Tambuwala, Murtaza M.

Thumbnail Image
Preferred name
Tambuwala, Murtaza M.
Official Name
Tambuwala, Murtaza M.

Research Output

Filters

3
3
Reset filters

Settings

Now showing 1 - 3 of 3
  • Publication
    REST is a hypoxia-responsive transcriptional repressor
    (Springer Nature, 2016-08-17)
    Cavadas, Miguel A. S. 
    ;
    Mesnieres, Marion 
    ;
    Crifo, Bianca 
    ;
    Manresa, Mario C. 
    ;
    Selfridge, Andrew C. 
    ;
    Keogh, Ciara E. 
    ;
    Fábián, Zsolt 
    ;
    Scholz, Carsten C. 
    ;
    Nolan, Karen A. 
    ;
    Rocha, Liliane M.A. 
    ;
    Tambuwala, Murtaza M. 
    ;
    Brown, Stuart 
    ;
    Wdowicz, Anita 
    ;
    Corbett, Danielle 
    ;
    Murphy, Keith J. 
    ;
    Godson, Catherine 
    ;
    Cummins, Eoin P. 
    ;
    Taylor, Cormac T. 
    ;
    Cheong, Alex 
    Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia.
      351Scopus© Citations 54
  • Publication
    Regulation of IL-1β-induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways
    (National Academy of Sciences, 2013-10)
    Scholz, Carsten C. 
    ;
    Cavadas, Miguel A. S. 
    ;
    Tambuwala, Murtaza M. 
    ;
    Hams, Emily 
    ;
    Rodriguez, Javier 
    ;
    Kriegsheim, Alexander von 
    ;
    Cotter, Philip 
    ;
    Bruning, Ulrike 
    ;
    Fallon, Padraic G. 
    ;
    Cheong, Alex 
    ;
    Cummins, Eoin P. 
    ;
    Taylor, Cormac T. 
    Hypoxia is a prominent feature of chronically inflamed tissues. Oxygen-sensing hydroxylases control transcriptional adaptation to hypoxia through the regulation of hypoxia-inducible factor (HIF) and nuclear factor κB (NF-κB), both of which can regulate the inflammatory response. Furthermore, pharmacologic hydroxylase inhibitors reduce inflammation in multiple animal models. However, the underlying mechanism(s) linking hydroxylase activity to inflammatory signaling remains unclear. IL-1β, a major proinflammatory cytokine that regulates NF-κB, is associated with multiple inflammatory pathologies. We demonstrate that a combination of prolyl hydroxylase 1 and factor inhibiting HIF hydroxylase isoforms regulates IL-1β-induced NF-κB at the level of (or downstream of) the tumor necrosis factor receptor-associated factor 6 complex. Multiple proteins of the distal IL-1β-signaling pathway are subject to hydroxylation and form complexes with either prolyl hydroxylase 1 or factor inhibiting HIF. Thus, we hypothesize that hydroxylases regulate IL-1β signaling and subsequent inflammatory gene expression. Furthermore, hydroxylase inhibition represents a unique approach to the inhibition of IL-1β-dependent inflammatory signaling.
      272Scopus© Citations 142
  • Publication
    Loss of Prolyl Hydroxylase-1 Protects Against Colitis Through Reduced Epithelial Cell Apoptosis and Increased Barrier Function
    (Elsevier - WB Saunders, 2010-12)
    Tambuwala, Murtaza M. 
    ;
    Cummins, Eoin P. 
    ;
    Lenihan, Colin R. 
    ;
    et al. 
    Background & Aims: Hypoxia inducible factor (HIF) prolyl hydroxylase inhibitors are protective in mouse models of inflammatory bowel disease (IBD). Here, we investigated the therapeutic target(s) and mechanism(s) involved. Methods: The effect of genetic deletion of individual HIF-prolyl hydroxylase (PHD) enzymes on the development of dextran sulphate sodium (DSS)–induced colitis was examined in mice. Results: PHD1−/−, but not PHD2+/− or PHD3−/−, mice were less susceptible to the development of colitis than wild-type controls as determined by weight loss, disease activity, colon histology, neutrophil infiltration, and cytokine expression. Reduced susceptibility of PHD1−/− mice to colitis was associated with increased density of colonic epithelial cells relative to wild-type controls, which was because of decreased levels of apoptosis that resulted in enhanced epithelial barrier function. Furthermore, with the use of cultured epithelial cells it was confirmed that hydroxylase inhibition reversed DSS-induced apo tosis and barrier dysfunction. Finally, PHD1 levels were increased with disease severity in intestinal tissue from patients with IBD and in colonic tissues from DSS-treated mice. Conclusions: These results imply a role for PHD1 as a positive regulator of intestinal epithelial cell apoptosis in the inflamed colon. Genetic loss of PHD1 is protective against colitis through decreased epithelial cell apoptosis and consequent enhancement of intestinal epithelial barrier function. Thus, targeted PHD1 inhibition may represent a new therapeutic approach in IBD.
      562Scopus© Citations 169