References of "Close, Pierre"
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See detailWobble uridine tRNA modification: a new vulnerability of refractory melanoma
Rapino, Francesca ULiege; Close, Pierre ULiege

in Molecular and Cellular Oncology (2018)

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See detailCodon-specific translation reprogramming promotes resistance to targeted therapy
Rapino, Francesca ULiege; Delaunay, Sylvain ULiege; Rambow, Florian et al

in Nature (2018), 558

Reprogramming of mRNA translation has a key role in cancer development and drug resistance. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA ... [more ▼]

Reprogramming of mRNA translation has a key role in cancer development and drug resistance. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U34) tRNA (U34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAFV600E oncogene and by resistance to targeted therapy in melanoma. We show that BRAFV600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1α. Together, these results demonstrate that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation. [less ▲]

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See detailThe endosomal protein CEMIP links Wnt signaling to MEK1-ERK1/2 activation in Selumetinib-resistant intestinal organoids
Duong, Hong-Quan; Nemazanyy, Ivan; Rambow, Florian et al

in Cancer Research (2018)

MAPK signaling pathways are constitutively active in colon cancer and also promote acquired resistance to MEK1 inhibition. Here we demonstrate that BRAFV600E-mutated colorectal cancers acquire resistance ... [more ▼]

MAPK signaling pathways are constitutively active in colon cancer and also promote acquired resistance to MEK1 inhibition. Here we demonstrate that BRAFV600E-mutated colorectal cancers acquire resistance to MEK1 inhibition by inducing expression of the scaffold protein CEMIP through a beta-catenin- and FRA-1-dependent pathway. CEMIP was found in endosomes and bound MEK1 to sustain ERK1/2 activation in MEK1 inhibitor-resistant BRAFV600E-mutated colorectal cancers. The CEMIP-dependent pathway maintained c-Myc protein levels through ERK1/2 and provided metabolic advantage in resistant cells, potentially by sustaining amino acids synthesis. CEMIP silencing circumvented resistance to MEK1 inhibition, partly, through a decrease of both ERK1/2 signaling and c-Myc. Together, our data identify a cross-talk between Wnt and MAPK signaling cascades, which involves CEMIP. Activation of this pathway promotes survival by potentially regulating levels of specific amino acids via a Myc-associated cascade. Targeting this node may provide a promising avenue for treatment of colon cancers that have acquired resistance to targeted therapies [less ▲]

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See detailLoss of transfer RNA U34 modifying enzymes impairs hematopoietic stem and progenitor cell differentiation and function
Rosu, Adeline ULiege; Bai, Qiang ULiege; Ramery, Eve ULiege et al

Poster (2017, February 03)

Hematopoietic stem and progenitor cells (HSPCs) require fine-tuned protein translation for their normal maintenance and function. Conserved modifications of the wobble uridine base (U34) in transfer RNAs ... [more ▼]

Hematopoietic stem and progenitor cells (HSPCs) require fine-tuned protein translation for their normal maintenance and function. Conserved modifications of the wobble uridine base (U34) in transfer RNAs catalyzed by the Elongator complex are required for optimal protein translation efficacy and fidelity, but their biological importance in mammalian stem and progenitor cells remains largely unexplored. Here, we studied the impact of loss of activity of the catalytic subunit Elp3 of Elongator on HSPC differentiation and function. Hematopoietic-cell-specific depletion of Elp3 in conditional knockout mice resulted in shortened lifespan associated with hematopoietic failure and lymphoma development. Elp3 deletion caused apoptosis of specific bone marrow multipotent progenitors and blocked differentiation of committed progenitors, resulting in blood and bone marrow pancytopenia. In contrast, Elp3-deficient hematopoietic stem cells (HSCs) expanded with age and did not exhaust throughout life, although they were defective in reconstituting hematopoiesis in competitive transplantation assays. Mechanistically, loss of Elp3 did not result in detectable alterations in global protein synthesis rates in any HSPC subset. Rather, Elp3-deficient HSPCs displayed enhanced activity of the stress integrator and apoptosis and cell cycle regulator p53. Thus, this study supports the notion that Elongator activity is required in distinct HSPC subsets to avoid aberrant p53 activation, which otherwise results in discrete loss of function phenotypes in HSCs and downstream progenitors. [less ▲]

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See detailLoss of Elp3 Impairs the Acetylation and Distribution of Connexin-43 in the Developing Cerebral Cortex.
Laguesse, Sophie ULiege; Close, Pierre ULiege; Van Hees, Laura ULiege et al

in Frontiers in Cellular Neuroscience (2017), 11

The Elongator complex is required for proper development of the cerebral cortex. Interfering with its activity in vivo delays the migration of postmitotic projection neurons, at least through a defective ... [more ▼]

The Elongator complex is required for proper development of the cerebral cortex. Interfering with its activity in vivo delays the migration of postmitotic projection neurons, at least through a defective alpha-tubulin acetylation. However, this complex is already expressed by cortical progenitors where it may regulate the early steps of migration by targeting additional proteins. Here we report that connexin-43 (Cx43), which is strongly expressed by cortical progenitors and whose depletion impairs projection neuron migration, requires Elongator expression for its proper acetylation. Indeed, we show that Cx43 acetylation is reduced in the cortex of Elp3cKO embryos, as well as in a neuroblastoma cell line depleted of Elp1 expression, suggesting that Cx43 acetylation requires Elongator in different cellular contexts. Moreover, we show that histones deacetylase 6 (HDAC6) is a deacetylase of Cx43. Finally, we report that acetylation of Cx43 regulates its membrane distribution in apical progenitors of the cerebral cortex. [less ▲]

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See detailtRNA modification: is cancer having a wobble?
Rapino, Francesca ULiege; Zhou, Zhaoli ULiege; Delaunay, Sylvain et al

in Trends in Cancer (2017), 3

Translational control of protein synthesis supports tumor development and progression to metastasis. Wobble tRNA modifications are required during translation elongation and sustain proteome homeostasis ... [more ▼]

Translational control of protein synthesis supports tumor development and progression to metastasis. Wobble tRNA modifications are required during translation elongation and sustain proteome homeostasis. Recent work has highlighted the surprising upregulation of the wobble uridine 34 (U34) tRNA cascade in cancer, which underlies the specific requirement for this pathway in tumor development. [less ▲]

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See detailELP3 links tRNA modification to IRES-dependent translation of LEF-1 to promote metastasis in breast cancer
Delaunay, Sylvain ULiege; Rapino, Francesca ULiege; Tharun, Lars et al

in Journal of Experimental Medicine (2016), 213

Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Post-transcriptional nucleoside modifications of transfer RNAs (tRNAs) at the ... [more ▼]

Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Post-transcriptional nucleoside modifications of transfer RNAs (tRNAs) at the wobble U34 base are highly conserved and contribute to translation fidelity. Here, we show that ELP3 and CTU1/2, partner enzymes in U34 mcm5s2-tRNA modification, are upregulated in human breast cancers and sustain metastasis. Elp3 genetic ablation strongly impaired invasion and metastasis formation in the PyMT model of invasive breast cancer. Mechanistically, ELP3 and CTU1/2 support cellular invasion through the translation of the oncoprotein DEK. As a result, DEK promotes the IRES-dependent translation of the pro-invasive transcription factor LEF1. Consistently, a DEK mutant, whose codon composition is independent of U34 mcm5s2-tRNA modification, escapes the ELP3- and CTU1-dependent regulation and restores the IRES-dependent LEF1 expression. Our results demonstrate the key role of U34 tRNA modification to support specific translation during breast cancer progression and highlight a functional link between tRNA modification- and IRES-dependent translation during tumor cell invasion and metastasis. [less ▲]

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See detailtRNA modification: Elogator sustains Breast cancer metastasis
Delaunay, Sylvain ULiege; Rapino, Francesca ULiege; Tharun, Lars et al

Conference (2016, May)

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See detailtRNA modification: Elogator promotes breast metastasis in breast cancer
Delaunay, Sylvain ULiege; Rapino, Francesca ULiege; Zhou, Zhaoli ULiege et al

Conference (2016, January 25)

Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Post-transcriptional nucleoside modifications of transfer RNAs (tRNAs) at the ... [more ▼]

Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Post-transcriptional nucleoside modifications of transfer RNAs (tRNAs) at the wobble U34 base are highly conserved and contribute to translation fidelity. Here, we show that ELP3 and CTU1/2, partner enzymes in U34 mcm5s2-tRNA modification, are upregulated in human breast cancers and sustain metastasis. Elp3 genetic ablation strongly impaired invasion and metastasis formation in the PyMT model of invasive breast cancer. Mechanistically, ELP3 and CTU1/2 support cellular invasion through the translation of the oncoprotein DEK. As a result, DEK promotes the IRES-dependent translation of the pro-invasive transcription factor LEF1. Consistently, a DEK mutant, whose codon composition is independent of U34 mcm5s2-tRNA modification, escapes the ELP3- and CTU1- dependent regulation and restores the IRES-dependent LEF1 expression. Our results demonstrate the key role of U34 tRNA modification to support specific translation during breast cancer progression and highlight a functional link between tRNA modification- and IRES-dependent translation during tumor cell invasion and metastasis. [less ▲]

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See detailElp3 drives Wnt-dependent tumor initiation and regeneration in the intestine
LADANG, Aurélie ULiege; Rapino, Francesca ULiege; Heukamp, Lukas et al

in Journal of Experimental Medicine (2015), 212(12), 2057-75

Tumor initiation in the intestine can rapidly occur from Lgr5(+) crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer ... [more ▼]

Tumor initiation in the intestine can rapidly occur from Lgr5(+) crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required for Wnt-driven intestinal tumor initiation and radiation-induced regeneration by maintaining a subpool of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Elp3 deficiency dramatically delayed tumor appearance in Apc-mutated intestinal epithelia and greatly prolonged mice survival without affecting the normal epithelium. Specific ablation of Elp3 in Lgr5(+) cells resulted in marked reduction of polyp formation upon Apc inactivation, in part due to a decreased number of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Mechanistically, Elp3 is induced by Wnt signaling and promotes Sox9 translation, which is needed to maintain the subpool of Lgr5(+)/Dclk1(+) cancer stem cells. Consequently, Elp3 or Sox9 depletion led to similar defects in Dclk1(+) cancer stem cells in ex vivo organoids. Finally, Elp3 deficiency strongly impaired radiation-induced intestinal regeneration, in part because of decreased Sox9 protein levels. Together, our data demonstrate the crucial role of Elp3 in maintaining a subpopulation of Lgr5-derived and Sox9-expressing cells needed to trigger Wnt-driven tumor initiation in the intestine. [less ▲]

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See detailElongator: mcm5s2 modification fosters breast cancer metastasis
Delaunay, Sylvain ULiege; Rapino, Francesca ULiege; Zhou, Zhaoli ULiege et al

Scientific conference (2015, March 09)

Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Post-transcriptional nucleoside modifications of transfer RNAs (tRNAs) at the ... [more ▼]

Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Post-transcriptional nucleoside modifications of transfer RNAs (tRNAs) at the wobble U34 base are highly conserved and contribute to translation fidelity. Here, we show that ELP3 and CTU1/2, partner enzymes in U34 mcm5s2-tRNA modification, are upregulated in human breast cancers and sustain metastasis. Elp3 genetic ablation strongly impaired invasion and metastasis formation in the PyMT model of invasive breast cancer. Mechanistically, ELP3 and CTU1/2 support cellular invasion through the translation of the oncoprotein DEK. As a result, DEK promotes the IRES-dependent translation of the pro-invasive transcription factor LEF1. Consistently, a DEK mutant, whose codon composition is independent of U34 mcm5s2-tRNA modification, escapes the ELP3- and CTU1- dependent regulation and restores the IRES-dependent LEF1 expression. Our results demonstrate the key role of U34 tRNA modification to support specific translation during breast cancer progression and highlight a functional link between tRNA modification- and IRES-dependent translation during tumor cell invasion and metastasis. [less ▲]

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See detailElongator promotes breast cancer metastasis
Delaunay, Sylvain ULiege; Rapino, Francesca ULiege; Heukamp, Lukas et al

Poster (2015, March)

Elongator is a protein complex (Elp1-6) involved in diverse cellular processes, such as protein acetylation and tRNA modification and whose function is essential for cell migration and neuronal ... [more ▼]

Elongator is a protein complex (Elp1-6) involved in diverse cellular processes, such as protein acetylation and tRNA modification and whose function is essential for cell migration and neuronal differentiation. Although it is well established that tumor development involves modifications of acetylation-deacetylation dynamics, as well as changes in protein translation, the role of Elongator in tumor initiation and invasion remains to be investigated in vivo. We generated a mouse model in which the Elp3 gene, encoding the catalytic subunit of the complex, is conditionally inactivated in the mammary gland epithelium by using the MMTV-CRE transgenic mouse. The role of Elp3 in tumor development and metastasis formation is then assessed in the PyMT model of invasive breast cancer. [less ▲]

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See detailA dynamic unfolded protein response contributes to the control of cortical neurogenesis
Laguesse, Sophie ULiege; Creppe, Catherine ULiege; Nedialkova, Dany et al

in Developmental Cell (2015), 35

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See detailA role for APPL1 in tlr3/4-dependent TBK1 and IKKε activation in macrophages
Chau, Tieu-Lan ULiege; Göktuna, Serkan ULiege; Rammal, Ayman et al

in Journal of Immunology (2015)

Endosomes have important roles in intracellular signal transduction as a sorting platform. Signaling cascades from TLR engagement to IRF3-dependent gene transcription rely on endosomes, yet the proteins ... [more ▼]

Endosomes have important roles in intracellular signal transduction as a sorting platform. Signaling cascades from TLR engagement to IRF3-dependent gene transcription rely on endosomes, yet the proteins that specifically recruit IRF3-activating molécules to them are poorly defined. We show that adaptor protein containing a pleckstrin-homology domain, a phosphotyrosine-binding domain, and a leucine zipper motif (APPL)1, an early endosomal protein, is required for both TRIF- and retinoic acid–inducible gene 1–dependent signaling cascades to induce IRF3 activation. APPL1, but not early endosome Ag 1, deficiency impairs IRF3 target gene expression upon engagement of both TLR3 and TLR4 pathways, as well as in H1N1-infected macrophages. The IRF3-phosphorylating kinases TBK1 and IKK« are recruited to APPL1 endosomes in LPS-stimulated macrophages. Interestingly, APPL1 undergoes proteasome-mediated degradation through ERK1/2 to turn off signaling. APPL1 degradation is blocked when signaling through the endosome is inhibited by chloroquine or dynasore. Therefore, APPL1 endosomes are critical for IRF3-dependent gene expression in response to some viral and bacterial infections in macrophages. Those signaling pathways involve the signal-induced degradation of APPL1 to prevent aberrant IRF3-dependent gene expression linked to immune diseases. [less ▲]

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See detailA dynamic Unfolded Protein Response controls cortical neurogenesis
Creppe, Catherine ULiege; Laguesse, Sophie; Nedialkova, Dany et al

Poster (2015)

Detailed reference viewed: 21 (4 ULiège)
See detailA dynamic Unfolded Protein Response controls cortical neurogenesis
Creppe, Catherine ULiege; Laguesse, sophie; Nedialkova, Dany et al

Poster (2015)

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See detailMicroRNA Targeting of CoREST controls polarization of migrating cortical neurons
Volvert; Prévot, Pierre-Paul; Close, Pierre ULiege et al

in Cell Reports (2014), 7(4), 1168-83

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See detailMDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation.
Shostak, Kateryna ULiege; Patrascu, F.; Göktuna, Serkan ULiege et al

in Cell Death and Differentiation (2014), 5(21), 811-24

Restoration of p53 tumor suppressor function through inhibition of its interaction and/or enzymatic activity of its E3 ligase, MDM2, is a promising therapeutic approach to treat cancer. However, because ... [more ▼]

Restoration of p53 tumor suppressor function through inhibition of its interaction and/or enzymatic activity of its E3 ligase, MDM2, is a promising therapeutic approach to treat cancer. However, because the MDM2 targetome extends beyond p53, MDM2 inhibition may also cause unwanted activation of oncogenic pathways. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. Importantly, decreasing Mdm2 gene dosage in mouse mammary epithelial cells potentiates estrogen-dependent AKT activation owing to HPIP stabilization. In addition, we identified HPIP as a novel p53 transcriptional target, and pharmacological inhibition of MDM2 causes p53-dependent increase in HPIP transcription and also prevents HPIP degradation by turning off TBK1 activity. Our data indicate that p53 reactivation through MDM2 inhibition may result in ectopic AKT oncogenic activity by maintaining HPIP protein levels.Cell Death and Differentiation advance online publication, 31 January 2014; doi:10.1038/cdd.2014.2. [less ▲]

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See detailNF-kappaB-induced KIAA1199 promotes survival through EGFR signalling.
Shostak, Kateryna ULiege; Zhang, Xin; Hubert, Pascale ULiege et al

in Nature Communications (2014), 5

Constitutive activation of EGFR- and NF-kappaB-dependent pathways is a hallmark of cancer, yet signalling proteins that connect both oncogenic cascades are poorly characterized. Here we define KIAA1199 as ... [more ▼]

Constitutive activation of EGFR- and NF-kappaB-dependent pathways is a hallmark of cancer, yet signalling proteins that connect both oncogenic cascades are poorly characterized. Here we define KIAA1199 as a BCL-3- and p65-dependent gene in transformed keratinocytes. KIAA1199 expression is enhanced on human papillomavirus (HPV) infection and is aberrantly expressed in clinical cases of cervical (pre)neoplastic lesions. Mechanistically, KIAA1199 binds Plexin A2 and protects from Semaphorin 3A-mediated cell death by promoting EGFR stability and signalling. Moreover, KIAA1199 is an EGFR-binding protein and KIAA1199 deficiency impairs EGF-dependent Src, MEK1 and ERK1/2 phosphorylations. Therefore, EGFR stability and signalling to downstream kinases requires KIAA1199. As such, KIAA1199 promotes EGF-mediated epithelial-mesenchymal transition (EMT). Taken together, our data define KIAA1199 as an oncogenic protein induced by HPV infection and constitutive NF-kappaB activity that transmits pro-survival and invasive signals through EGFR signalling. [less ▲]

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See detailElp3 is required for initiation of colon cancer
Ladang, Aurélie ULiege; Heukamp, L; Buettner, R et al

Poster (2013, September 18)

Detailed reference viewed: 31 (10 ULiège)