References of "Habraken, Yvette"
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See detailMelanoma antigen-D2 controls cell cycle progression and modulates the DNA damage response.
Trussart, Charlotte ULiege; Pirlot, Céline; Di Valentin, Emmanuel ULiege et al

in Biochemical Pharmacology (2018)

Overexpression of the ubiquitous type II melanoma antigen-D2 (MAGED2) in numerous types of cancer suggests that this protein contributes to carcinogenesis, a well-documented characteristic of other MAGE ... [more ▼]

Overexpression of the ubiquitous type II melanoma antigen-D2 (MAGED2) in numerous types of cancer suggests that this protein contributes to carcinogenesis, a well-documented characteristic of other MAGE proteins. Modification of MAGED2 intracellular localization during cell cycle phases and following treatment with camptothecin (CPT) and phosphorylation by ATM/ATR following ionizing irradiation led us to investigate the molecular functions of MAGED2 in the cellular response to DNA damage. Cell cycle regulators, cell cycle progression, and bromodeoxyuridine (BrdU) incorporation were compared between MAGED2-sufficient and -depleted U2OS cells following exposure to CPT. At 24 h post-CPT removal, MAGED2-depleted cells had lower levels of p21 and p27, and there was an increase in S phase BrdU-positive cells with a concurrent decrease in cells in G2. These cell cycle modifications were p21-independent, but ATR-, SKP2-, and CDC20-dependent. Importantly, while MAGED2 depletion reduced CHK2 phosphorylation after 8 h of CPT treatment, it enhanced and prolonged CHK1 phosphorylation after a 24 h recovery period, indicating sustained ATR activation. MAGED2 depletion had no impact on cell survival under our experimental conditions. In summary, our data indicate that MAGED2 reduced CPT-related replicative stress, suggesting a role for this protein in genomic stability. [less ▲]

Detailed reference viewed: 12 (0 ULiège)
See detailAlternative splicing induced by cisplatin : Effect on mitochondria shape
Chakrama, Fatima ULiege; Lambert, Charles ULiege; Gabriel, Maude et al

Poster (2017, October)

Detailed reference viewed: 8 (3 ULiège)
See detailMAGED2 function as cell cycle regulator after a genotoxic stress
Trussart, Charlotte ULiege; Pirlot, Céline; Piette, Jacques ULiege et al

Poster (2017, May 11)

Detailed reference viewed: 16 (1 ULiège)
See detailLes dommages à l’ADN et leurs réponses cellulaires
Habraken, Yvette ULiege

Conference given outside the academic context (2017)

Introduction à l'origine et la nature des différents types de dommages à l'ADN et leur mécanisme de réparation.

Detailed reference viewed: 16 (0 ULiège)
See detailIncidence of MAGED2 on cell cycle after a camptothecin treatment
Trussart, Charlotte ULiege; Pirlot, Céline; Piette, Jacques ULiege et al

Poster (2017)

Detailed reference viewed: 23 (2 ULiège)
See detailc-Jun regulates altered pre-mRNA splicing in response to cisplatin
Deward, Adeline; Gabriel, Maude; Klinck, Roscoe et al

Poster (2016, September 11)

Genotoxic stress is a well-known inducer of pre-mRNa alternative splicing . In this work, we aim at identifying keys componants of the signaling cascade linking the DNA lesion to the splcing machiney.and ... [more ▼]

Genotoxic stress is a well-known inducer of pre-mRNa alternative splicing . In this work, we aim at identifying keys componants of the signaling cascade linking the DNA lesion to the splcing machiney.and thus gain better knowledge od the molecular mechanism controling large scale splcing decision in stress situation. Nous avons établi que C-Jun est important pour l'épissage alternatif de nombreux ARN pré-messagers. [less ▲]

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See detailNew role of osteopontin in DNA repair and impact on human glioblastoma radiosensitivity
Henry, Aurélie ULiege; Nokin, Marie-Julie ULiege; Leroi, Natacha ULiege et al

in Oncotarget (2016)

Glioblastoma (GBM) represents the most aggressive and common solid human brain tumor. We have recently demonstrated the importance of osteopontin (OPN) in the acquisition/maintenance of stemness ... [more ▼]

Glioblastoma (GBM) represents the most aggressive and common solid human brain tumor. We have recently demonstrated the importance of osteopontin (OPN) in the acquisition/maintenance of stemness characters and tumorigenicity of glioma initiating cells. Consultation of publicly available TCGA database indicated that high OPN expression correlated with poor survival in GBM patients. In this study, we explored the role of OPN in GBM radioresistance using an OPN-depletion strategy in U87-MG, U87-MG vIII and U251-MG human GBM cell lines. Clonogenic experiments showed that OPN-depleted GBM cells were sensitized to irradiation. In comet assays, these cells displayed higher amounts of unrepaired DNA fragments post-irradiation when compared to control. We next evaluated the phosphorylation of key markers of DNA double-strand break repair pathway. Activating phosphorylation of H2AX, ATM and 53BP1 was signi cantly decreased in OPN-de cient cells. The addition of recombinant OPN prior to irradiation rescued phospho-H2AX foci formation thus establishing a new link between DNA repair and OPN expression in GBM cells. Finally, OPN knockdown improved mice survival and induced a signi cant reduction of heterotopic human GBM xenograft when combined with radiotherapy. This study reveals a new function of OPN in DNA damage repair process post-irradiation thus further con rming its major role in GBM aggressive disease. [less ▲]

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See detailOsteopontin predicts radiotherapy response of glioblastoma patients : new role in DNA damage repair
Henry, Aurélie ULiege; Nokin, Marie-Julie; Leroi, Natacha ULiege et al

Conference (2016, March 22)

- Introduction: Glioblastoma (GBM) is the most aggressive and common solid human brain tumor. Because of GBM heterogeneity, location and aggressiveness, none of the available treatment is curative. These ... [more ▼]

- Introduction: Glioblastoma (GBM) is the most aggressive and common solid human brain tumor. Because of GBM heterogeneity, location and aggressiveness, none of the available treatment is curative. These treatments include maximal surgical resection, radiotherapy and concomitant or adjuvant chemotherapy with Temozolomide. However, the prognosis of adult patients with GBM remains poor and the survival outcome after treatment does not exceed 15 months. GBM-composing cells have developed many strategies to counteract these current therapies. Among the wide hallmarks acquired to survive, high osteopontin (OPN) expression correlates with lower overall and disease-free/relapse-free survival in all tumors combined, as well in brain cancer. Our recent study (Lamour V and Henry A, IJC 2015) has demonstrated the role of OPN in the tumorigenicity of glioblastoma cells and its importance in the maintenance of the stem characters. In the continuation of this work, our recent studies focused on the potential role of OPN in the resistance of GBM cells to radiotherapy and its potential implication in the initiation of Double Strand Breaks (DSBs) repair mechanisms. - Aims: In the context of this study, different GBM cell lines (U251-MG, U87-MG and U87 Viii) were used to assess the role of OPN in the initiation of the DSBs repair mechanism after an exposure to gamma-irradiation. - Methods and results: We performed the transient transfection of different GBM cell lines (U251-MG, U87-MG and U87-MG overexpressing EGFR VIII) with siRNAs specifically directed against OPN. After irradiation, all these OPN-depleted cells consistently showed a lower induction of γ–H2AX compared to control (irrelevant siRNA) as evidenced by western blot and immunofluorescence techniques. Thereafter, clonogenic assays allowed to prove that the survival of OPN-depleted cells was affected after an exposure to irradiation. To assess the importance of OPN expression in the response to radiotherapy, an heterotopic xenograft model was used. In brief, IPTG-inducible U87 shOPN clones were injected subcutaneously in NOD-SCID mice and were allowed to form a tumor. When average tumor volume reached a predetermined size range, mice were treated (or not) with IPTG by intraperitoneal injection during five days. At the end of the treatment, tumors were selectively exposed to gamma-irradiation by using a small animal irradiator X-RAD 225Cx (Precision X-Ray Inc., North Branford, CT). One week later, mice were sacrificed and tumors were measured. In this pilot study, we observed that mice in which the tumor was depleted in OPN displayed a slight regression in the tumor growth compared to mice that received radiotherapy alone (no IPTG), where the tumor volume remained constant. - Conclusions: Taken together, these preliminary data meet the fact that OPN is important in the response of GBM to radiotherapy. The in vitro results converge to the fact that OPN might be implicated in the initiation of the DSBs repair following irradiation. Currently, we would like to investigate this hypothesis in vivo but also to check the effect of OPN depletion combined to radiotherapy on the survival of mice in an orthotopic xenograft model. [less ▲]

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See detailA c-jun/splicing factors complex triggers altered pre-mRNA splcing in response to cisplatin
Deward, Adeline; Gabriel, Maude; Klinck, Roscoe et al

Poster (2016, January 25)

DNA lesions induce alternative splicing of hundreds of pre-messengers RNA. We established than c-Jun is required for this large scale reorganisation of the proteome after cisplatin treatment. .

Detailed reference viewed: 36 (6 ULiège)
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See detailMelanoma antigen-D2: a nucleolar protein undergoing delocalization during cell cycle and after cellular stress
Pirlot, Céline ULiege; Thiry, Marc ULiege; Trussart, Charlotte ULiege et al

in BBA Molecular Cell Research (2016), 1853(3), 581-595

Detailed reference viewed: 25 (8 ULiège)
See detailMelanoma antigen D2, a substrate of ATM, is a nucleolar protein that shuttles with cell cycle and cellular stress.
Pirlot, Céline; Thiry, Marc ULiege; Trussart, Charlotte ULiege et al

Poster (2015, November 03)

ATM coordinates numerous facets of the highly regulated DDR network. In order to identify new ATM substrates we have performed a yeast two hybrid experiment with HEAT domains of ATM and an HeLa cDNA ... [more ▼]

ATM coordinates numerous facets of the highly regulated DDR network. In order to identify new ATM substrates we have performed a yeast two hybrid experiment with HEAT domains of ATM and an HeLa cDNA library. Melanoma antigen D2 (MAGED2) was one of the interacting proteins identified in this screen. MAGED2 belongs to the type II Melanoma AntiGEn (MAGE) family. MAGE homology domain, shared by all MAGE proteins, was shown to enhance E3 ligase activity. Actually, little is known about MAGED2 functions. Like every type II MAGE protein, it is expressed in all adult tissues. However, MAGE-D2 has the particularity to be over-expressed in numerous primary cancer and metastasis and it is now recognized as a tumour marker. This over-expression suggests that MAGED2 could be important for the process of cancerisation. MAGED2 was also shown to be a negative regulator of p53, but we did not confirm this property. Proteomic analyses also detected numerous phosphorylated or acetylated residues in response to stress and during cell cycle progression, suggesting a role in cellular signal transduction. We identified the residues targeted by ATM in MAGE-D2 and analysed the localisation of MAGED2 during the interphase and after genotoxic/nucleolar stresses. [less ▲]

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See detailMelanoma AntiGEn D2 : a new nucleolar protein undergoing delocalization during cell cycle and after cellular stress
Pirlot, Céline; Thiry, Marc ULiege; Trussart, Charlotte ULiege et al

Poster (2015, September 28)

MAGED2 belongs to the Melanoma AntiGEn (MAGE) family of proteins. Actually, little is known on MAGED2 function. It contributes to the initiation of melanoma when its overexpression is associated with the ... [more ▼]

MAGED2 belongs to the Melanoma AntiGEn (MAGE) family of proteins. Actually, little is known on MAGED2 function. It contributes to the initiation of melanoma when its overexpression is associated with the mutation of BRAF and it increases apoptosis induced by TRAIL in a p53-dependent manner. MAGED2 was also shown to be a negative regulator of p53, bur we did not confirm this properties. Moreover, proteomic analyses detected numerous phosphorylated or acetylated residues in response to stess and within cell cycle suggesting its involvement in cellular signal transduction. We investigated the intra-cellular re-localization of MAGED2 during cell cycle and after genotixc stress. Both nucleolar and nuclear signals were identifed. [less ▲]

Detailed reference viewed: 14 (1 ULiège)
See detailc-Jun : a new regulatory element for cisplatin induced alternative splicing
Deward, Adeline; Gabriel, Maude; Delforge, Yves et al

Poster (2015, September 28)

DNA damaging agents induce a large scale reorganisation of the proteome through pre messenger alternative splicing. We present evidence that c-Jun is required to induce this altered stress related ... [more ▼]

DNA damaging agents induce a large scale reorganisation of the proteome through pre messenger alternative splicing. We present evidence that c-Jun is required to induce this altered stress related proteome. [less ▲]

Detailed reference viewed: 21 (4 ULiège)
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See detailOsteopontin as a new target in glioblastoma progression and resistance to radiotherapy
Henry, Aurélie ULiege; Bellahcene, Akeila ULiege; Castronovo, Vincenzo ULiege et al

Conference (2015, September 10)

Glioblastoma (GBM) is the most aggressive and common solid human brain tumor. Because of GBM heterogeneity, location and aggressiveness, none of the available treatment is curative. These treatments ... [more ▼]

Glioblastoma (GBM) is the most aggressive and common solid human brain tumor. Because of GBM heterogeneity, location and aggressiveness, none of the available treatment is curative. These treatments include maximal surgical resection, radiotherapy and concomitant or adjuvant chemotherapy with Temozolomide (TMZ). However, the prognosis of adult patients with GBM remains poor and the survival outcome after treatment does not exceed 15 months. Glioblastoma-composing cells have developed many strategies to counteract these current therapies. Among the wide hallmarks acquired to survive, osteopontin (OPN) ranks correlates with lower overall and disease-free/relapse-free survival in all tumors combined, as well in brain cancer. OPN expression is largely considered as a molecular cancer marker associated with poor prognosis for patients with cancer. Our preliminary works (Lamour V and Henry A, IJC 2015) have demonstrated the role of OPN in the tumorigenicity of glioblastoma cells and its importance in the maintenance of the stem charachters. Within the continuance of this work, our recent studies focused on the potential role of OPN in the resistance of glioblastoma cells to radiotherapy and its implication in the initiation of Double Strand Breaks (DSBs) repair mechanism. In this context, U251-MG and U87-MG cells were used to assess the role of OPN in the initiation of the DSBs repair mechanism after an exposure to gamma-irradiation (γ–IR). The transient transfection of both cell lines with siRNA directed against OPN shown a lower induction of γ–H2AX compared to control (irrelevant siRNA). The survival of U251-OPN depleted cells was also affected after an exposure to γ–IR (based on clonogenic assays). However, the sole depletion of OPN in U87 cells affected their survival (independently of the γ–IR). To prove that the secreted form of OPN is necessary to survive after γ–IR, conditionned medium of U87-shSCR clones (rich in OPN) was used to treat U87shOPN clones before an exposure to γ–IR. By immunofluorescence, we observed that the γ–H2AX staining was higher in U87 shOPN clones than when treated with their own conditionned medium (poor in OPN). Currently, we are investigating the in vivo implication of OPN in the initiation of DSBs repair mechanism after an exposure of mice to γ–IR (whole brain exposure). For this purpose, IPTG-inducible U87 shRNA clones (SCR and OPN) have been generated and validated for an orthotopic xenograft model in NOD-SCID mice. The survival after a radiotherapy of 10 Gy (2Gy per day for 5 days) will be assessed in OPN-positive and –negative tumor-bearing mice. Taken together, these datas suggest that OPN could represent an important pronostic factor for patient response to radiotherapy in the context of GBM. [less ▲]

Detailed reference viewed: 135 (33 ULiège)
See detailMelanoma AntiGEn D2 (MAGED2): a new nucleolar protein undergoing re-localization after cellular stress
Pirlot, Céline; Thiry, Marc ULiege; Trussart, Charlotte ULiege et al

Poster (2015, February 06)

MAGED2 belongs to the Melanoma AntiGEn (MAGE) family of proteins. Actually, the only known function of this protein is its involvement in the p53 pathway. Indeed, MAGED2 could be a negative regulator of ... [more ▼]

MAGED2 belongs to the Melanoma AntiGEn (MAGE) family of proteins. Actually, the only known function of this protein is its involvement in the p53 pathway. Indeed, MAGED2 could be a negative regulator of p53. It contributes to the initiation of melanoma when its overexpression is associated with the mutation of BRAF and it increases apoptosis induced by TRAIL in a p53 dependent manner. Moreover, phosphoproteomic experiments have shown that this protein is likely phosphorylated by kinases implicated in the DNA damage response (DDR). We decided to investigate the intra-cellular localization of MAGED2 in order to find new functions of this protein. In resting cell, MAGE D2 is detected is the nucleus, the nucleolus and the cytoplasm. We observed that MAGED2 localization change during cell cycle and genotoxic stress. Nuclear and nucleolar localization signals were identified. Though present in the nucleolus, the depletion of MAGED2 does not affect the structure of this organel. [less ▲]

Detailed reference viewed: 21 (2 ULiège)
See detailThe phosphorylation of RelA on Ser547 does not modulate NF-kB activation after TNFa treatment like after a genotoxic stress
Trussart, Charlotte ULiege; Orban, Tanguy ULiege; Di Valentin, Emmanuel ULiege et al

Poster (2015, February 06)

NF-kB controls the expression of hundred of genes involved in inflammatory and innate responses, proliferation, survival, cancer initiation and progression. Numerous post-translational modifications of ... [more ▼]

NF-kB controls the expression of hundred of genes involved in inflammatory and innate responses, proliferation, survival, cancer initiation and progression. Numerous post-translational modifications of p65 modulating NF-kB transcriptional activity are known. We identified Ser547 as a new site of p65 phosphorylation targeted by ATM kinase, which coordinates the “DNA Damage Response” pathway in the event of DNA double-strand breaks. We demonstrated that the phosphorylation of Ser547 regulates the transcription of a sub-set of NF-κB dependent genes after genotoxic stress by modifying HDAC1 recruitment(1). Presently, we are investigating the role of this specific phosphorylation in an inflammatory context. We observe that the mutations of p65 (S547A or S547D) also affect the transcriptional potential of the NF-κB in a promoter specific manner after an exposition to TNFα and H2O2. The study of the molecular mechanism of this regulation after TNFα and H2O2 exposition are both in progress. [less ▲]

Detailed reference viewed: 49 (0 ULiège)
See detailPromoter specific regulation of NF-kappaB by RelA phosphorylation on Ser547
Trussart, Charlotte ULiege; Orban, Tanguy; Di Valentin, Emmanuel ULiege et al

Poster (2014, August 29)

NF-KB (p50/RelA) controls the expression of numerous genes involved in inflammation, survival, proliferation, and cancer initiation and progression. Both classical NF-kB activation by pro-inflammatory ... [more ▼]

NF-KB (p50/RelA) controls the expression of numerous genes involved in inflammation, survival, proliferation, and cancer initiation and progression. Both classical NF-kB activation by pro-inflammatory cytokines and ATM-dependant activation by DNA damage require IKK activation and IkBa degradation. Stimuli dependant phosphorylation of p65 controls its transcriptional potential often in a gene specific manner. Previously, we have reported a direct interaction between RelA and ATM, and, demonstrated the in vitro phosphorylation of Ser547 by this kinase. A comparative transcriptomic analysis performed in HEK cells expressing either p65WT or p65S547A identified several differentially transcribed genes after an etoposide treatment. Substitution of S547 to alanine does not affect p65 binding on the kB site of the modulated promoters but it reduces p65 interaction with HDAC1. The resulting enhanced histone H3 acetylation increases gene transcription at some specific promoters. Our data indicate that ATM regulates a sub-set of NF-kB dependent genes after a genotoxic stress by direct phosphorylation of p65. Presently, we are investigating the impact of p65S547A/D mutations after the addition of TNFa in Mefs p65 KO complemented with HA-p65WT or S547A/D. No differences are observed in the degradation of IkBb or the nuclear translocation of p50/p65. However both basal and TNFa-induced transcription levels of some kB dependent genes are elevated in Mefs expressing p65S547D. The role of ATM in NF-kB activation by TNFa is analyzed. [less ▲]

Detailed reference viewed: 66 (13 ULiège)