle Proteins ; Cell Line ; Citrulline/metabolism ; Cytokines/genetics ; E2F1 Transcription Factor/chemistry ; E2F1 Transcription Factor/genetics ; E2F1 Transcription Factor/metabolism ; Gene Expression Regulation ; HL-60 Cells ; Humans ; Hydrolases/antagonists & inhibitors ; Hydrolases/genetics ; Hydrolases/metabolism ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/metabolism ; Male ; Mice ; Mice, Inbred DBA ; Nuclear Proteins/metabolism ; Promoter Regions, Genetic ; Protein-Arginine Deiminase Type 4 ; Protein-Arginine Deiminases ; RNA, Small Interfering/genetics ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Transcription Factors/metabolism
    Chemical Substances BRD4 protein, human ; Cell Cycle Proteins ; Cytokines ; E2F1 Transcription Factor ; E2F1 protein, human ; Nuclear Proteins ; RNA, Small Interfering ; Recombinant Proteins ; Transcription Factors ; Citrulline (29VT07BGDA) ; Hydrolases (EC 3.-) ; PADI4 protein, human (EC 3.5.3.15) ; Protein-Arginine Deiminase Type 4 (EC 3.5.3.15) ; Protein-Arginine Deiminases (EC 3.5.3.15) ; peptidylarginine deiminase 4, mouse (EC 3.5.3.15)
    Language English
    Publishing date 2016-02-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.1501257
    Database MEDical Literature Analysis and Retrieval System OnLINE

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