jean-christophe Bourdon

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  Available from: jean-christophe Bourdon

  Article: Drosophila p53 isoforms differentially regulate apoptosis and apoptosis-induced proliferation.

  M-L Dichtel-Danjoy, D Ma, P Dourlen, G Chatelain, F Napoletano, M Robin, M Corbet, C Levet, H Hafsi, P Hainaut, H D Ryoo, J-C Bourdon, B Mollereau
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  ABSTRACT: Irradiated or injured cells enter apoptosis, and in turn, promote proliferation of surrounding unaffected cells. In Drosophila, apoptotic cells have an active role in proliferation, where the caspase Dronc and p53 induce mitogen expression and growth in the surrounding tissues. The Drosophila p53 gene structure is conserved and encodes at least two protein isoforms: a full-length isoform (Dp53) and an N-terminally truncated isoform (DΔNp53). Historically, DΔNp53 was the first p53 isoform identified and was thought to be responsible for all p53 biological activities. It was shown that DΔNp53 induces apoptosis by inducing the expression of IAP antagonists, such as Reaper. Here we investigated the roles of Dp53 and DΔNp53 in apoptosis and apoptosis-induced proliferation. We found that both isoforms were capable of activating apoptosis, but that they each induced distinct IAP antagonists. Expression of DΔNp53 induced Wingless (Wg) expression and enhanced proliferation in both 'undead cells' and in 'genuine' apoptotic cells. In contrast to DΔNp53, Dp53 did not induce Wg expression in the absence of the endogenous p53 gene. Thus, we propose that DΔNp53 is the main isoform that regulates apoptosis-induced proliferation. Understanding the roles of Drosophila p53 isoforms in apoptosis and in apoptosis-induced proliferation may shed new light on the roles of p53 isoforms in humans, with important implications in cancer biology.Cell Death and Differentiation advance online publication, 17 August 2012; doi:10.1038/cdd.2012.100.
  Cell death and differentiation 08/2012; · 8.24 Impact Factor
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  Article: The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression.

  H Bernard, B Garmy-Susini, N Ainaoui, L Van Den Berghe, A Peurichard, S Javerzat, A Bikfalvi, D P Lane, J C Bourdon, A-C Prats
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  ABSTRACT: The tumour suppressor p53, involved in DNA repair, cell cycle arrest and apoptosis, also inhibits blood vessel formation, that is, angiogenesis, a process strongly contributing to tumour development. The p53 gene expresses 12 different proteins (isoforms), including TAp53 (p53 (or p53α), p53β and p53γ) and Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ). The Δ133p53α isoform was shown to modulate p53 transcriptional activity and is overexpressed in various human tumours. However, its role in tumour progression is still unexplored. In the present study, we examined the involvement of Δ133p53 isoforms in tumoural angiogenesis and tumour growth in the highly angiogenic human glioblastoma U87. Our data show that conditioned media from U87 cells depleted for Δ133p53 isoforms block endothelial cell migration and tubulogenesis without affecting endothelial cell proliferation in vitro. The Δ133p53 depletion in U2OS osteosarcoma cells resulted in a similar angiogenesis blockade. Furthermore, using conditioned media from U87 cells ectopically expressing each Δ133p53 isoform, we determined that Δ133p53α and Δ133p53γ but not Δ133p53β, stimulate angiogenesis. Our in vivo data using the chicken chorio-allantoic membrane and mice xenografts establish that angiogenesis and growth of glioblastoma U87 tumours are inhibited upon depletion of Δ133p53 isoforms. By TaqMan low-density array, we show that alteration of expression ratio of Δ133p53 and TAp53 isoforms differentially regulates angiogenic gene expression with Δ133p53 isoforms inducing pro-angiogenic gene expression and repressing anti-angiogenic gene expression.Oncogene advance online publication, 25 June 2012; doi:10.1038/onc.2012.242.
  Oncogene 06/2012; · 6.37 Impact Factor
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  Article: p53 is activated in response to disruption of the pre-mRNA splicing machinery.

  N Allende-Vega, S Dayal, U Agarwala, A Sparks, J-C Bourdon, M K Saville
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  ABSTRACT: In this study, we show that interfering with the splicing machinery results in activation of the tumour-suppressor p53. The spliceosome was targeted by small interfering RNA-mediated knockdown of proteins associated with different small nuclear ribonucleoprotein complexes and by using the small-molecule splicing modulator TG003. These interventions cause: the accumulation of p53, an increase in p53 transcriptional activity and can result in p53-dependent G(1) cell cycle arrest. Mdm2 and MdmX are two key repressors of p53. We show that a decrease in MdmX protein level contributes to p53 activation in response to targeting the spliceosome. Interfering with the spliceosome also causes an increase in the rate of degradation of Mdm2. Alterations in splicing are linked with tumour development. There are frequently global changes in splicing in cancer. Our study suggests that p53 activation could participate in protection against potential tumour-promoting defects in the spliceosome. A number of known p53-activating agents affect the splicing machinery and this could contribute to their ability to upregulate p53. Preclinical studies indicate that tumours can be more sensitive than normal cells to small-molecule spliceosome inhibitors. Activation of p53 could influence the selective anti-tumour activity of this therapeutic approach.Oncogene advance online publication, 20 February 2012; doi:10.1038/onc.2012.38.
  Oncogene 02/2012; · 6.37 Impact Factor
• Article: p53 Protein Isoforms: Key Regulators in the Front Line of Pathogen Infections?

  Olivier Terrier, Jean-Christophe Bourdon, Manuel Rosa-Calatrava
  PLoS Pathogens 04/2013; 9(4):e1003246. · 9.13 Impact Factor
• Article: Host microRNA molecular signatures associated with human H1N1 and H3N2 influenza A viruses reveal an unanticipated antiviral activity for miR-146a.

  Olivier Terrier, Julien Textoris, Coralie Carron, Virginie Marcel, Jean-Christophe Bourdon, Manuel Rosa-Calatrava
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  ABSTRACT: While post-transcriptional regulation of gene expression by miRNAs have been shown to be involved in influenza virus replication cycle, only a few studies have further investigated this aspect in a human cellular model infected with human influenza viruses. In this study, we performed miRNA global profiling in human lung epithelial cells (A549) infected by two different subtypes of human influenza A viruses (H1N1 and H3N2). We identified a common miRNA signature in response to infection by the two different strains, highlighting a pool of five miRNAs commonly deregulated, which are known to be involved in the innate immune response or apoptosis. Among the five miRNA hits, the only up-regulated miRNA in response to influenza infection corresponded to miR-146a. Based on a previously published gene expression dataset, we extracted inversely correlated miR-146a target genes and determined their first-level interactants. This functional analysis revealed 8 distinct biological processes strongly associated with these interactants: TLR pathway, innate immune response, cytokine production and apoptosis. To better understand the biological significance of miR-146a up-regulation, using a reporter assay and a specific anti-miR-146a inhibitor, we confirmed that infection increases the endogenous miR-146a promoter activity and that inhibition of miR-146a significantly increased viral propagation. Altogether, our results suggest a functional role of miR-146a in the outcome of influenza infection, at the crossroads of several biological processes.
  Journal of General Virology 01/2013; · 3.36 Impact Factor