Fabrice Mélet - Academia.edu (original) (raw)

Papers by Fabrice Mélet

Molecular and Cellular Biology, Dec 1, 1995

The proto-oncogene Fli-1 is a member of the ets family of transcription factor genes. Its high ex... more The proto-oncogene Fli-1 is a member of the ets family of transcription factor genes. Its high expression in the thymus and spleen and the presence of DNA binding sites for Fli-1 in a number of lymphoid cell-specific genes suggest that Fli-1 is involved in the regulation of lymphopoiesis. Activation of the Fli-1 gene by either chromosomal translocation or viral insertion leads to Ewing's sarcoma in humans and erythroleukemia in mice, respectively. Thus, Fli-1 is normally involved in pathways involved in the regulation of cell growth and differentiation. We have generated H-2K k-Fli-1 transgenic mice that overexpress Fli-1 in various mouse tissues, with the highest levels of Fli-1 protein in the thymus and spleen. These Fli-1 transgenic mice developed a high incidence of a progressive immunological renal disease and ultimately died of renal failure caused by tubulointerstitial nephritis and immune-complex glomerulonephritis. The incidences of renal disease correlated with the levels of Fli-1 protein in lymphoid tissues of transgenic lines. The hypergammaglobulinemia, splenomegaly, B-cell hyperplasia, accumulation of abnormal CD3 ؉ B220 ؉ T lymphoid cells and CD5 ؉ B220 ؉ B cells in peripheral lymphoid tissues, and detection of various autoantibodies in the sera of diseased Fli-1 transgenic mice suggested the involvement of an immune dysfunction in the pathogenesis of the renal disease. In addition, splenic B cells from transgenic mice exhibited increased proliferation and prolonged survival in vitro in response to mitogens. Taken together, these data suggest that overexpression or ectopic expression of Fli-1 perturbs normal lymphoid cell function and programmed cell death. Thus, H-2K k-Fli-1 transgenic mice may serve as a murine model for autoimmune disease in humans, such as systemic lupus erythematosus.

Immunity, Aug 1, 2000

and Cancer 1992). Transcriptional activation of Fli-1 by either chro-Samuel Lunenfeld Research In... more and Cancer 1992). Transcriptional activation of Fli-1 by either chro-Samuel Lunenfeld Research Institute mosomal translocation or proviral insertion leads to Ew-Mount Sinai Hospital ings sarcoma in humans (Delattre et al., 1992) and eryth-600 University Avenue roleukemia in mice, respectively (Ben David et al., 1991). Toronto, Ontario M5G 1X5 The human Fli-1 gene is rearranged in Ͼ90% of Ewings 2 Department of Medical Genetics and Microbiology sarcomas, a common pediatric tumor of neuroectoder-University of Toronto mal origin (Ida et al., 1995). In this disease, the DNA Toronto, Ontario M5S 1A8 binding (ETS) domain of Fli-1 is translocated to the EWS 3 Canadian Institutes of Health Research locus on chromosome 22 [t(11;22)(q24;q12)], forming a 410 Laurier Avenue West fusion protein with altered expression and transactiva-Postal Locator 4209A tion properties (Bailly et al., 1994). In mice infected with Ottawa, Ontario K1A 0W9 the Friend murine leukemia virus (F-MuLV), 75% of the Canada resulting erythroleukemias have insertional activation of the Fli-1 gene (Ben David et al., 1991). Thus, dysregula-4 UCSD-Salk Program in Molecular Medicine tion of Fli-1 is a common factor in the progression of at University of California, San Diego least two distinct tumor types. School of Medicine The human Fli-1 gene maps to chromosome 11q24 in 9500 Gilman Drive a region that is deleted in Jacobsen and Paris-Trousseau La Jolla, California 92093 syndrome in humans (Breton-Gorius et al., 1995). Jacob-5 Department of Experimental Hematology sen syndrome is a relatively infrequent ‫)000,001/1ف(‬ St. Bartholomew's and Royal London Medical congenital disorder that often includes growth and menand Dental School tal retardation, cardiac defects (Grossfeld et al., 1999), Turner Street dysmorphogenesis of the digits and face, pancytopenia, London E1 2AD and thrombocytopenia (Penny et al., 1995). Most Jacob-6 Institute of Biotechnology sen syndrome deletions occur distal to the FRA11B lo-University of Cambridge cus at 11q23.3, resulting in deletion of the Fli-1 gene Tennis Court Road (Tunnacliffe et al., 1999). Cambridge CB2 1QT Murine Fli-1 is expressed at E8.5 in the blood islands United Kingdom of the extra embryonic visceral yolk sac in a pattern 7 INSERM U.91 consistent with its expression in putative erythroid/ endothelial precursors or hemangioblasts present at this Hopital D'enfants Armand-Trousseau time (Melet et al., 1996). Later in gestation, Fli-1 is ex-26, avenue du Arnold-Netter pressed in the developing vasculature and within the 75571 Paris liver, coincident with fetal hematopoiesis. Homologs of France the mammalian Fli-1 gene have been identified in several other vertebrates, including quail (Mager et al., 1998), Xenopus (Meyer et al., 1995), and zebrafish (Brown et Summary al., 2000). The sequence of Fli-1 and its expression in developing vascular endothelial cells is highly con-The ETS gene Fli-1 is involved in the induction of erythserved throughout vertebrate evolution. roleukemia in mice by Friend murine leukemia virus The biological function of Fli-1 has been addressed and Ewings sarcoma in children. Mice with a targeted by examining its DNA binding specificity, pattern of exnull mutation in the Fli-1 locus die at day 11.5 of empression during development, and phenotypic effects bryogenesis with loss of vascular integrity leading to in mutant mice. In cell culture experiments, Fli-1, and/ bleeding within the vascular plexus of the cerebral or closely related members of the ETS family, bind to enhancer sequences and transactivate a number of meninges and specific downregulation of Tek/Tie-2, genes involved in vasculogenesis, hematopoiesis, and the receptor for angiopoietin-1. We also show that cell adhesion, including the endothelial-specific vascudysmegakaryopoiesis in Fli-1 null embryos resembles lar endothelial-cadherin (VE-CAD) (Gory et al., 1998), that frequently seen in patients with terminal deletions Tek/Tie-2 (Dube et al., 1999), intercellular cellular adheof 11q (Jacobsen or Paris-Trousseau Syndrome). We sion (I-CAM) genes (de Launoit et al., 1998), and the map the megakaryocytic defects in 14 Jacobsen pamegakaryocyte-specific genes glycoprotein IIB (GpIIb) tients to a minimal region on 11q that includes the Fli-1 (Zhang et al., 1993), GpIX (Bastian et al., 1996), Von gene and suggest that dysmegakaryopoiesis in these Willebrand factor (VWF) (Schwachtgen et al., 1997), and patients may be caused by hemizygous loss of Fli-1. platelet factor 4 (PF4) (Lemarchandel et al., 1993). In addition, overexpression of Fli-1 in K562 cells correlates with, and can induce, megakaryocytic differentiation 8 To whom correspondence should be addressed (e-mail: hart@ mshri.on.ca).

Molecular and Cellular Biology, Jun 1, 1996

The proto-oncogene Fli-1 is a member of the ets family of transcription factor genes. Its activat... more The proto-oncogene Fli-1 is a member of the ets family of transcription factor genes. Its activation by either chromosomal translocation or proviral insertion leads to Ewing's sarcoma in humans or erythroleukemia in mice, respectively. Fli-1 is preferentially expressed in hematopoietic and endothelial cells. This expression pattern resembled that of c-ets-1, another ets gene closely related and physically linked to Fli-1. We also generated a germ line mutation in Fli-1 by homologous recombination in embryonic stem cells. Homozygous mutant mice exhibit thymic hypocellularity which is not related to a defect in a specific subpopulation of thymocytes or to increased apoptosis, suggesting that Fli-1 is an important regulator of a prethymic T-cell progenitor. This thymus phenotype was corrected by crossing the Fli-1-deficient mice with transgenic mice expressing Fli-1 cDNA. Homozygous mutant mice remained susceptible to erythroleukemia induction by Friend murine leukemia virus, although the latency period was significantly increased. Surprisingly, the mutant Fli-1 allele was still a target for Friend murine leukemia virus integration, and leukemic spleens with a rearranged Fli-1 gene expressed a truncated Fli-1 protein that appears to arise from an internal translation initiation site and alternative splicing around the neo cassette used in the gene targeting. The fortuitous discovery of the mutant Fli-1 protein, revealed only as the result of the clonal expansion of leukemic cells harboring a rearranged Fli-1 gene, suggests caution in the interpretation of gene-targeting experiments that result in either no or only a subtle phenotypic alteration.

The New biologist, 1990

The v-erbA oncogene encodes an altered form of the nuclear receptor of the thyroid hormone triiod... more The v-erbA oncogene encodes an altered form of the nuclear receptor of the thyroid hormone triiodothyronine (T3). This altered receptor is unable to bind T3, and blocks the differentiation of chicken erythrocyte progenitor cells. To identify the cellular target genes of v-ErbA in the transformed cells, we analysed the expression of several genes in normal erythrocytic cells exposed to T3, and found that the gene encoding carbonic anhydrase II is transcriptionally activated by the hormone. In contrast, this gene is repressed in erythroleukemic cells transformed by the v-erbA product. To investigate in more details the effects of v-ErbA, we constructed a mutant of v-ErbA in which we restored the ability to bind T3. This mutant developed its oncogenicity only in the absence of T3. Upon binding of T3, the transformed cells differentiated and immediately expressed the carbonic anhydrase II gene. These data show that v-ErbA directly inhibits the transcription of the carbonic anhydrase II ...

Molecular and Cellular Biology, 1996

Molecular and Cellular Biology, 1995

Molecular and Cellular Biology, 2000

The proto-oncogene Fli-1 encodes a transcription factor of the ets family whose overexpression is... more The proto-oncogene Fli-1 encodes a transcription factor of the ets family whose overexpression is associated with multiple virally induced leukemias in mouse, inhibits murine and avian erythroid cell differentiation, and induces drastic perturbations of early development in Xenopus . This study demonstrates the surprisingly sophisticated regulation of Fli-1 mRNA translation. We establish that two FLI-1 protein isoforms (of 51 and 48 kDa) detected by Western blotting in vivo are synthesized by alternative translation initiation through the use of two highly conserved in-frame initiation codons, AUG +1 and AUG +100. Furthermore, we show that the synthesis of these two FLI-1 isoforms is regulated by two short overlapping 5′ upstream open reading frames (uORF) beginning at two highly conserved upstream initiation codons, AUG −41 and GUG −37, and terminating at two highly conserved stop codons, UGA +35 and UAA +15. The mutational analysis of these two 5′ uORF revealed that each of them n...

Immunity, 2000