References of "Chariot, Alain"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailMolecular Mechanisms Involved in Schwann Cell Plasticity
Boerboom, Angélique ULg; Dion, Valérie ULg; CHARIOT, Alain ULg et al

in Frontiers in Molecular Neuroscience (2017)

Detailed reference viewed: 24 (6 ULg)
Full Text
Peer Reviewed
See detailLoss of Elp3 Impairs the Acetylation and Distribution of Connexin-43 in the Developing Cerebral Cortex.
Laguesse, Sophie; Close, Pierre ULg; Van Hees, Laura ULg 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 ▲]

Detailed reference viewed: 9 (1 ULg)
Full Text
Peer Reviewed
See detailtRNA modification: is cancer having a wobble?
Rapino, Francesca ULg; Zhou, Zhaoli ULg; 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 ▲]

Detailed reference viewed: 13 (0 ULg)
Full Text
Peer Reviewed
See detailELP3 links tRNA modification to IRES-dependent translation of LEF-1 to promote metastasis in breast cancer
Delaunay, Sylvain ULg; Rapino, Francesca ULg; Tharun, Lars et al

in The 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 ▲]

Detailed reference viewed: 41 (12 ULg)
See detailtRNA modification: Elogator sustains Breast cancer metastasis
Delaunay, Sylvain ULg; Rapino, Francesca ULg; Tharun, Lars et al

Conference (2016, May)

Detailed reference viewed: 43 (6 ULg)
Peer Reviewed
See detailtRNA modification: Elogator promotes breast metastasis in breast cancer
Delaunay, Sylvain ULg; Rapino, Francesca ULg; Zhou, Zhaoli ULg 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 ▲]

Detailed reference viewed: 51 (8 ULg)
Full Text
See detailUnravelling the roles of lysine acetylation by Elp3 during inner ear development
Mateo Sanchez, Susana ULg; Delacroix, Laurence ULg; Freeman, Stephen ULg et al

Poster (2016, January 25)

We planned to investigate the role of Elp3 acetyl-transferase, a member of the Elongator complex, in inner ear formation. We first analysed the spatio-temporal pattern of Elp3 mRNA expression and showed ... [more ▼]

We planned to investigate the role of Elp3 acetyl-transferase, a member of the Elongator complex, in inner ear formation. We first analysed the spatio-temporal pattern of Elp3 mRNA expression and showed that it was expressed in the entire early otocyst at E11.5 and persisted later in the sensory epithelium of the cochlea, in the spiral ganglion and in the vestibule. To unravel functions of Elp3, we used conditional knock-out mice in which Elp3 gene is deleted from early otocyst (Elp3cKO). We submitted these mice to a battery of vestibular testing and found significant abnormalities. Besides, the auditory brain stem response of Elp3cKO indicated that these mice are severely deaf. We were also able to demonstrate an increased level of apoptosis in the Elp3cKO spiral ganglion leading to a reduced number of neurons and fibers innervating the sensory cells as well as a reduced number of their synaptic ribbons. Moreover, the remaining spiral ganglion neurons extend processes showing clearly defects regarding sensory cell innervation. In conclusion, our results clearly show a role for Elp3 both in hearing and balance. We plan to go deeper in the mechanisms involved through the identification of the proteins that are targeted for acetylation by Elp3. [less ▲]

Detailed reference viewed: 78 (8 ULg)
Full Text
Peer Reviewed
See detailThe Prosurvival IKK-Related Kinase IKK« Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine
Göktuna, SI.; Shostak, Kateryna ULg; Chau, TL. et al

in Cancer Research (2016), 76

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to ... [more ▼]

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikke in Wnt-driven tumor development. We found that Ikke was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikke in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikke to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikke was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikke-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikke phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikke to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. [less ▲]

Detailed reference viewed: 8 (1 ULg)
Full Text
Peer Reviewed
See detailElongator controls cortical interneuron migration by regulating actomyosin dynamics.
Tielens, Sylvia ULg; Huysseune, Sandra; Godin, Juliette D. et al

in Cell Research (2016)

The migration of cortical interneurons is a fundamental process for the establishment of cortical connectivity and its impairment underlies several neurological disorders. During development, these ... [more ▼]

The migration of cortical interneurons is a fundamental process for the establishment of cortical connectivity and its impairment underlies several neurological disorders. During development, these neurons are born in the ganglionic eminences and they migrate tangentially to populate the cortical layers. This process relies on various morphological changes that are driven by dynamic cytoskeleton remodelings. By coupling time lapse imaging with molecular analyses, we show that the Elongator complex controls cortical interneuron migration in mouse embryos by regulating nucleokinesis and branching dynamics. At the molecular level, Elongator fine-tunes actomyosin forces by regulating the distribution and turnover of actin microfilaments during cell migration. Thus, we demonstrate that Elongator cell-autonomously promotes cortical interneuron migration by controlling actin cytoskeletal dynamics.Cell Research advance online publication 27 September 2016; doi:10.1038/cr.2016.112. [less ▲]

Detailed reference viewed: 25 (17 ULg)
Full Text
See detailUNRAVELLING THE ROLES OF LYSINE ACETYLATION BY ELP3 DURING INNER EAR DEVELOPMENT
Mateo Sanchez, Susana ULg; Delacroix, Laurence ULg; Freeman, Stephen ULg et al

Poster (2015, November 23)

We planned to investigate the role of Elp3 acetyl-transferase, a member of the Elongator complex, in inner ear formation. We first analysed the spatio-temporal pattern of Elp3 mRNA expression and showed ... [more ▼]

We planned to investigate the role of Elp3 acetyl-transferase, a member of the Elongator complex, in inner ear formation. We first analysed the spatio-temporal pattern of Elp3 mRNA expression and showed that it was expressed in the entire early otocyst at E11.5 and persisted later in the sensory epithelium of the cochlea, in the spiral ganglion and in the vestibule. To unravel functions of Elp3, we used conditional knock-out mice in which Elp3 gene is deleted from early otocyst (Elp3cKO). We submitted these mice to a battery of vestibular testing and found significant abnormalities. Besides, the auditory brain stem response of Elp3cKO indicated that these mice are severely deaf. We were also able to demonstrate an increased level of apoptosis in the Elp3cKO spiral ganglion leading to a reduced number of neurons and fibers innervating the sensory cells as well as a reduced number of their synaptic ribbons. Moreover, the remaining spiral ganglion neurons extend processes showing clearly defects regarding sensory cell innervation. In conclusion, our results clearly show a role for Elp3 both in hearing and balance. We plan to go deeper in the mechanisms involved through the identification of the proteins that are targeted for acetylation by Elp3. [less ▲]

Detailed reference viewed: 58 (5 ULg)
Full Text
Peer Reviewed
See detailElp3 drives Wnt-dependent tumor initiation and regeneration in the intestine
LADANG, Aurélie ULg; Rapino, Francesca ULg; 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 ▲]

Detailed reference viewed: 118 (37 ULg)
Full Text
See detailUNRAVELLING THE ROLES OF LYSINE ACETYLATION BY ELP3 DURING INNER EAR DEVELOPMENT
Mateo Sanchez, Susana ULg; Delacroix, Laurence ULg; Freeman, Stephen ULg et al

Poster (2015, June 06)

Given the importance of acetylation homeostasis in controlling developmental processes [1-3], we planned to investigate its role in inner ear formation and focused our attention on Elp3 acetyl-transferase ... [more ▼]

Given the importance of acetylation homeostasis in controlling developmental processes [1-3], we planned to investigate its role in inner ear formation and focused our attention on Elp3 acetyl-transferase, a member of the Elongator complex recently implicated in neurogenesis [4]. To determine the role of Elp3 in the inner ear, we first analysed the spatio-temporal pattern of ELp3 mRNA expression and showed that it was expressed in the entire early otocyst at E11.5 and persisted later in the sensory epithelium of the cochlea (the organ of Corti), in the spiral ganglion, in the stria vascularis and in the vestibule. To unravel in vivo functions of Elp3 in the inner ear, we used conditional knock-out mice in which Elp3 gene is deleted from early otocyst (Elp3 cKO). We submitted these mice to a battery of vestibular testing (i.e. stereotyped circling ambulation, head bobbing, retropulsion, and absence of reaching response in the tail-hanging test) and found significant abnormalities. Besides, the auditory brain stem response of Elp3 cKO indicated that these mice are severely deaf. At the cellular level, we did not find any structural abnormalities nor cell patterning defects that could explain deafness or balance dysfunction in Elp3 cKO mice. However, we detected some defaults in the planar orientation of their auditory hair cell bundle. We were also able to demonstrate an increased level of apoptosis in the Elp3 cKO spiral ganglion at E14.5 leading to a reduced number of neurons and fibers innervating the cochlear hair cells as well as a reduced number of their synaptic ribbons at P15. Moreover, the remaining spiral ganglion neurons extend processes showing clearly defects regarding hair cells innervation (misorientation of fibers). In conclusion, our results clearly show a role for Elp3 both in hearing and balance. We plan to go deeper in the mechanisms involved through the identification of the proteins that are targeted for acetylation by Elp3. [less ▲]

Detailed reference viewed: 79 (15 ULg)
Full Text
Peer Reviewed
See detailEGFR and NF-kB: partners in cancer
Shostak, Kateryna ULg; Chariot, Alain ULg

in Trends in Molecular Medicine (2015), 21

Oncogenic proteins cooperate to promote tumor development and progression by sustaining cell proliferation, survival and invasiveness. Constitutive EGFR and NF-kappaB activities are seen in multiple solid ... [more ▼]

Oncogenic proteins cooperate to promote tumor development and progression by sustaining cell proliferation, survival and invasiveness. Constitutive EGFR and NF-kappaB activities are seen in multiple solid tumors and combine to provide oncogenic signals to cancer cells. Understanding how these oncogenic pathways are connected is critical, given their role in intrinsic or acquired resistance to targeted anti-cancer therapies. We review molecular mechanisms by which both EGFR- and NF-kappaB-dependent pathways establish positive loops to increase their oncogenic potential. We also describe how NF-kappaB promotes resistance to EGFR inhibitors. [less ▲]

Detailed reference viewed: 80 (6 ULg)
Full Text
See detailUnravelling Cemip expression and functions in the auditory portion of the inner ear.
Czajkowski, Amandine ULg; Chariot, Alain ULg; Delacroix, Laurence ULg et al

Poster (2015, May 29)

The inner ear is a complex organ composed of the vestibular system – which is the balancing system – and the cochlea – which is the earing system. The cochlea is a coiled shape organ composed of three ... [more ▼]

The inner ear is a complex organ composed of the vestibular system – which is the balancing system – and the cochlea – which is the earing system. The cochlea is a coiled shape organ composed of three main structures: the spiral ligament sitting on top of the stria vascularis, the organ of Corti with sensory hair cells and supporting cells and the spiral ganglion composed of neurons and glial cells. After an auditory stimulus, the sound wave progresses in the scala media filled with endolymph and induces a stimulation of sensory hair cells. These cells then transmit the information to the spiral ganglion neurons connected to them. Of course, the correct ionic homeostasis of endolymph is required for a good sound wave transmission. This homeostatic function is assured by the stria vascularis and the spiral ligament. The alteration of one of the structures mentioned before induces deafness. Currently, numerous genes have been associated to this kind of hearing loss. In the present work, we focus our attention Cemip – also known as KIAA1199 – that has been associated to human hereditary neurosensory deafness. Indeed, three missense mutations consisting in non-synonymous amino acid changes (R187L, R187H and H783Y) have been associated to this form of deafness. Therefore we would like to understand the role of Cemip in the cochlea. For that we have analysed Cemip mRNA pattern of expression by in situ hybridization at different developmental stages on cochlear sections. It seems Cemip mRNA is not present in the auditory portion of the inner ear at early embryonic stage 14 (E14) while it is largely present at E17 in the spiral ganglion, in supporting cells of the organ of Corti and in the spiral ligament. This expression is maintained post-nattily until P7. At P21 the expression is restricted to the spiral lamina - an osseous structure surrounding the spiral ganglion. Our on going work is aimed at revealing the biological role of Cemip in the cochlea in conditional knock-out mice. [less ▲]

Detailed reference viewed: 55 (5 ULg)
See detailElongator: mcm5s2 modification fosters breast cancer metastasis
Delaunay, Sylvain ULg; Rapino, Francesca ULg; Zhou, Zhaoli ULg 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 ▲]

Detailed reference viewed: 42 (9 ULg)
Full Text
Peer Reviewed
See detailElongator promotes breast cancer metastasis
Delaunay, Sylvain ULg; Rapino, Francesca ULg; 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 ▲]

Detailed reference viewed: 32 (6 ULg)