M. Elchebly - Academia.edu (original) (raw)

Papers by M. Elchebly

Journal of Thoracic Oncology

Journal of Lipid Research, 1998

Science translational medicine, Dec 14, 2016

Male gender is independently and significantly associated with poor prognosis in melanoma of all ... more Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesized that gene expression from gonosomes (sex chromosomes) might play an important role. We demonstrate that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit from two X chromosomes. The gonosomal protein phosphatase 2 regulatory subunit B, beta (PPP2R3B) gene is located on the pseudoautosomal region (PAR) of the X chromosome in females and the Y chromosome in males. We observed that, despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression was lower in males than in females and was independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate-recognizing subunit of protein phosphatas...

Biochemical and Molecular Medicine, 1995

Progrès en Urologie, 2015

Objectifs Le recepteur aux androgenes (RA) module l’expression de ses genes cibles en se liant au... more Objectifs Le recepteur aux androgenes (RA) module l’expression de ses genes cibles en se liant aux elements de reponse aux androgenes (ERA). La liaison du RA sur ses ERA pourrait etre empechee par Paired-Box6 (PAX6), un facteur suppresseur de tumeur. Notre objectif est d’etudier l’interaction entre PAX6, le RA et les ERA sur le promoteur du gene du PSA, conduisant a inhiber la transcription du PSA. Methodes Nous avons utilise les techniques de RT-PCR et Western Blot pour evaluer l’expression de PAX6, du RA et du PSA dans les lignees cellulaires LnCaP, DuCaP et PC3. L’expression de PAX6 a ete modulee par un Lentivirus et nous avons evalue les effets induits sur la transcription et la traduction de ces genes. L’interaction de PAX6 et du RA avec les ERA sur le promoteur du PSA a ete etudiee par immunoprecipitation de la chromatine. Resultats Nos resultats preliminaires indiquent qu’une surexpression de PAX6 inhibe l’expression du PSA aux niveaux nucleique et proteique. L’expression du RA n’etait pas significativement inhibee suggerant que PAX6 modifie l’interaction du RA avec ses sequences cibles et diminue ainsi l’activation de la transcription du PSA. L’hypothese que PAX6 inhibe la transcription du PSA de facon directe en se fixant au RA, ou indirectement par competition sur les sites ERA est en cours d’etude. Conclusion Ces premieres donnees suggerent que PAX6 est une nouvelle cible therapeutique potentielle dans le cancer avance de la prostate car il pourrait inhiber l’expression du gene du PSA et moduler le volume tumoral en reprimant l’activite du RA.

Nature genetics, 1999

Protein tyrosine phosphatase sigma (PTP-sigma, encoded by the Ptprs gene) is a member of the LAR ... more Protein tyrosine phosphatase sigma (PTP-sigma, encoded by the Ptprs gene) is a member of the LAR subfamily of receptor-like protein tyrosine phosphatases that is highly expressed during mammalian embryonic development in the germinal cell layer lining the lateral ventricles of the developing brain, dorsal root ganglia, Rathke's pouch, olfactory epithelium, retina and developing lung and heart. On the basis of its expression and homology with the Drosophila melanogasterorthologues DPTP99 and DPTP100A (refs 5,6), which have roles in the targeting of axonal growth cones, we hypothesized that PTP-sigma may also have a modulating function in cell-cell interactions, as well as in axon guidance during mammalian embryogenesis. To investigate its function in vivo, we generated Ptprs-deficient mice. The resulting Ptprs-/-animals display retarded growth, increased neonatal mortality, hyposmia and hypofecundity. Anatomical and histological analyses showed a decrease in overall brain size wi...

médecine/sciences, 1999

Un nouvel espoir dans le traitement du diabète de type 2 et de l'obésité

Nature Medicine, 2001

All nuclear-encoded mRNAs contain a 5&amp;#39; cap structure (m7GpppN, where N is any nuc... more All nuclear-encoded mRNAs contain a 5&amp;#39; cap structure (m7GpppN, where N is any nucleotide), which is recognized by the eukaryotic translation initiation factor 4E (eIF4E) subunit of the eIF4F complex. The eIF4E-binding proteins constitute a family of three polypeptides that reversibly repress cap-dependent translation by binding to eIF4E, thus preventing the formation of the eIF4F complex. We investigated the biological function of 4E-BP1 by disrupting its gene (Eif4ebp1) in the mouse. Eif4ebp1-/- mice manifest markedly smaller white fat pads than wild-type animals, and knockout males display an increase in metabolic rate. The males&amp;#39; white adipose tissue contains cells that exhibit the distinctive multilocular appearance of brown adipocytes, and expresses the uncoupling protein 1 (UCP1), a specific marker of brown fat. Consistent with these observations, translation of the peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC1), a transcriptional co-activator implicated in mitochondrial biogenesis and adaptive thermogenesis, is increased in white adipose tissue of Eif4ebp1-/- mice. These findings demonstrate that 4E-BP1 is a novel regulator of adipogenesis and metabolism in mammals.

Science, 1999

Protein tyrosine phosphatase–1B (PTP-1B) has been implicated in the negative regulation of insuli... more Protein tyrosine phosphatase–1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B +/+ littermates. The enhanced insulin sensitivity of the PTP-1B −/− mice was also evident in glucose and insulin tolerance tests. The PTP-1B −/− mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B +/+ mice. On a high-fat diet, the PTP-1B −/− and PTP-1B +/− mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B +/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potentia...

Dietary vitamin A and its active metabolites are essential nutrients for many functions as well a... more Dietary vitamin A and its active metabolites are essential nutrients for many functions as well as potent regulators of gene transcription and growth. Although the epithelium of the small intestine is characterized by rapid and constant renewal and enterocytes play a central role in the absorption and metabolism of alimentary retinol, very little is known about the function of retinoids in the human gastrointestinal epithelium and mechanisms by which programs engage the cell cycle are poorly understood. We have assessed the effects of 10 M 9-and 13-cisretinoic acid (RA) on proliferation and differentiation processes, lipid esterification, apolipoprotein (apo) biogenesis and lipoprotein secretion along with nuclear factor gene transcription. Treatment of Caco-2 cells with RA at different concentrations and incubation periods revealed the reduction of thymidine incorporation in 60% preconfluent or 100% confluent cells. Concomitantly, RA 1) modulated D-type cyclins by reducing the mitogen-sensitive cyclin D1 and upregulating cyclin D3 expressions and 2) caused a trend of increase in p38 MAPK, which triggers CDX2, a central protein in cell differentiation. RA remained without effect on lipoprotein output and apo synthesis, even for apo A-I that possesses RARE in its promoter. RA, in combination with 22-hydroxycholesterol, could induce apo A-I gene expression without any impact on apo A-I mass. Only the gene expression of peroxisome proliferator-activated receptor (PPAR)␤, retinoic receptor (RAR)␤, and RAR␥ was augmented and no alteration was noted in PPAR␣, PPAR␥, liver X receptor (LXR)␣, LXR␤, and retinoid X receptors. Taken together, these data highlight RA-induced cell differentiation via specific signaling without a significant impact on apo A-I synthesis. retinoids; apolipoproteins; lipoproteins; nuclear factors; lipids RETINOIC ACID (RA), a low-molecular-weight lipophilic metabolite of vitamin A or retinol, is the most potent natural retinoid able to influence biological processes, such as cell growth and differentiation of various epithelia in the body (17, 51). RA acts by binding to retinoic receptors (RAR)␣,-␤,-␥, which form heterodimers with retinoid X receptors (RXR-␣,-␤,-␥), thereby inducing transcription of a wide array of specific target genes (41). Synthesis and degradation of RAR and RXR by proteasomes and phosphorylations control amount and timing of the retinoid responses.

Molecular and Cellular Biology, 2008

Functional inactivation of the protein tyrosine phosphatase DEP-1 leads to increased endothelial ... more Functional inactivation of the protein tyrosine phosphatase DEP-1 leads to increased endothelial cell proliferation and failure of vessels to remodel and branch. DEP-1 has also been proposed to contribute to the contact inhibition of endothelial cell growth via dephosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), a mediator of vascular development. However, how DEP-1 regulates VEGF-dependent signaling and biological responses remains ill-defined. We show here that DEP-1 targets tyrosine residues in the VEGFR2 kinase activation loop. Consequently, depletion of DEP-1 results in the increased phosphorylation of all major VEGFR2 autophosphorylation sites, but surprisingly, not in the overall stimulation of VEGF-dependent signaling. The increased phosphorylation of Src on Y529 under these conditions results in impaired Src and Akt activation. This inhibition is similarly observed upon expression of catalytically inactive DEP-1, and coexpression of an active Src-Y5...

Journal of Molecular Medicine, 2000

Non-insulin-dependent diabetes mellitus (NIDDM) is a worldwide endocrine disorder afflicting pers... more Non-insulin-dependent diabetes mellitus (NIDDM) is a worldwide endocrine disorder afflicting persons of all races and age groups. At the molecular level NIDDM is often characterized by impaired insulin action on peripheral tissues. One important mechanism in regulating insulin signaling is mediated by protein tyrosine phosphatases, which may act on the insulin receptor itself and/or its substrates. Understanding the molecular events triggered by insulin has undoubtedly provided important clues in the treatment of NIDDM. In particular, the use of mouse models has helped us to focus on specific gene targets that are involved in the onset and progression of diabetes. Here we present an overview of the biochemical and genetic evidence supporting the role of five protein tyrosine phosphatases in insulin-mediated responses.

Journal of Lipid Research, 2008

European Journal of Clinical Investigation, 1996

Transfers or exchanges of cholesterol esters and triglycerides between lipoproteins are mediated ... more Transfers or exchanges of cholesterol esters and triglycerides between lipoproteins are mediated by a specialized protein referred to as cholesteryl ester transfer protein (CETP), whereas those of phospholipids (PLs) are facilitated by both CETP and a specific phospholipid transfer protein (PLTP). In the present study, the authors compared phospholipid transfer (PLT) in normal subjects and in patients with non‐insulin‐dependent diabetes (NIDD), which is associated with an increased risk of atherosclerosis. PLT was measured in different recombination experiments using an isotopic assay in which the transfer of labelled PLs from very low‐density lipoprotein (VLDLs) and low‐density lipoproteins (LDLs) to high‐density lipoproteins (HDLs) was determined. This allowed discrimination between the roles of VLDLs+LDLs, HDLs, and plasma PLT activity (PLTA). VLDL+LDL‐dependent PLT, HDL‐dependent PLT and PLTA were decreased in NIDD. VLDL+LDL‐dependent PLT was found to be negatively correlated wi...

Endocrinology, 2010

Insulin resistance and type 2 diabetes (T2D) are characterized by hyperlipidemia. The aim of the ... more Insulin resistance and type 2 diabetes (T2D) are characterized by hyperlipidemia. The aim of the present study was to elucidate whether T2D contributes to abnormal cholesterol (CHOL) homeostasis. Experiments were carried out in the small intestine and liver of Psammomys obesus, a model of nutritionally induced T2D. Our results show that diabetic animals exhibited a lower intestinal CHOL uptake, which was associated with a decrease in 1) the gene and protein expression of Niemann-Pick C1 like 1 that plays a pivotal role in CHOL incorporation in the enterocytes; and 2) mRNA of ATP-binding cassette transporters (ABC)A1 that mediates CHOL efflux from intestinal cells to apolipoprotein A-I and high-density lipoprotein. No changes were observed in the other intestinal transporters scavenger receptor-class B type I (SR-BI) and annexin 2. On the other hand, in diabetic animals, a significant mRNA decrease was noticed in intestinal ABCG5 and ABCG8 responsible for the secretion of absorbed CH...

Endocrinology, 2009

Carcinoembryonic antigen-related cell adhesion molecule 1 (CC1) is a cell adhesion molecule withi... more Carcinoembryonic antigen-related cell adhesion molecule 1 (CC1) is a cell adhesion molecule within the Ig superfamily. The Tyr-phosphorylated isoform of CC1 (CC1-L) plays an important metabolic role in the regulation of hepatic insulin clearance. In this report, we show that CC1-deficient (Cc1−/−) mice are prone to hepatic steatosis, as revealed by significantly elevated hepatic triglyceride and both total and esterified cholesterol levels compared with age-matched wild-type controls. Cc1−/− mice were also predisposed to lipid-induced hepatic steatosis and dysfunction as indicated by their greater susceptibility to store lipids and express elevated levels of enzymatic markers of liver damage after chronic feeding of a high-fat diet. Hepatic steatosis in the Cc1−/− mice was linked to a significant increase in the expression of key lipogenic (fatty acid synthase, acetyl CoA carboxylase) and cholesterol synthetic (3-hydroxy-3-methylglutaryl-coenzyme A reductase) enzymes under the contr...

Diabetologia, 2006

Aims/hypothesis Emerging evidence underscores the important role of the small intestine in the pa... more Aims/hypothesis Emerging evidence underscores the important role of the small intestine in the pathogenesis of dyslipidaemia in insulin resistance and type 2 diabetes. We therefore tested the hypothesis that n-3 fatty acids improve the various events governing intra-enterocyte lipid transport in Psammomys obesus gerbils, a model of nutritionally induced metabolic syndrome. Materials and methods Experiments were carried out on Psammomys obesus gerbils that were assigned to an isocaloric control diet and a diet rich in fish oil for 6 weeks. Results Increased dietary intake of fish oil lowered body weight and improved hyperglycaemia and hyperinsulinaemia. It simultaneously decreased de novo intestinal lipogenesis and lipid esterification of the major lipid classes, e.g. triglycerides, phospholipids and cholesteryl esters, particularly in insulinresistant and diabetic animals. Accordingly, lessened activity of monoacylglycerol and diacylglycerol acyltransferase was recorded. As assessed in cultured jejunal explants incubated with either [ 14 C]-oleic acid or [ 35 S]-methionine, fish oil feeding resulted in diminished triglyceride-rich lipoprotein assembly and apolipoprotein (apo) B-48 biogenesis, respectively. The mechanisms did not involve apo B-48 transcription or alter the gene expression and activity of the critical microsomal triglyceride transfer protein. Rather, the suppressed production of apo B-48 by n-3 fatty acids was associated with intracellular proteasome-mediated posttranslational downregulation in insulin-resistant and diabetic animals. Conclusions/interpretation Our data highlight the beneficial impact of n-3 fatty acids on adverse effects of the metabolic syndrome and emphasise their influence on intestinal lipid transport, an effect which may limit postprandial lipaemia and the risk of atherosclerosis.

Blood, 2012

DEP-1/CD148 is a receptor-like protein tyrosine phosphatase with antiproliferative and tumor-supp... more DEP-1/CD148 is a receptor-like protein tyrosine phosphatase with antiproliferative and tumor-suppressive functions. Interestingly, it also positively regulates Src family kinases in hematopoietic and endothelial cells, where we showed it promotes VE-cadherin–associated Src activation and endothelial cell survival upon VEGF stimulation. However, the molecular mechanism involved and its biologic functions in endothelial cells remain ill-defined. We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1–catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin. Accordingly, RNA interference (RNAi)–mediated knockdown of DEP-1 or expression of DEP-1 Y1311F/Y1320F impairs Src-dependent biologic responses mediated by VEGF including permeability, invasion, and branching capillary formation. In addition, our work furth...

Atherosclerosis, 1996

Cholesteryl esters (CE) exchange between lipoproteins through the action of cholesteryl ester tra... more Cholesteryl esters (CE) exchange between lipoproteins through the action of cholesteryl ester transfer protein (CETP). Situations at high risk for atherosclerosis are often accompanied by an accelerated net mass CE transfer (CET) from high density lipoproteins (HDL) to very low (VLDL) and low density lipoproteins (LDL). However, the question as to whether the net mass CET is increased or decreased in non-insulin-dependent diabetes mellitus (NIDDM) has led to controversial data. To clarify this point, we have undertaken a detailed study of CET in 105 NIDDM patients by comparison with 17 control subjects. Net mass CET was approximately doubled in NIDDM. Plasma CETP activity and unidirectional CET from HDL to VLDL + LDL (CETHDL-->VLDL + LDL) or from VLDL + LDL to HDL (CETVLDL + LDL-->HDL) were measured under controlled lipoprotein concentrations using radioisotopic assays. No difference was observed in plasma CETP activity between NIDDM and controls. In NIDDM, CETHDL-->VLDL + LDL and CETVLDL + LDL-->HDL were decreased by 25% and 20%, respectively, as a consequence of alterations in lipoprotein compositions. Net mass CET was highly correlated with plasma triglyceride (TG) concentration (r = 0.66, P < 0.001) but not with that of LDL-cholesterol (r = 0.06, P > 0.6). When TG levels were decreased following dietetic recommendations or insulinotherapy, the net mass CET was lowered accordingly. We conclude that net mass CET is accelerated in NIDDM in spite of a decreased unidirectional CETHDL-->VLDL + LDL. This results from a lowered CETVLDL + LDL-->HDL and from elevated TG concentration, and the latter probably reflects a concentration effect of VLDL.

American Journal of Physiology-Gastrointestinal and Liver Physiology, 2008

Growing evidence suggests that the small intestine may contribute to excessive postprandial lipem... more Growing evidence suggests that the small intestine may contribute to excessive postprandial lipemia, which is highly prevalent in insulin-resistant/Type 2 diabetic individuals and substantially increases the risk of cardiovascular disease. The aim of the present study was to determine the role of high glucose levels on intestinal cholesterol absorption, cholesterol transporter expression, enzymes controlling cholesterol homeostasis, and the status of transcription factors. To this end, we employed highly differentiated and polarized cells (20 days of culture), plated on permeable polycarbonate filters. In the presence of [14C]cholesterol, glucose at 25 mM stimulated cholesterol uptake compared with Caco-2/15 cells supplemented with 5 mM glucose ( P < 0.04). Because combination of 5 mM glucose with 20 mM of the structurally related mannitol or sorbitol did not change cholesterol uptake, we conclude that extracellular glucose concentration is uniquely involved in the regulation of ...