Joëlle Wiels | Paris Sud XI University (original) (raw)

Papers by Joëlle Wiels

Pro-apoptotic meiogynin A derivatives that target Bcl-xL and Mcl-1

Bioorg. Med. Chem. Lett., 2014

The biological evaluation of a natural sesquiterpene dimer meiogynin A 1, is described as well as... more The biological evaluation of a natural sesquiterpene dimer meiogynin A 1, is described as well as that of five non-natural analogues. Although active on a micromolar range on the inhibition of Bcl-xL/Bak and Mcl-1/Bid interaction, meiogynin A 1 is not cytotoxic on three cell lines that overexpress Bcl-xL and Mcl-1. Contrarily, one of its analogues 6 with an inverted configuration on the side chain and an aromatic moiety replacing the cyclohexane ring was active on both target proteins, cytotoxic on a micromolar range and was found to induce apoptosis through a classical pathway.

Virology, 1997

Latent Membrane Protein 1 (LMP1) is an EBV-transforming protein which is detected both in lymphob... more Latent Membrane Protein 1 (LMP1) is an EBV-transforming protein which is detected both in lymphoblastoid cell linesresulting from EBV-immortalization in vitro-and in undifferentiated nasopharyngeal carcinoma (NPC), an EBV-associated malignancy of epithelial origin. To better define LMP1 subcellular targets, LMP1 distribution was analyzed in cellular glycosphingolipid-rich complexes (GSL-complexes) derived from epithelial and lymphoid cells. These complexes are obtained by extraction of glycosphingolipid-rich membrane domains (GSL-domains), which are clustering sites for heterotrimeric Gproteins and G-protein-associated receptors. LMP1 concentration was enriched 50-fold in GSL-complexes extracted from a NPC tumor line, C15. High concentrations of LMP1 were also observed in GSL-complexes derived from cultured lymphoid and epithelial cells. These data suggest that association with GSL-domains is an important step in LMP1 trafficking and is probably required for some aspects of its biological activity. ᭧ 1997 Academic Press

NATURAL KILLER CELL ACTIVITY IN HUMAN BONE MARROW RECIPIENTS EARLY REAPPEARANCE OF PERIPHERAL NATURAL KILLER ACTIVITY IN GRAFT-VERSUS-HOST DISEASE

Transplantation, 1981

Natural killer (NK) cell activity toward K562 target cells and antibody-dependent cell-mediated c... more Natural killer (NK) cell activity toward K562 target cells and antibody-dependent cell-mediated cytotoxicity (ADCC) toward L1210 cell sensitized with anti-L1210 antisera were sequentially tested in peripheral blood lymphocytes (PBLs) from 24 human bone marrow (BM) recipients. Although consistently decreased before the transplant, NK cell activity was restored in all of the patients tested that argues for a bone marrow origin of NK progenitors in humans. In patients without graft-versus-host disease (GVHD), peripheral NK cell activity remained low during the 1st month after the transplant, then rapidly increased and reached normal values usually between days 30 and 50. By contrast, peripheral ADCC appeared earlier restored (since day 13), suggesting that NK and ADCC are two distinct effector mechanisms. When restored, peripheral NK cell activity remained within normal range, except in seven cases with a drastic fall in NK cell values contemporary with a severe viral infection, mainly with cytomegalovirus (CMV). NK cells are thus suggested to play an important role in the control of viral infections in these deeply immunodepressed patients. In patients with acute GVHD, strikingly high NK values were observed early after the transplant, and during the 1st month a strong correlation did exist between high NK values and acute GVHD occurrence. These results suggest that cells involved in GVHD mechanism are able to exert NK cell activity at some stages of their maturation. The assessment of NK cell activity could be an attractive routine procedure for monitoring the prophylaxis of GVHD in human BM recipients.

A glycolipid antigen associated with Burkitt lymphoma defined by a monoclonal antibody

Science, 1983

The antigen defined by a rat monoclonal antibody directed to a Burkitt lymphoma cell line was ide... more The antigen defined by a rat monoclonal antibody directed to a Burkitt lymphoma cell line was identified as globotriaosylceramide [Gal alpha (1 leads to 4)-Gal beta (1 leads to 4)-Glc beta (1 leads to 1)-ceramide]. The antibody demonstrated a strict steric specificity since it did not react with globoisotriaosylceramide [Gal alpha (1 leads to 3)-Gal beta (1 leads to 4)-Glc beta (1 leads to 1)-ceramide], the positional isomer of the antigen associated with the Burkitt lymphoma. Chemical analysis of various Burkitt lymphoma cell lines revealed that the Burkitt lymphoma cells contained more than 100 times as much of the glycolipid antigen as was found in other human lymphoma and leukemia cell lines.

Proceedings of the National Academy of Sciences, 1998

Previously, we showed that the addition of human erythrocyte glycosphingolipids (GSLs) to nonhuma... more Previously, we showed that the addition of human erythrocyte glycosphingolipids (GSLs) to nonhuman CD4 ؉ or GSL-depleted human CD4 ؉ cells rendered those cells susceptible to HIV-1 envelope glycoprotein-mediated cell fusion. Individual components in the GSL mixture were isolated by fractionation on a silica-gel column and incorporated into the membranes of CD4 ؉ cells. GSL-supplemented target cells were then examined for their ability to fuse with TF228 cells expressing HIV-1 LAI envelope glycoprotein. We found that one GSL fraction, fraction 3, exhibited the highest recovery of fusion after incorporation into CD4 ؉ nonhuman and GSLdepleted HeLa-CD4 cells and that fraction 3 contained a single GSL fraction. Fraction 3 was characterized by MS, NMR spectroscopy, enzymatic analysis, and immunostaining with an antiglobotriaosylceramide (Gb3) antibody and was found to be Gal(␣134)Gal(␤134)Glc-Cer (Gb3). The addition of fraction 3 or Gb3 to GSL-depleted HeLa-CD4 cells recovered fusion, but the addition of galactosylceramide, glucosylceramide, the monosialoganglioside, GM3, lactosylceramide, globoside, the disialoganglioside, GD3, or ␣-galactosidase A-digested fraction 3 had no effect. Our findings show that the neutral GSL, Gb3, is required for CD4͞CXCR4dependent HIV-1 fusion.

Journal of Virology, 2007

The Epstein-Barr virus (EBV)-encoded leader protein, EBNA-LP, strongly activates the EBNA2-mediat... more The Epstein-Barr virus (EBV)-encoded leader protein, EBNA-LP, strongly activates the EBNA2-mediated transcriptional activation of cellular and viral genes and is therefore important for EBV-induced B-cell transformation. However, a truncated form of EBNA-LP is produced in cells infected with variant EBV strains lacking EBNA2 due to a genetic deletion. The function of this truncated form is unknown. We show here that some Burkitt's lymphoma cells harboring defective EBV strains are specifically resistant to the caspasedependent apoptosis induced by verotoxin 1 (VT-1) or staurosporine. These cells produced low-molecularweight Y1Y2-truncated isoforms of EBNA-LP, which were partly localized in the cytoplasm. The transfection of sensitive cells with constructs encoding truncated EBNA-LP isoforms, but not full-length EBNA-LP, induced resistance to caspase-mediated apoptosis. Furthermore, VT-1 induced protein phosphatase 2A (PP2A) activation in sensitive cells but not in resistant cells, in which the truncated EBNA-LP interacted with this protein. Thus, the resistance to apoptosis observed in cells harboring defective EBV strains most probably results from the inactivation of PP2A via interactions with low-molecular-weight Y1Y2-truncated EBNA-LP isoforms.

Journal of Molecular Biology, 2008

The opportunistic pathogen Pseudomonas aeruginosa contains several carbohydrate-binding proteins,... more The opportunistic pathogen Pseudomonas aeruginosa contains several carbohydrate-binding proteins, among which is the P. aeruginosa lectin I (PA-IL), which displays affinity for α-galactosylated glycans. Glycan arrays were screened and demonstrated stronger binding of PA-IL toward αGal1-4βGal-terminating structures and weaker binding to αGal1-3βGal ones in order to determine which human glycoconjugates could play a role in the carbohydrate-mediated adhesion of the bacteria. This was confirmed in vivo by testing the binding of the lectin to Burkitt lymphoma cells that present large amounts of globotriaosylceramide antigen Gb3/CD77/P k . Trisaccharide moieties of Gb3 (αGal1-4βGal1-4Glc) and isoglobotriaosylceramide (αGal1-3βGal1-4Glc) were tested by titration microcalorimetry, and both displayed similar affinity to PA-IL in solution. The crystal structure of PA-IL complexed to αGal1-3βGal1-4Glc trisaccharide has been solved at 1.9-Ǻ resolution and revealed how the second galactose residue makes specific contacts with the protein surface. Molecular modeling studies were performed in order to compare the binding mode of PA-IL toward αGal1-3Gal with that toward αGal1-4Gal. Docking studies demonstrated that αGal1-4Gal creates another network of contacts for achieving a very similar affinity, and 10-ns molecular dynamics in explicit water allowed for analyzing the flexibility of each disaccharide ligand in the protein binding site. The higher affinity observed for binding to Gb3 epitope, both in vivo and on glycan array, is likely related to the presentation effect of the oligosaccharide on a surface, since only the Gb3 glycosphingolipid geometry is fully compatible with parallel insertion of neighboring trisaccharide heads in two binding sites of the same tetramer of PA-IL.

Journal of Cellular Biochemistry, 1986

International Journal of Cancer, 1999

Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) protein expressed in EBV-transfor... more Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV) protein expressed in EBV-transformed B lymphocytes and in approximately 50% of nasopharyngeal carcinomas (NPCs). LMP1 signaling involves several cellular signaling intermediates, especially TNF receptor-associated factors (TRAFs). We have shown previously that LMP1 is highly concentrated in a cell fraction called glycosphingolipid-rich membrane complexes (GSL complexes). We report here that parallel accumulation of LMP1 and TRAF3, but not TRAF1 or TRADD, was observed in GSL complexes from lymphoblastoid and LMP1-positive NPC cells. In contrast, TRAF3 was not concentrated in GSL complexes from LMP1negative cells. Binding of LMP1 and TRAF3 in GSL complexes was demonstrated in lymphoblastoid and NPC cells, by co-immunoprecipitation with both anti-LMP1 and anti-TRAF3 antibodies. Int.

Perinucleolar relocalization and nucleolin as crucial events in the transcriptional activation of key genes in mantle cell lymphoma

Blood, Jan 27, 2014

In mantle cell lymphoma (MCL), one allele of the cyclin D1 (Ccnd1) gene is translocated from its ... more In mantle cell lymphoma (MCL), one allele of the cyclin D1 (Ccnd1) gene is translocated from its normal localization on chromosome 11 to chromosome 14. This is considered as the crucial event in the transformation process of a normal naive B-cell; however, the actual molecular mechanism leading to Ccnd1 activation remains to be deciphered. Using a combination of three-dimensional and immuno-fluorescence in situ hybridization experiments, the radial position of the 2 Ccnd1 alleles was investigated in MCL-derived cell lines and malignant cells from affected patients. The translocated Ccnd1 allele was observed significantly more distant from the nuclear membrane than its nontranslocated counterpart, with a very high proportion of IgH-Ccnd1 chromosomal segments localized next to a nucleolus. These perinucleolar areas were found to contain active RNA polymerase II (PolII) clusters. Nucleoli are rich in nucleolin, a potent transcription factor that we found to bind sites within the Ccnd1 ...

Apoptosis of tumoral and nontumoral lymphoid cells is induced by both mdm2 and p53 antisense oligodeoxynucleotides

Blood, 2001

Following stress signals, the p53 tumor suppressor protein plays a critical role in regulation of... more Following stress signals, the p53 tumor suppressor protein plays a critical role in regulation of cell proliferation, mainly through induction of growth arrest or apoptosis. Therefore, this protein needs to be strictly regulated and numerous studies have shown that the MDM2 protein is an essential element for p53 regulation in normal cells and, most importantly, that overexpression of MDM2 is responsible for p53 inactivation in various types of tumors. A previous study showed that this is the case in some Burkitt lymphoma (BL) cell lines, where enhanced translation of mdm2 messenger RNA results in overexpression of the protein that complexes and inactivates wild-type p53. To further investigate the role of the p53/MDM2 complex in these BL cells, as well as in other lymphoid cells that do not overexpress MDM2, this study used antisense oligodeoxynucleotides directed either against mdm2 or against p53. Results show that the mdm2 antisense oligodeoxynucleotide induces apoptosis of cells that express a high or low level of MDM2 protein, only if they contain wild-type p53. Moreover, apoptosis is independent of the accumulation of p53 following mdm2 antisense treatment. Finally, the p53 antisense oligodeoxynucleotide, which inhibits the expression of wild-type p53, also induces a decrease of the MDM2 level in cells, whether or not they overexpress this protein, and causes apoptosis of these cells. These results indicate that decreasing the MDM2 protein level by directly or indirectly targeting its biosynthesis is a potent tool for the induction of apoptosis.

Biology of the Cell, 1996

PC12 cells, isolated from a rat pheochromocytoma, arc widely used as a model to study the regulat... more PC12 cells, isolated from a rat pheochromocytoma, arc widely used as a model to study the regulation of neuronal differentiation versus proliferation. When grown in the presence of Nerve Growth Factor (NGF) these cells stop dividing, form neurites and become electrically excitable. The observed cell cycle arrest takes place in the GI phase of the cell cycle and is characterized by a decreased kinase activity of G 1 phase specific CDKs (Cyclin-Dependent Kinase). We determined the implication of CAK in this NGF-induced cell cycle arrest by studying the expression of its three subunits (CDK7, cycline H and MATI) as welt as its CDKZ-specific kinase activity. CAK is associated with the transcription factor TFHH and is capable of phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase II. Therefore, the phosphorylation of CTD_ by CAK during NGF treatment of PC12 cells was also analysed. Our results show a moderate increase in the kinase activity of CDK7 (catalytic subunit of CAK) on both the substrates GST-CDK2 and GST-CTD when PC12 cells are treated with NGF. These results do nof explain the decreased G l-phase specific CDK kinase activity observed during NGF treatment of PC12 cells, suggesting that the regulation of CAK activity is not directly implicated in the anti-mitogenic effect of NGF

PLoS ONE, 2009

Additional chromosomal abnormalities are currently detected in Burkitt's lymphoma. They play majo... more Additional chromosomal abnormalities are currently detected in Burkitt's lymphoma. They play major roles in the progression of BL and in prognosis. The genes involved remain elusive. A whole-genome oligonucleotide array CGH analysis correlated with karyotype and FISH was performed in a set of 27 Burkitt's lymphoma-derived cell lines and primary tumors. More than half of the 145 CNAs,2 Mb were mapped to Mendelian CNVs, including GSTT1, glutathione s-transferase and BIRC6, an anti-apoptotic protein, possibly predisposing to some cancers. Somatic cell line-specific CNVs localized to the IG locus were consistently observed with the 244 K aCGH platform. Among 136 CNAs .2 Mb, gains were found in 1q (12/27), 13q (7/27), 7q (6/27), 8q(4/27), 2p (3/27), 11q (2/27) and 15q (2/27). Losses were found in 3p (5/27), 4p (4/27), 4q (4/27), 9p (4/27), 13q (4/27), 6p (3/27), 17p (3/27), 6q (2/27),11pterp13 (2/27) and 14q12q21.3 (2/27). Twenty one minimal critical regions (MCR), (range 0.04-71.36 Mb), were delineated in tumors and cell lines. Three MCRs were localized to 1q. The proximal one was mapped to 1q21.1q25.2 with a 6.3 Mb amplicon (1q21.1q21.3) harboring BCA2 and PIAS3. In the other 2 MCRs, 1q32.1 and 1q44, MDM4 and AKT3 appeared as possible drivers of these gains respectively. The 13q31.3q32.1 ,89.58-96.81. MCR contained an amplicon and ABCC4 might be the driver of this amplicon. The 40 Kb 2p16.1 ,60.96-61. MCR was the smallest gained MCR and specifically encompassed the REL oncogene which is already implicated in B cell lymphomas. The most frequently deleted MCR was 3p14.1 ,60.43-60.53. that removed the fifth exon of FHIT. Further investigations which combined gene expression and functional studies are essential to understand the lymphomagenesis mechanism and for the development of more effective, targeted therapeutic strategies.