G Grimber

Université René Descartes - Paris 5, Lutetia Parisorum, Île-de-France, France

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Publications (50)261.56 Total impact

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    ABSTRACT: The Wnt/beta-catenin pathway is a key developmental pathway for which alterations have been described in various human cancers. The aberrant activation of this pathway is a major event in human hepatocellular carcinoma. Several laboratories have shown that the Wnt/beta-catenin pathway plays an essential role in all phases of liver development and maturation, and is required for the metabolic function of this organ. In this review, we summarize current knowledge regarding the role of the Wnt/beta-catenin pathway in hepatocellular carcinoma pathogenesis and liver biology, and the possibilities for developing new therapeutic interventions based on this knowledge.
    Future Oncology 11/2008; 4(5):647-60. · 3.20 Impact Factor
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    ABSTRACT: The Wnt/beta-catenin signalling pathway is activated in many human hepatocellular carcinomas (HCC). Identification of beta-catenin mutation relies mostly on sequence analysis and/or immunohistochemistry. beta-catenin mutation may also be detected by analysing the expression of its target genes. The GLUL gene encoding glutamine synthetase (GS), for example, appears to be a pertinent marker. The aim of this study was to correlate GS immunostaining and beta-catenin mutations with clinicopathological features in HCC. We found that GS immunostaining had a sensitivity of 90% for the detection of beta-catenin mutations, with 98% specificity, whereas beta-catenin immunostaining had a sensitivity of 63% with 98% specificity. We used the sensitive GS marker to characterize 190 HCC cases. Sixty-eight (36%) cases displayed Wnt/beta-catenin activation. In addition to their well-differentiated pattern, these tumours exhibited significant features such as a homogeneous microtrabeculo-acinar pattern, low-grade cellular atypia, and cholestasis. As these tumours exhibited cholestasis, we hypothesized that beta-catenin acts on specific bile synthesis and/or transport pathways. In conclusion, we propose that GS immunostaining and a cholestatic pattern are relevant criteria for the identification of HCC with beta-catenin mutations.
    The Journal of Pathology 08/2007; 212(3):345-52. · 7.59 Impact Factor
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    ABSTRACT: Perturbations to the Wnt signaling pathway have been implicated in a large proportion of human hepatocellular carcinomas (HCCs). Activating beta-catenin mutations and loss of function mutations in Axin1 are thought to be functionally equivalent. We examined the Wnt pathway in HCC by comparing the expression of beta-catenin target genes and the level of beta-catenin-dependent transcriptional activation, in 45 HCC tumors and four cell lines. Among these samples, beta-catenin and AXIN1 were mutated in 20 and seven cases, respectively. We found a significant correlation between activated beta-catenin mutations and overexpression of mRNA for the target genes glutamine synthetase (GS), G-protein-coupled receptor (GPR)49 and glutamate transporter (GLT)-1 (P=0.0001), but not for the genes ornithine aminotransferase, LECT2, c-myc and cyclin D1. We also showed that GS is a good immunohistochemical marker of beta-catenin activation in HCC. However, we observed no induction of GS, GPR49 or GLT-1 in the five inactivated Axin1 tumors. Beta-catenin-dependent transcriptional activation in two Axin1-mutated HCC cell lines was much weaker than in beta-catenin-mutated cell lines. Our results strongly suggest that in HCC, contrary to expectation, the loss of function of Axin1 is not equivalent to the gain of function of beta-catenin. Our results also suggest that the tumor suppressor function of Axin1 in HCC may be related to another, non-Wnt pathway.
    Oncogene 03/2007; 26(5):774-80. · 8.56 Impact Factor
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    ABSTRACT: The Wnt/beta-catenin signaling pathway is activated in many human hepatocellular carcinomas (HCC). We tried to identify the genes involved in carcinogenesis and progression of HCC with beta-catenin mutations. We used PCR-based subtractive hybridization to compare gene expression between malignant and benign components of a human HCC occurring in pre-existing adenoma activated for beta-catenin. Two of the genes identified belong to the Regenerating gene (REG) family. They encode the Regenerating islet-derived 3 alpha (REG3A/HIP/PAP/REG-III) and 1 alpha (REG1A) proteins, both involved in liver and pancreatic regeneration and proliferation. Using siRNA directed against beta-catenin, we demonstrated that REG3A is a target of beta-catenin signaling in Huh7 hepatoma cells. The upregulation of REG3A and REG1A expression is significantly correlated to the beta-catenin status in 42 HCC and 28 hepatoblastomas characterized for their beta-catenin status. Thus, we report strong evidence that both genes are downstream targets of the Wnt pathway during liver tumorigenesis.
    Oncogene 02/2006; 25(4):599-608. · 8.56 Impact Factor
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    ABSTRACT: In a transgenic model of hepatocellular carcinoma induced by the expression of SV40 early sequences (TAg mice), deregulation of hepatocyte proliferation induces an apoptotic process whose decrease coincides with the appearance of neoplastic foci. Mating these mice with transgenic mice overexpressing Bcl-2 led to a dramatic reduction in the number of apoptotic hepatocytes during preneoplasia, resulting in an enlargement of the liver. This decrease in apoptosis was followed, 2 weeks later, by a reduction in hepatocellular proliferation. Sequential reduction in apoptosis and proliferation rate suggests that the anti-apoptotic and the anti-mitotic activities of Bcl-2 might be operative in distinct stages of preneoplasia.
    Cancer Letters 04/2002; 177(2):189-95. · 5.02 Impact Factor
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    ABSTRACT: We have previously demonstrated that CD95-mediated apoptosis of hepatocytes is blocked in a murine model of hepatocarcinogenesis due to the expression of SV40 early sequences encoding the large-T and small-t antigens. In this study, we set out to pinpoint the sequences involved in this apoptosis-resistant phenotype, and tested several mutants of the SV40 early region for their ability to confer protection against CD95-induced apoptosis in transgenic mice. We show that resistance to apoptosis is independent of the transforming character of the mutants and demonstrate that the expression of the small-t antigen alone in transgenic mice is sufficient to confer this resistance. Our data also reveal an increased level of activated Akt kinase in these transgenic mice, and this could account for this hitherto unknown function of the SV40 small-t antigen.
    Biochemical and Biophysical Research Communications 07/2001; 284(2):369-76. · 2.28 Impact Factor
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    ABSTRACT: The role of EGF in the evolution of renal lesions after injury is still controversial. To determine whether the EGF expression is beneficial or detrimental, we generated transgenic mice expressing a COOH-terminal-truncated EGF-R under the control of the kidney-specific type 1 gamma-glutamyl transpeptidase promoter. As expected, the transgene was expressed exclusively at the basolateral membrane of proximal tubular cells. Under basal conditions, transgenic mice showed normal renal morphology and function. Infusion of EGF to transgenic animals revealed that the mutant receptor behaved in a dominant-negative manner and prevented EGF-signaled EGF-R autophosphorylation. We next evaluated the impact of transgene expression on the development of renal lesions in two models of renal injury. After 75% reduction of renal mass, tubular dilations were less severe in transgenic mice than in wild-type animals. After prolonged renal ischemia, tubular atrophy and interstitial fibrosis were reduced in transgenic mice as compared with wild-type mice. The beneficial effect of the transgene included a reduction of tubular cell proliferation, interstitial collagen accumulation, and mononuclear cell infiltration. In conclusion, functional inactivation of the EGF-R in renal proximal tubular cells reduced tubulo-interstitial lesions after renal injury. These data suggest that blocking the EGF pathway may be a therapeutic strategy to reduce the progression of chronic renal failure.
    Journal of Clinical Investigation 08/2000; 106(2):225-34. · 12.81 Impact Factor
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    ABSTRACT: To analyse the effect of p53 on liver tumor development, we generated transgenic mice overexpressing wild-type p53 in the liver and crossed them with transgenic mice in which the expression of the SV40 large T antigen (TAg) induces hepatic tumors. Remarkably, whereas preneoplastic TAg liver exhibited anisocaryosis and anisocytosis, TAg/p53 liver never presented any dysplastic cells. Moreover, whereas expression of p53 did not affect hepatic development, its constitutive expression in tumorigenic livers resulted in a significantly enhanced apoptosis once nodules had appeared. In contrast, p53 overexpression did not modify the elevated proliferation of TAg-transformed hepatocytes and had no effect on hepatocarcinoma progression. In vitro analysis of primary hepatocytes exposed to various genotoxic agents showed that p53 failed to sensitize normal or TAg-transformed hepatocytes to apoptosis, except when high doses of doxorubicin, UV-B and UV-C radiation were used. Our results confirmed that the hepatocyte cell type is very resistant to genotoxic agents and showed that constitutive expression of p53 failed to improve their responsiveness. In addition, our results showed that suppression of dysplastic cells, probably by restoring normal cytokinesis and karyokinesis, and enhancement of apoptosis by means of p53 overexpression were insufficient to counteract or delay the TAg-induced liver tumoral progression. Oncogene (2000) 19, 3498 - 3507
    Oncogene 08/2000; 19(31):3498-507. · 8.56 Impact Factor
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    ABSTRACT: The transforming activity of SV40 large T-antigen (Tag) depends on its binding to cellular proteins involved in the control of the cell cycle (p53, pRb, p300..) and on the J-domain region in the amino-terminus. We established transgenic lines expressing wild-type or Tag mutant proteins lacking one of the three transforming domains, to determine the respective contributions of these domains to hepatic tumour formation. Tag mutants with no pRb-binding domain or N-terminal fragment did not cause neoplastic liver abnormalities. The d11137 Tag mutant protein, which inhibits pRb function without affecting p53, induced hepatic tumours. These tumours grew significantly faster than those induced by wild-type Tag. Our results demonstrate different requirements for each of the inactivating functions of SV40 Tag in hepatocyte transformation and show that the loss of p53 function has only a moderate effect on hepatic tumour formation.
    Oncogene 10/1998; 17(10):1253-9. · 8.56 Impact Factor
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    ABSTRACT: T-cell prolymphocytic leukemia (T-PLL) is a rare form of mature T-cell leukemia associated with chromosomal rearrangements implicating MTCP1 or TCL1 genes. These genes encode two homologous proteins, p13(MTCP1) and p14(TCL1), which share no similarity with other known protein. To determine the oncogenic role of MTCP1, mice transgenic for MTCP1 under the control of CD2 regulatory regions (CD2-p13 mice) were generated. No abnormality was detected during the first year after birth. A late effect of the transgene was searched for in a cohort of 48 CD2-p13 mice aged 15 to 20 months, issued from 3 independent founders. Lymphoid hemopathies, occurring in the three transgenic lines, were characterized by lymphoid cells with an irregular nucleus, a unique and prominent nucleolus, condensed chromatin, a basophilic cytoplasm devoid of granules, and an immunophenotype of mature T cells. The molecular characterization of Tcrb rearrangements demonstrated the monoclonal origin of these populations. Histopathological analysis of the cohort demonstrated early splenic and hepatic infiltrations, whereas lymphocytosis and medullar infiltrations were found infrequently. The engraftment of these proliferations in H2-matched animals demonstrated their malignant nature. Cumulative incidence of the disease at 20 months was 100%, 50%, and 21% in F3, F4, and F7 lines, respectively, and null in the control group. The level of expression of the transgene, as estimated by Western blotting in the transgenic lines correlated with the tumoral incidence, with the highest expression of p13(MTCP1) being found in F3 mice. CD2-p13 transgenic mice developed an hemopathy similar to human T-PLL. These data demonstrate that p13(MTCP1) is an oncoprotein and that CD2-p13 transgenic mice represent the first animal model for mature T-PLL.
    Blood 08/1998; 92(2):368-73. · 9.78 Impact Factor
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    ABSTRACT: Up to now, transgenic mice models created to study the physiological impact of alterations in the human beta-adrenoceptor system have only focused on cardiac tissues and carried hybrid transgenes with strong cardiac promoters. We have developed a transgenic mouse strain (F28) carrying the human beta 2-adrenoceptor gene with its natural promoter region with the aim of producing a model that more closely reproduces the natural human beta 2-adrenoceptor tissue expression pattern. By means of northern blot analyses, using the appropriate probes, we have obtained evidence that (a) the human beta 2-adrenoceptor's structural gene is transcribed in several tissues of F28 mice; (b) the tissue distribution pattern of human beta 2-adrenoceptor mRNA in F28 mice completely differs from that of mouse beta 2-adrenoceptor mRNA; and (c) the tissue distribution pattern of mouse beta 2-adrenoceptor mRNA in F28 mice is very similar to that observed in their non-transgenic littermates. Like humans, F28 mice express human beta 2-adrenoceptor mRNA in liver, lung, brain, heart, and muscle. However, unlike humans, F28 mice do not accumulate human beta 2-adrenoceptor mRNA in kidney and spleen. By using [125I]iodocyanopindolol to label all beta-adrenoceptors and ICI 118,551 to discriminate between the binding to beta 2- and beta 1-adrenoceptors we have demonstrated that the beta 2-adrenoceptor binding activity increases over control values in F28 mouse tissues that accumulate transgenic mRNA. Accordingly, the number of beta 2-adrenoceptors increased slightly over the control values in muscle, heart, brain, and lung of F28 mice, while in liver these receptors were strongly overexpressed. We further showed that transgene beta 2-adrenoceptors couple to GTP-binding proteins, mediate beta-adrenoceptor agonist-stimulated adenylyl cyclase activation, and cause a strong enhancement of this response in liver membranes of F28 versus control mice. Finally, F28 mice show a phenotype of depressed ponderal development and perturbed hindquarter movements. This unique model should be useful to further investigate beta 2-adrenoceptor causal relationships with human pathologies.
    European Journal of Biochemistry 11/1996; 241(2):417-24. · 3.58 Impact Factor
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    ABSTRACT: Insertional mutagenesis of the spi-1 gene is associated with the emergence of malignant proerythroblasts during Friend virus-induced acute erythroleukemia. To determine the role of spi-1/PU.1 in the genesis of leukemia, we generated spi-1 transgenic mice. In one founder line the transgene was overexpressed as an unexpected-size transcript in various mouse tissues. Homozygous transgenic animals gave rise to live-born offspring, but 50% of the animals developed a multistep erythroleukemia within 1.5 to 6 months of birth whereas the remainder survived without evidence of disease. At the onset of the disease, mice became severely anemic. Their hematopoietic tissues were massively invaded with nontumorigenic proerythroblasts that express a high level of Spi-1 protein. These transgenic proerythroblasts are partially blocked in differentiation and strictly dependent on erythropoietin for their proliferation both in vivo and in vitro. A complete but transient regression of the disease was observed after erythrocyte transfusion, suggesting that the constitutive expression of spi-1 is related to the block of the differentiation of erythroid precursors. At relapse, erythropoietin-independent malignant proerythroblasts arose. Growth factor autonomy could be partially explained by the autocrine secretion of erythropoietin; however, other genetic events appear to be necessary to confer the full malignant phenotype. These results reveal that overexpression of spi-1 is essential for malignant erythropoiesis and does not alter other hematopoietic lineages.
    Molecular and Cellular Biology 06/1996; 16(5):2453-63. · 5.37 Impact Factor
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    ABSTRACT: Apoptosis is crucial for the normal development of multicellular organisms and is also important for clearing injured cells, such as virus-infected cells or cancer cells. Defective regulation of apoptosis may contribute to viral pathogenesis and aetiology of cancer. Apoptosis of injured cells is principally triggered by the immune system through cytokines such as Fas-ligand and TNF-alpha. Thus, one of the functions of a viral oncogene, such as SV40T-antigen, may be to inhibit cytokine-mediated apoptosis. We previously demonstrated that Fas-mediated apoptosis of hepatocytes is blocked by the wild-type SV40T-antigen during hepatocarcinogenesis. We determined whether this inhibition was directly related to the T-antigen or whether it is a secondary event of cell transformation, by generating transgenic mice expressing a non-transforming T-antigen mutant able to bind endogenous p53 in the liver. This T-antigen mutant cannot induce hepatocarcinoma, unlike the wild-type T-antigen. However, like the wild-type T-antigen, the mutant was a potent inhibitor of apoptosis induced by the Fas-receptor, but not by the TNF-receptor. Therefore, SV40T-antigen has a new property; the inhibition of Fas-mediated apoptosis, which could facilitate the emergence of transformed hepatocytes, but is not sufficient to induce it.
    Cell Death and Differentiation 02/1996; 3(1):91-6. · 8.37 Impact Factor
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    ABSTRACT: Transgenesis allows the in vivo determination of the effects of oncogene expression in normal tissues. In an attempt to understand the mechanism underlying liver transformation, we have previously created transgenic mice carrying the SV40 early gene sequences, which developed hepatocarcinoma in a reproducible way. In the present study, we show that constant expression of the transgene was directly correlated to an abnormally increased hepatocyte proliferation, even at the adult stage. We further demonstrate in this model that the preneoplastic stage of hepatocarcinoma is characterized by marked ploidy alterations as early as 1 month, including the emergence of aneuploid and hyperpolyploid cells, and the persistence of an important diploid cell population. We show that this elevated proliferation is early and transiently counterbalanced by a mechanism of apoptosis, which maintains liver homeostasis. The disappearance of this programmed cell death response effective during preneoplasia might signal the commitment of the liver to neoplasia.
    Oncogene 01/1996; 11(12):2583-90. · 8.56 Impact Factor
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    ABSTRACT: Up to now, transgenic mice models created to study the physiological impact of alterations in the human -adrenoceptor system have only focused on cardiac tissues and carried hybrid transgenes with strong cardiac promoters. We have developed a transgenic mouse strain (F28) carrying the human 2-adrenoceptor gene with its natural promoter region with the aim of producing a model that more closely reproduces the natural human 2-adrenoceptor tissue expression pattern. By means of northern blot analyses, using the appropriate probes, we have obtained evidence that (a) the human 2-adrenoceptor's structural gene is transcribed in several tissues of F28 mice; (b) the tissue distribution pattern of human 2-adrenoceptor mRNA in F28 mice completely differs from that of mouse 2-adrenoceptor mRNA; and (c) the tissue distribution pattern of mouse 2-adrenoceptor mRNA in F28 mice is very similar to that observed in their non-transgenic littermates. Like humans, F28 mice express human 2-adrenoceptor mRNA in liver, lung, brain, heart, and muscle. However, unlike humans, F28 mice do not accumulate human 2-adrenoceptor mRNA in kidney and spleen. By using [125I]idocyanpindolol to label all -adrenoceptors and ICI 118,551 to discriminate between the binding to 2- and 1-adrenoceptors we have demonstrated that the 2-adrenoceptor binding activity increases over control values in F28 mouse tissues that accumulate transgenic mRNA. Accordingly, the number of 2-adrenoceptors increased slightly over the control values in muscle, heart, brain, and lung of F28 mice, while in liver these receptors were strongly overexpressed. We further showed that transgene 2-adrenoceptors couple to GTP-binding proteins, mediate P-adrenoceptor agonist-stimulated adenylyl cyclase activation, and cause a strong enhancement of this response in liver membranes of F28 versus control mice. Finally, F28 mice show a phenotype of depressed ponderal development and perturbed hindquarter movements. This unique model should be useful to further investigate 2-adrenoceptor causal relationships with human pathologies.
    European Journal of Biochemistry 01/1996; 241(2):417-424. · 3.58 Impact Factor
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    ABSTRACT: The contribution of the hepatitis B virus enhancers I and II in the regulation of the activity of the core and the X promoters was assessed in transgenic mice. Surprisingly, despite the presence of heterologous promoters linked 5' of the X gene, the transgene expression is mostly due to core promoter (Cp) activity present in the X coding sequence. Moreover, the restriction of Cp activity to hepatic tissue required the combined action of both enhancers I and II, whereas the proximity of these two enhancers was insufficient to confer tissue specificity on Xp activity. Furthermore, the liver-specific activity of the Cp was developmentally regulated in an enhancer I-independent manner.
    Journal of Virology 10/1995; 69(9):5912-6. · 5.08 Impact Factor
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    ABSTRACT: The product of the tat gene is the most potent transcriptional trans-activator of the HIV-1 LTR (Human Immunodeficiency Virus type 1 Long Terminal Repeat) and might be predicted to be one of the HIV-1 proteins involved in the pathogenesis of AIDS-associated tumors. Deciphering its role in vivo may imply generation of transgenic mouse models displaying different spectra of tat expression. However, it remains difficult to correlate the mRNA expression, the protein production and the eventual pathological consequences in the animal. Our goal in this work was to elaborate a binary transgenic system allowing such an approach, the correlation of the transgene expression in different tissues and the production of the Tat protein, tested as a trans-activator in vivo, with its pathogenic effects. No direct linkage was evident between the degree of transactivation and pathogenesis. Indeed, only benign lesions were observed in malpighian epithelia, where the production of the Tat protein was clearly evidenced by its transactivating property.
    Comptes Rendus de l Académie des Sciences - Series III - Sciences de la Vie 04/1995; 318(3):329-37.
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    ABSTRACT: It has previously been shown that the hepatitis B virus X gene product, pX, transactivates homologous and heterologous transcriptional regulatory sequences of viruses and various cellular genes in vitro. However, there is no evidence about the reproducibility and the relevance of this phenomenon in vivo. In this study we crossbred transgenic mice expressing the X gene under the control of the human antithrombin III (ATIII) gene regulatory sequences with transgenics carrying either the chloramphenicol acetyl-transferase or the LacZ bacterial reporter genes driven by the HIV1-LTR, which is known to be activated in trans by pX. Expression of pX in the liver stimulates the HIV1-LTR driven expression of both chloramphenicol acetyl-transferase and beta-galactosidase reporter genes in double transgenic mice. No detectable increase in chloramphenicol acetyl-transferase expression was observed in tissues, such as the spleen, brain and heart, that do not express pX. Our results confirm the transactivating properties of pX in vivo for the first time and support the hypothesis that pX might indeed modify gene expression in HBV-infected hepatocytes and influence viral pathogenesis.
    Journal of Hepatology 08/1994; 21(1):103-9. · 9.86 Impact Factor
  • Journal of Hepatology - J HEPATOL. 01/1994; 21(1):103-109.
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    ABSTRACT: We report here that the transcriptional activity of early mouse embryos is affected by their manipulation and culture in vitro, using transgenic embryos that express the reporter gene lacZ. We examined the pattern of expression of the lacZ gene fused to the human immunodeficiency virus type 1 long terminal repeat during the preimplantation stages. Transgene expression is induced as early as the two-cell stage in embryos developed in vitro, while there is no constitutive expression at the same stage in embryos developed in vivo. We have established a relation between this inducible expression occurring in vitro and an oxidative stress phenomenon. Indeed, when the culture medium is supplemented with antioxidants such N-acetyl-cysteine or CuZn-superoxide dismutase the transgene expression is markedly reduced. We also present evidence that the transgene expression in vitro coincides with the onset of the embryonic genome activation as attested by the synthesis of the 70 x 10(3) M(r) protein complex. Therefore, this transgene expression could prove to be a useful tool in our understanding of the molecular mechanisms involved in this crucial developmental event.
    Development 01/1994; 119(4):1293-300. · 6.21 Impact Factor

Publication Stats

1k Citations
261.56 Total Impact Points

Institutions

  • 2007
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 1991–2001
    • Institut de Génétique Moléculaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France
  • 1990–1995
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1993
    • Institut de Génétique et de Biologie Moléculaire et Cellulaire
      Strasburg, Alsace, France
  • 1990–1992
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1987
    • Collège de France
      Lutetia Parisorum, Île-de-France, France