References of "Twizere, Jean-Claude"
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See detailA specificity map for HTLV-1 Tax/PDZ interactions.
Twizere, Jean-Claude ULg; DEWULF, Jean-François; Blibek, Karim ULg et al

Poster (2011, June 06)

Human T-cell leukemia virus type I (HTLV-1) encodes a Tax oncoprotein that is critical for both viral replication and cellular transformation. HTLV-1 Tax possesses a PDZ domain binding motif (PBM) at its ... [more ▼]

Human T-cell leukemia virus type I (HTLV-1) encodes a Tax oncoprotein that is critical for both viral replication and cellular transformation. HTLV-1 Tax possesses a PDZ domain binding motif (PBM) at its C-terminus that is essential for its transforming activity in a Rat-1 model and for IL-2. Tax has been shown to interact with several PDZ domain containing proteins including PSD-95, Beta1-syntrophin, the precursor of interleukin-16, the mammalian homolog of the Drosophila discs large tumor suppressor protein Dlg, PDLIM2, Lin7, hTid1, Tip1, hScrib and MAGI3. In the 15th International Conference on Human Retrovirology: HTLV and Related Retroviruses, we will present a specificity map for the Tax/PDZ domain interactions generated using the human ORFeome 5.1. and we will focus on some of the new Tax/PDZ interactions. [less ▲]

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See detailEstablishment of an interactomic map of the Ets factors family: Towards a better understanding of their roles in oncogenic processes
Rambout, Xavier ULg; Simonis, Nicolas; Demoitié, Pauline et al

Poster (2011, April 29)

Ets transcription factors have been involved in several cancers such as leukemia, prostate cancer and Ewing’s sarcoma. They regulate the expression of genes controlling important biological processes such ... [more ▼]

Ets transcription factors have been involved in several cancers such as leukemia, prostate cancer and Ewing’s sarcoma. They regulate the expression of genes controlling important biological processes such as cellular proliferation, differentiation, apoptosis, metastasis, and transformation. This family of transcription factors is characterized by its highly conserved DNA-binding domain called the ETS domain and members are classified into subfamilies based on sequence homology criterion. We built a protein-protein interaction (PPI) network of the 27 Ets proteins and of their individual functional domains using a high-throughput yeast-two hybrid (Y2H) screening method. That Y2H network was expanded with confident literature-curated PPIs to obtain a comprehensive Ets interaction network. By considering connectivity between Ets interaction partners, we were able to segregate highly connected clusters of proteins from that network. Analysis of ontologies enrichment of those clusters enabled to confirm well-established roles and regulations of Ets factors, but also to suggest new ones. Biological validation of one precise cluster could be used as a rule of a thumb to globally confirm the bioinformatic analysis of our Ets PPI network and the potential physiological or pathological roles and regulation of Ets factors. [less ▲]

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See detailIdentification of a Brucella spp. secreted effector specifically interacting with human small GTPase Rab2.
de Barsy, Marie; Jamet, Alexandre; Filopon, Didier et al

in Cellular microbiology (2011), 13(7), 1044-58

Bacteria of the Brucella genus are facultative intracellular class III pathogens. These bacteria are able to control the intracellular trafficking of their vacuole, presumably by the use of yet unknown ... [more ▼]

Bacteria of the Brucella genus are facultative intracellular class III pathogens. These bacteria are able to control the intracellular trafficking of their vacuole, presumably by the use of yet unknown translocated effectors. To identify such effectors, we used a high-throughput yeast two-hybrid screen to identify interactions between putative human phagosomal proteins and predicted Brucella spp. proteins. We identified a specific interaction between the human small GTPase Rab2 and a Brucella spp. protein named RicA. This interaction was confirmed by GST-pull-down with the GDP-bound form of Rab2. A TEM-beta-lactamase-RicA fusion was translocated from Brucella abortus to RAW264.7 macrophages during infection. This translocation was not detectable in a strain deleted for the virB operon, coding for the type IV secretion system. However, RicA secretion in a bacteriological culture was still observed in a DeltavirB mutant. In HeLa cells, a DeltaricA mutant recruits less GTP-locked myc-Rab2 on its Brucella-containing vacuoles, compared with the wild-type strain. We observed altered kinetics of intracellular trafficking and faster proliferation of the B. abortusDeltaricA mutant in HeLa cells, compared with the wild-type control. Altogether, the data reported here suggest RicA as the first reported effector with a proposed function for B. abortus. [less ▲]

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See detailThe HTLV-1 Tax protein inhibits formation of stress granules by interacting with histone deacetylase 6.
Legros, S.; Boxus, Mathieu ULg; Gatot, J. S. et al

in Oncogene (2011)

Human T cell leukemia virus type-1 (HTLV-1) is the causative agent of a fatal adult T-cell leukemia. Through deregulation of multiple cellular signaling pathways the viral Tax protein has a pivotal role ... [more ▼]

Human T cell leukemia virus type-1 (HTLV-1) is the causative agent of a fatal adult T-cell leukemia. Through deregulation of multiple cellular signaling pathways the viral Tax protein has a pivotal role in T-cell transformation. In response to stressful stimuli, cells mount a cellular stress response to limit the damage that environmental forces inflict on DNA or proteins. During stress response, cells postpone the translation of most cellular mRNAs, which are gathered into cytoplasmic mRNA-silencing foci called stress granules (SGs) and allocate their available resources towards the production of dedicated stress-management proteins. Here we demonstrate that Tax controls the formation of SGs and interferes with the cellular stress response pathway. In agreement with previous reports, we observed that Tax relocates from the nucleus to the cytoplasm in response to environmental stress. We found that the presence of Tax in the cytoplasm of stressed cells prevents the formation of SGs and counteracts the shutoff of specific host proteins. Unexpectedly, nuclear localization of Tax promotes spontaneous aggregation of SGs, even in the absence of stress. Mutant analysis revealed that the SG inhibitory capacity of Tax is independent of its transcriptional abilities but relies on its interaction with histone deacetylase 6, a critical component of SGs. Importantly, the stress-protective effect of Tax was also observed in the context of HTLV-1 infected cells, which were shown to be less prone to form SGs and undergo apoptosis under arsenite exposure. These observations identify Tax as the first virally encoded inhibitory component of SGs and unravel a new strategy developed by HTLV-1 to deregulate normal cell processes. We postulate that inhibition of the stress response pathway by Tax would favor cell survival under stressful conditions and may have an important role in HTLV-1-induced cellular transformation.Oncogene advance online publication, 2 May 2011; doi:10.1038/onc.2011.120. [less ▲]

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See detailEstablishment of an interactomic map of the Ets factors family: Towards a better understanding of their roles in oncogenic processes
Rambout, Xavier ULg; Twizere, Jean-Claude ULg; Dequiedt, Franck ULg

in Inserm Workshop: Interactomics: at the crossroads of biology and bioinformatics (2010, March)

Ets transcription factors play key roles in several cancers such as leukemia, prostate cancer and Ewing’s sarcoma. They regulate the expression of genes controlling biological processes such as cellular ... [more ▼]

Ets transcription factors play key roles in several cancers such as leukemia, prostate cancer and Ewing’s sarcoma. They regulate the expression of genes controlling biological processes such as cellular proliferation, differentiation, apoptosis, metastasis, and transformation. This family is characterized by a highly conserved DNA-binding domain (ETS domain) and is classified into subfamilies according to sequence homology between the members. Using a high-throughput yeast two-hybrid (Y2H) method, we tested the interaction of the major splicing variants of the 28 human Ets factors and their functional domains of interest against the last available version of the human ORFeome (hORFeome v5.1). This screen has identified more than 200 new partners of Ets proteins. Further validation of these new interactions together with previously described interactions will enable a global evaluation of the regulation, and normal and cancerous roles of Ets factors. [less ▲]

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See detailNOD2 interactome
Lecat, Aurore ULg; Di Valentin, Emmanuel ULg; Fillet, Marianne ULg et al

Poster (2010, January 28)

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See detailProtein-protein interactions and gene expression regulation in HTLV-1 infected cells.
Legros, Sébastien ULg; Boxus, Mathieu ULg; Dewulf, Jean Francois et al

in Frontiers in Bioscience : A Journal and Virtual Library (2009), 14

Human T-cell leukemia virus type 1 (HTLV-1) propagates in CD4 or CD8 T cells and, after extended latency periods of 30-50 years, causes a rapidly fatal leukemia called adult T-cell leukemia/lymphoma (ATL ... [more ▼]

Human T-cell leukemia virus type 1 (HTLV-1) propagates in CD4 or CD8 T cells and, after extended latency periods of 30-50 years, causes a rapidly fatal leukemia called adult T-cell leukemia/lymphoma (ATL). Infection with HTLV-1 is also associated with a degenerative neuromuscular disease referred to as tropical spastic paraparesis or HTLV-1-associated myelopathy. HTLV genome, in addition to the structural proteins and retroviral enzymes, codes for a region at its 3' end originally designated pX. The products of this region (Tax, Rex, p12I, p13II, p30II and HBZ) play important roles in deregulation of cellular functions by either directly disrupting cellular factors or altering transcription of viral and cellular genes. Here, we will review current knowledge of protein-protein interactions that regulate transcriptional functions of proteins encoded by the pX region. [less ▲]

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See detailProtein Phosphatase 2a Controls The Activity Of Histone Deacetylase 7 During T Cell Apoptosis And Angiogenesis
Martin, Maud ULg; Potente, M.; Janssens, V. et al

in Proceedings of the National Academy of Sciences of the United States of America (2008), 105(12), 4727-4732

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See detailThe HTLV-1 Tax interactome.
Boxus, Mathieu ULg; Twizere, Jean-Claude ULg; Legros, Sebastien et al

in Retrovirology (2008), 5

The Tax1 oncoprotein encoded by Human T-lymphotropic virus type I is a major determinant of viral persistence and pathogenesis. Tax1 affects a wide variety of cellular signalling pathways leading to ... [more ▼]

The Tax1 oncoprotein encoded by Human T-lymphotropic virus type I is a major determinant of viral persistence and pathogenesis. Tax1 affects a wide variety of cellular signalling pathways leading to transcriptional activation, proliferation and ultimately transformation. To carry out these functions, Tax1 interacts with and modulates activity of a number of cellular proteins. In this review, we summarize the present knowledge of the Tax1 interactome and propose a rationale for the broad range of cellular proteins identified so far. [less ▲]

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See detailNucleolin binds specifically to an AP-1 DNA sequence and represses AP1-dependent transactivation of the matrix metalloproteinase-13 gene.
Samuel, Shaija; Twizere, Jean-Claude ULg; Beifuss, Katherine K et al

in Molecular Carcinogenesis (2008), 47(1), 34-46

Transcriptional regulation via activator protein-1 (AP-1) protein binding to AP-1 binding sites within gene promoter regions of AP-1 target genes plays a key role in controlling cellular invasion ... [more ▼]

Transcriptional regulation via activator protein-1 (AP-1) protein binding to AP-1 binding sites within gene promoter regions of AP-1 target genes plays a key role in controlling cellular invasion, proliferation, and oncogenesis, and is important to pathogenesis of arthritis and cardiovascular disease. To identify new proteins that interact with the AP-1 DNA binding site, we performed the DNA affinity chromatography-based Nucleotide Affinity Preincubation Specificity TEst of Recognition (NAPSTER) assay, and discovered a 97 kDa protein that binds in vitro to a minimal AP-1 DNA sequence element. Mass spectrometric fragmentation sequencing determined that p97 is nucleolin. Immunoblotting of DNA affinity-purified material with anti-nucleolin antibodies confirmed this identification. Nucleolin also binds the AP-1 site in gel shift assays. Nucleolin interacts in NAPSTER with the AP-1 site within the promoter sequence of the metalloproteinase-13 gene (MMP-13), and binds in vivo in chromatin immunoprecipitation assays in the vicinity of the AP-1 site in the MMP-13 promoter. Overexpression of nucleolin in human HeLa cervical carcinoma cells significantly represses AP-1 dependent gene transactivation of a minimal AP-1 reporter construct and of an MMP-13 promoter reporter sequence. This is the first report of nucleolin binding and transregulation at the AP-1 site. [less ▲]

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See detailCell dynamics and immune response to BLV infection: a unifying model
Florins, Arnaud-Francois ULg; Gillet, Nicolas ULg; Asquith, Becca et al

in Frontiers in Bioscience : A Journal and Virtual Library (2007), 12

Bovine Leukemia virus (BLV) is the natural etiological agent of a lymphoproliferative disease in cattle. BLV can also be transmitted experimentally to a related ruminant species, sheep, in which the ... [more ▼]

Bovine Leukemia virus (BLV) is the natural etiological agent of a lymphoproliferative disease in cattle. BLV can also be transmitted experimentally to a related ruminant species, sheep, in which the pathogenesis is more acute. Although both susceptible species develop a strong anti-viral immune response, the virus persists indefinitely throughout life, apparently at a transcriptionally silent stage, at least in a proportion of infected cells. Soon after infection, these humoral and cytotoxic activities very efficiently abolish the viral replicative cycle, permitting only mitotic expansion of provirus-carrying cells. Short term cultures of these infected cells initially indicated that viral expression protects against spontaneous apoptosis, suggesting that leukemia is a process of accumulation of long-lived cells. This conclusion was recently reconsidered following in vivo dynamic studies based on perfusions of nucleoside (bromodeoxyuridine) or fluorescent protein markers (CFSE). In sheep, the turnover rate of infected cells is increased, suggesting that a permanent clearance process is exerted by the immune system. Lymphocyte trafficking from and to the secondary lymphoid organs is a key component in the maintenance of cell homeostasis. The net outcome of the immune selective pressure is that only cells in which the virus is transcriptionally silenced survive and accumulate, ultimately leading to lymphocytosis. Activation of viral and/or cellular expression in this silent reservoir with deacetylase inhibitors causes the collapse of the proviral loads. In other words, modulation of viral expression appears to be curative in lymphocytic sheep, an approach that might also be efficient in patients infected with the related Human T-lymphotropic virus type 1. In summary, a dynamic interplay between BLV and the host immune response modulates a complex equilibrium between (i) viral expression driving (or) favoring proliferation and (ii) viral silencing preventing apoptosis. As conclusion, we propose a hypothetical model unifying all these mechanisms. [less ▲]

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See detailHuman T-cell leukemia virus type-1 Tax oncoprotein regulates G-protein signaling.
Twizere, Jean-Claude ULg; Springael, Jean-Yves; Boxus, Mathieu ULg et al

in Blood (2007), 109(3), 1051-60

Human T-cell leukemia virus type-1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and neurological syndromes. HTLV-1 encodes the oncoprotein Tax-1, which modulates viral and cellular gene ... [more ▼]

Human T-cell leukemia virus type-1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and neurological syndromes. HTLV-1 encodes the oncoprotein Tax-1, which modulates viral and cellular gene expression leading to T-cell transformation. Guanine nucleotide-binding proteins (G proteins) and G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins known and are involved in the regulation of most biological functions. Here, we report an interaction between HTLV-1 Tax oncoprotein and the G-protein beta subunit. Interestingly, though the G-protein beta subunit inhibits Tax-mediated viral transcription, Tax-1 perturbs G-protein beta subcellular localization. Functional evidence for these observations was obtained using conditional Tax-1-expressing transformed T-lymphocytes, where Tax expression correlated with activation of the SDF-1/CXCR4 axis. Our data indicated that HTLV-1 developed a strategy based on the activation of the SDF-1/CXCR4 axis in the infected cell; this could have tremendous implications for new therapeutic strategies. [less ▲]

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See detailNew Role For Hpar-1 Kinases Emk And C-Tak1 In Regulating Localization And Activity Of Class Iia Histone Deacetylases
Dequiedt, Franck ULg; Martin, Maud ULg; Von Blume, Julia et al

in Molecular and Cellular Biology (2006), 26(19), 7086-102

Class IIa histone deacetylases (HDACs) are found both in the cytoplasm and in the nucleus where they repress genes involved in several major developmental programs. In response to specific signals, the ... [more ▼]

Class IIa histone deacetylases (HDACs) are found both in the cytoplasm and in the nucleus where they repress genes involved in several major developmental programs. In response to specific signals, the repressive activity of class IIa HDACs is neutralized through their phosphorylation on multiple N-terminal serine residues and 14-3-3-mediated nuclear exclusion. Here, we demonstrate that class IIa HDACs are subjected to signal-independent nuclear export that relies on their constitutive phosphorylation. We identify EMK and C-TAK1, two members of the microtubule affinity-regulating kinase (MARK)/Par-1 family, as regulators of this process. We further show that EMK and C-TAK1 phosphorylate class IIa HDACs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function. Using HDAC7 as a paradigm, we extend these findings by demonstrating that signal-independent phosphorylation of the most N-terminal serine residue by the MARK/Par-1 kinases, i.e., Ser155, is a prerequisite for the phosphorylation of the nearby 14-3-3 site, Ser181. We propose that this multisite hierarchical phosphorylation by a variety of kinases allows for sophisticated regulation of class IIa HDACs function. [less ▲]

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See detailThe homeobox protein MSX2 interacts with tax oncoproteins and represses their transactivation activity.
Twizere, Jean-Claude ULg; Lefebvre, Laurent; Collete, Delphine et al

in Journal of Biological Chemistry (2005), 280(33), 29804-11

Bovine leukemia virus (BLV) tax is an essential gene involved in the transcriptional activation of viral expression. Tax is also believed to be implicated in leukemogenesis because of its ability to ... [more ▼]

Bovine leukemia virus (BLV) tax is an essential gene involved in the transcriptional activation of viral expression. Tax is also believed to be implicated in leukemogenesis because of its ability to immortalize primary cells in vitro. To gain insight into the molecular pathways mediating the activities of this important gene, we identified cellular proteins interacting with Tax. By means of a two-hybrid approach, we show that Tax specifically interacts with MSX2, a general repressor of gene expression. GST pull-down experiments and co-immunoprecipitation assays further confirmed binding specificity. Furthermore, the N-terminal residues 1-79 of MSX2 are required for binding, whereas the C-terminal residues 201-267 of MSX2 do not play a critical role. Whereas the oncogenic potential of Tax in primary cells was only slightly affected by overexpression of MSX2, the other function of Tax, namely LTR-dependent transcriptional activation, was inhibited by MSX2 in human HeLa and bovine B-lymphoblastoid (BL3) cell lines. This MSX2 repression function can be counteracted by overexpression of transcription factors CREB2 and RAP74. The Tax/MSX2 interplay thus results in repression of viral transcriptional activation possibly acting as a regulatory feedback loop. Importantly, this viral gene silencing is not strictly associated with a concomitant loss of Tax oncogenicity as measured by its ability to immortalize primary cells. And interestingly, MSX2 also interacts with and inhibits the transactivation function of the related Tax1 protein encoded by the Human T-cell leukemia virus type 1 (HTLV-1). [less ▲]

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See detailYB-1 represses AP1-dependent gene transactivation and interacts with an AP-1 DNA sequence.
Samuel, Shaija; Twizere, Jean-Claude ULg; Bernstein, Lori R

in Biochemical Journal (2005), 388(Pt 3), 921-8

Involvement of the AP-1 (activator protein-1) transcription factor has been demonstrated previously in the regulation of cell proliferation and cell-cycle progression, in the control of cell migration ... [more ▼]

Involvement of the AP-1 (activator protein-1) transcription factor has been demonstrated previously in the regulation of cell proliferation and cell-cycle progression, in the control of cell migration, invasion and metastasis, and in signal transduction, stress responsiveness, DNA replication and DNA repair. YB-1 (Y-box-binding protein-1) has also been implicated in many of these processes. However, the mechanism by which YB-1 mediates these processes is poorly understood. In the present study, we report that overexpression of a transfected gene encoding YB-1 in human HeLa cervical carcinoma cells significantly represses the transactivation of a minimal AP-1 reporter construct in response to the tumour promoter PMA. YB-1 also represses mRNA expression and PMA-induced promoter transactivation of the endogenous AP-1 target gene encoding matrix metalloproteinase-12 (metalloelastase). YB-1 transrepression of both the minimal and matrix metalloproteinase-12 promoter reporter constructs is dependent on the AP-1 sequence. To identify new nuclear proteins that bind specifically to the AP-1 DNA-binding site, we devised a DNA-affinity-chromatography-based assay termed NAPSTER (nucleotide-affinity preincubation specificity test of recognition) and discovered a 49 kDa protein from human cancer cells that binds in a sequence-specific manner to the AP-1 DNA sequence. By tandem MS fragmentation sequencing analyses we determined that p49 is a YB-1. Immunoblotting of the NAPSTER-purified p49 protein using anti-YB-1 antibodies confirmed YB-1 binding to the AP-1 DNA sequence, as did gel mobility-supershift assays using YB-1 antibodies. This is the first report of YB-1 transrepression and interaction at the AP-1 DNA-binding site. [less ▲]

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See detailInteraction of retroviral Tax oncoproteins with tristetraprolin and regulation of tumor necrosis factor-alpha expression.
Twizere, Jean-Claude ULg; Kruys, Veronique; Lefebvre, Laurent et al

in Journal of the National Cancer Institute (2003), 95(24), 1846-59

BACKGROUND: The Tax oncoproteins are transcriptional regulators of viral expression involved in pathogenesis induced by complex leukemogenic retroviruses (or delta-retroviruses, i.e., primate T-cell ... [more ▼]

BACKGROUND: The Tax oncoproteins are transcriptional regulators of viral expression involved in pathogenesis induced by complex leukemogenic retroviruses (or delta-retroviruses, i.e., primate T-cell leukemia viruses and bovine leukemia virus). To better understand the molecular pathways leading to cell transformation, we aimed to identify cellular proteins interacting with Tax. METHODS: We used a yeast two-hybrid system to identify interacting cellular proteins. Interactions between Tax and candidate interacting cellular proteins were confirmed by glutathione S-transferase (GST) pulldown assays, co-immunoprecipitation, and confocal microscopy. Functional interactions between Tax and one interacting protein, tristetraprolin (TTP), were assessed by analyzing the expression of tumor necrosis factor-alpha (TNF-alpha), which is regulated by TTP, in mammalian cells (HeLa, D17, HEK 293, and RAW 264.7) transiently transfected with combinations of intact and mutant Tax and TTP. RESULTS: We obtained seven interacting cellular proteins, of which one, TTP, was further characterized. Tax and TTP were found to interact specifically through their respective carboxyl-terminal domains. The proteins colocalized in the cytoplasm in a region surrounding the nucleus of HeLa cells. Furthermore, coexpression of Tax was associated with nuclear accumulation of TTP. TTP is an immediate-early protein that inhibits expression of TNF-alpha at the post-transcriptional level. Expression of Tax reverted this inhibition, both in transient transfection experiments and in stably transfected macrophage cell lines. CONCLUSION: Tax, through its interactions with the TTP repressor, indirectly increases TNF-alpha expression. This observation is of importance for the cell transformation process induced by leukemogenic retroviruses, because TNF-alpha overexpression plays a central role in pathogenesis. [less ▲]

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