113 results on '"Stéhelin, D."'
Search Results
2. Identification and Preferential Expression in Thymic and Bursal Lymphocytes of a c-ets Oncogene-Encoded Mr 54,000 cytoplasmic protein
- Author
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Ghysdael, J., Gegonne, A., Pognonec, P., Dernis, D., Leprince, D., and Stehelin, D.
- Published
- 1986
3. Stromelysin-1 expression is activated in vivo by Ets-1 through palindromic head-to-head Ets binding sites present in the promoter
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Baillat, D, Leprivier, G, Régnier, D, Vintonenko, N, Bègue, A, Stéhelin, D, and Aumercier, M
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- 2006
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4. The Nucleotide Sequence of the erbA Gene of Avian Erythroblastosis Virus Appears Unrelated to Other Known Oncogenes
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Henry, C., Debuire, B., Benaissa, M., Biserte, G., Saule, S., Martin, P., Stehelin, D., Gallo, Robert C., editor, Stehelin, Dominique, editor, and Varnier, Oliviero E., editor
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- 1985
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5. Retroviruses with Two Oncogenes
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Stehelin, D., Martin, P., Gallo, Robert C., editor, Stehelin, Dominique, editor, and Varnier, Oliviero E., editor
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- 1985
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6. Cooperation of Oncogenes in Malignant Transformation
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Stehelin, D. and Miller, Alain O. A., editor
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- 1989
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7. Retroviruses with Two Oncogenes
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Stehelin, D., Martin, P., Heimpel, H., editor, Huhn, D., editor, Mueller-Eckhardt, C., editor, Ruhenstroth-Bauer, G., editor, Neth, Rolf, editor, Gallo, Robert C., editor, Greaves, Melvyn F., editor, and Kabisch, Hartmut, editor
- Published
- 1987
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8. STRUCTURE OF AVIAN DEFECTIVE LEUKAEMIA VIRUS GENOMES
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Stéhelin, D., primary, Saule, S., additional, Roussel, M., additional, and Pluquet, N., additional
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- 1980
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9. Molecular cloning and characterization of human ERM, a new member of the Ets family closely related to mouse PEA3 and ER81 transcription factors
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Monté D, Jl, Baert, Pierre-Antoine Defossez, de Launoit Y, and Stéhelin D
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DNA-Binding Proteins ,Mice ,Open Reading Frames ,DNA, Complementary ,Base Sequence ,Proto-Oncogene Proteins ,Molecular Sequence Data ,Animals ,Humans ,Amino Acid Sequence ,Blotting, Northern ,Sequence Alignment ,Transcription Factors - Abstract
The ets-related transcription factors PEA3 and ER81 have recently been isolated and characterized in the mouse. They share 95% identity in a 85 amino acid (AA) domain termed the ETS domain which is responsible for DNA binding, and therefore they form an Ets family group. By screening a human testis cDNA library with a probe containing the mouse PEA3 ETS domain, we isolated a 2.2 kb clone containing a 510 AA open reading frame. Since the ETS domain, which is localized in the carboxy terminal region of the encoded protein, is 95% and 96% identical to that of PEA3 and ER81, respectively, we named this new member 'Ets Related Molecule PEA3-like' (ERM). Although the first 120 AA in the amino-terminal region of ERM share 47% identity with PEA3 and 66% with ER81, ERM contains a central region of approximately 35 AA not found in the two mouse proteins. Gel shift analysis indicates that the full-length ERM protein is able to bind specifically to an oligonucleotide containing the consensus nucleotide core sequence GGAA recognized by the Ets proteins. Moreover, in vitro translation of 83 AA of the ERM ETS domain led to the production of a truncated protein which also binds to DNA. Though differential expression is observed in primary tumors and normal lymphocytes do not express ERM, this gene is almost ubiquitously expressed in human normal tissues. ERM mRNA is highly expressed in brain as well as in placenta and, to a lesser degree, in lung, pancreas, and heart. Moreover, almost all human cell lines tested express it at varying levels. In mouse tissues, we showed that PEA3 and ER81 mRNAs display restricted expression, whereas ERM is almost ubiquitously expressed as observed for human tissues. Altogether these results indicate that ERM is clearly a new ets family member and not the human equivalent of PEA3 or ER81.
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- 1994
10. Definition of functional domains in P135gag-myb-ets and p48v-myb proteins required to maintain the response of neuroretina cells to basic fibroblast growth factor
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D Gospodarowicz, D Leprince, Joseph S. Lipsick, Saule S, Stéhelin D, and Carmen Garrido
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animal structures ,Immunology ,Basic fibroblast growth factor ,Molecular Sequence Data ,Retroviridae Proteins, Oncogenic ,Gene Products, gag ,Chick Embryo ,Biology ,Fibroblast growth factor ,Microbiology ,Oncogene Proteins v-myb ,Retina ,Cell Line ,Gene product ,chemistry.chemical_compound ,Virology ,Animals ,MYB ,Herpes simplex virus protein vmw65 ,Avian Myeloblastosis Virus ,Base Sequence ,Cell growth ,Molecular biology ,Kinetics ,chemistry ,Cell culture ,Insect Science ,DNA, Viral ,Mutation ,cardiovascular system ,Fibroblast Growth Factor 2 ,Cell Division ,circulatory and respiratory physiology ,Research Article - Abstract
The v-myb- and v-ets-containing E26 retrovirus induces the proliferation of chicken neuroretina (CNR) cells in minimal medium. Proliferation of E26 CNR cells is strongly stimulated by basic fibroblast growth factor (bFGF). The v-myb-containing avian myeloblastosis virus also induces the proliferation of infected CNR cells stimulated by bFGF. Both E26 CNR and avian myeloblastosis virus CNR cells are able to form colonies in soft agar in the presence of bFGF. This suggests that the v-myb product, a nuclear sequence-specific DNA-binding protein which activates gene expression in transient transfection assays, plays a role in the proliferative response of the infected CNR cells. To determine the structure-function relationships of P135gag-myb-ets and p48v-myb, we have used deletion mutants expressed in retroviral vectors and have analyzed their effect on CNR cell proliferation as well as their effect on the CNR cell response to bFGF. We show that v-ets is not required for bFGF stimulation but increases the proliferation of CNR cells in minimal medium. In the v-myb mutants, the gag sequences derived from the helper virus increase the potency of the myb gene. The carboxyl-terminal domain required for the growth and transformation of myeloid cells and needed for maximal trans-activation in transient DNA transfection assays in fibroblasts was not required for the growth and bFGF response of CNR cells. In contrast, the domain encompassing amino acids 240 to 301 (containing part of the transcriptional activation domain of v-myb) was absolutely required for the response of CNR cells to bFGF and could be functionally replaced by the carboxyl-terminal transcriptional activation domain of the VP16 protein of herpes simplex virus.
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- 1992
11. Characterization of a new melanocyte-specific gene (QNR-71) expressed in v-myc-transformed quail neuroretina.
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Turque, N., primary, Denhez, F., additional, Martin, P., additional, Planque, N., additional, Bailly, M., additional, Bègue, A., additional, Stéhelin, D., additional, and Saule, S., additional
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- 1996
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12. A functional Rev-erb alpha responsive element located in the human Rev-erb alpha promoter mediates a repressing activity.
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Adelmant, G, primary, Bègue, A, additional, Stéhelin, D, additional, and Laudet, V, additional
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- 1996
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13. Molecular cloning of a novel widely expressed human 80 kDa 17β-hydroxysteroid dehydrogenase IV
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Adamski, J, primary, Normand, T, additional, Leenders, F, additional, Monté, D, additional, Begue, A, additional, Stéhelin, D, additional, Jungblut, P W, additional, and de Launoit, Y, additional
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- 1995
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14. Analyse moléculaire de l'angiogenèse tumorale
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Vandenbunder, B, primary, Fafeur, V, additional, Wernert, N, additional, and Stéhelin, D, additional
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- 1994
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15. Interconnection between thyroid hormone signalling pathways and parvovirus cytotoxic functions
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Vanacker, J M, primary, Laudet, V, additional, Adelmant, G, additional, Stéhelin, D, additional, and Rommelaere, J, additional
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- 1993
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16. Evolution of the nuclear receptor gene superfamily.
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Laudet, V., primary, Hänni, C., additional, Coll, J., additional, Catzeflis, F., additional, and Stéhelin, D., additional
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- 1992
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17. Mitogenic stimulation of thymocytes results in the calcium‐dependent phosphorylation of c‐ets‐1 proteins.
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Pognonec, P., Boulukos, K. E., Gesquière, J. C., Stéhelin, D., and Ghysdael, J.
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Human, murine and chicken c‐ets‐1 proteins migrate in SDS‐polyacrylamide gels as multiple species. We show here that most if not all of this heterogeneity is due to phosphorylation events occurring predominantly on serine and to a lesser extent on threonine residues. These phosphorylations can be specifically and rapidly stimulated by treatment with the calcium ionophore A23187 or abolished by lowering the extracellular calcium concentration to less than 0.1 microM. The products encoded by c‐ets‐2 are also phosphorylated in a Ca2+‐dependent manner, indicating that these modifications have been conserved in the products encoded by different members of the same gene family. In thymocytes, where the expression of c‐ets‐1 is elevated as compared with other cell types, c‐ets‐1 protein phosphorylation occurs after stimulation with mitogenic doses of concanavalin A, is short lived and is strictly dependent upon extracellular Ca2+ sources. This suggests that the c‐ets‐1 gene product may play a role in the Ca2+‐mediated early events linked to T‐cell activation.
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- 1988
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18. Identification in chickens of an evolutionarily conserved cellular ets‐2 gene (c‐ets‐2) encoding nuclear proteins related to the products of the c‐ets proto‐oncogene.
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Boulukos, K. E., Pognonec, P., Begue, A., Galibert, F., Gesquière, J. C., Stéhelin, D., and Ghysdael, J.
- Abstract
In chicken cells, we previously identified a set of proteins (p58‐64) structurally related to, but distinct from, the products encoded by the c‐ets proto‐oncogene. We report here the isolation and nucleotide sequence of a cDNA encoding nuclear products of mol. wt 58, 60, 62 and 64 kd, indistinguishable from those detected in chicken cells. The p60 and p64 species appear to represent phosphorylated versions on serine and threonine residues of p58 and p62. The homology of p58‐64 to other ets‐related proteins, including the v‐ets encoded domain of the transforming protein of avian leukemia virus E26 and p54c‐ets, the translation product of the chicken (Ck) c‐ets gene, is confined to two regions of 175 and 96 amino acid residues localized respectively at the carboxy‐terminal domain and close to the amino‐terminal domain of these molecules. This cDNA corresponds to a gene localized in a locus distinct from that of c‐ets which is transcribed as a 4.0‐kb RNA species in most chicken tissues. We also identified the human (Hu) c‐ets‐2‐encoded products as two proteins of 60 and 62 kd, highly related to chicken p58‐64. This, together with the fact that the amino acid sequence of the cDNA encoding p58‐64 is 95% identical to the reported partial sequence of a Hu‐c‐ets‐2 cDNA, indicates that p58‐64 are the translation products of the Ck‐c‐ets‐2 gene.
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- 1988
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19. Expression patterns of c-myb and of v-myb induced myeloid-1 (mim-1) gene during the development of the chick embryo.
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Quéva, C, Ness, S A, Grässer, F A, Graf, T, Vandenbunder, B, and Stéhelin, D
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The v-myb oncogene of the acute avian leukemia virus E26 encodes a transcription factor that directly regulates the promyelocyte-specific mim-1 gene (Ness, S.A., Marknell, A. and Graf, T. Cell, 59, 1115-1125). We have investigated the relationship between the c-myb proto-oncogene and the transcription of the mim-1 gene both in vitro and in vivo. We demonstrate that the c-myb protein can transactivate the transcription of mim-1 in a transient transfection assay. In the chick embryo, we confirm that mim-1 is specifically expressed during granulopoiesis and we show that the expression of c-myb and mim-1 are perfectly correlated in the granulocytic spleen and pancreas. However we suggest that mim-1 is efficiently transcribed in the absence of c-myb in the yolk sac and in the promyelocytes at the onset of the colonization of the bursa of Fabricius. On the other hand c-myb transcripts detected in the early hemopoietic progenitor cells, in lymphoid cells and in proliferative epithelia are never associated with mim-1 transcription. We conclude that the granulocyte-specific mim-1 gene is regulated by c-myb-dependent and c-myb-independent mechanisms depending upon the environment in which granulocytic precursor cells differentiate.
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- 1992
20. The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner.
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Basuyaux, J P, Ferreira, E, Stéhelin, D, and Butticè, G
- Abstract
The transcription factors Fos, Jun, and Ets regulate the expression of human stromelysin-1 and collagenase-1 genes. Recently, we found that ERG, an Ets family member, activates collagenase-1 gene but not stromelysin-1 by physically interacting with c-Fos/c-Jun. Interestingly, ERG binds to stromelysin-1 promoter and represses its activation by ETS2. Here, to investigate the molecular mechanism of this regulation, we have used an in vitro protein-protein interaction assay and studied the transcription factor interactions of ETS2. We found that ETS2 could weakly associate with in vitro synthesized ETS1, c-Fos, and c-Jun and strongly with c-Fos/c-Jun complex and ERG via several distinct ETS2 domains including the C-terminal region that contains the DNA-binding domain. Strikingly, these interactions were stabilized in vitro by DNA as they were inhibited by ethidium bromide. Both the N-terminal region, comprising the transactivation domain, and the C-terminal region of ETS2 associated with ERG and, interestingly, the interaction of ERG through the transactivation domain of ETS2 was DNA-independent. The DNA-dependent interaction of ETS2 with c-Fos/c-Jun was enhanced by specific DNA fragments requiring two Ets-binding sites of the stromelysin-1 promoter. Using the two hybrid system, we also demonstrated that ETS2 interacts with c-Jun or ERG in vivo.
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- 1997
21. Two nuclear oncogenic proteins, P135gag-myb-ets and p61/63myc, cooperate to induce transformation of chicken neuroretina cells
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Amouyel, P, Laudet, V, Martin, P, Li, R P, Quatannens, B, Stéhelin, D, and Saule, S
- Abstract
Several studies have shown that full transformation of primary rodent fibroblasts can be achieved in vitro through the cooperation of two oncogenes (usually one nuclear and one cytoplasmic) classified on the basis of different complementation groups. We have shown previously that cooperation between v-mil (cytoplasmic, serine-threonine kinase product), and v-myc (nuclear, DNA-binding product) is required to transform 7-day-old chicken neuroretina cells, which in usual culture medium do not rapidly proliferate. v-mil induces sustained growth of chicken neuroretina cells without transformation; v-myc fails to stimulate the proliferation of chicken neuroretina cells but is required to achieve transformation of the proliferating cells. Here, we present results indicating that the P135gag-myb-ets nuclear protein of avian erythroblastosis virus E26 is able to induce proliferation but not transformation of chicken neuroretina cells. v-myc is required in addition to P135gag-myb-ets to achieve chicken neuroretina cell transformation. In contrast, we found that the P135gag-myb-ets and P100gag-mil proteins are not able to cooperate in this system.
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- 1989
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22. Heart tumors specifically induced in young avian embryos by the v-myc oncogene.
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Saule, S, Mérigaud, J P, Al-Moustafa, A E, Ferré, F, Rong, P M, Amouyel, P, Quatannens, B, Stéhelin, D, and Dieterlen-Lièvre, F
- Abstract
To determine if expression of the v-myc oncogene had any effect during ontogeny, we injected avian myelocytomatosis virus strain MC29 into avian embryos at various stages of development. The injection of MC29 at embryonic day 2 (E2) or 3 (E3) caused, about 10 days later, rhabdomyosarcomas of the heart and, in some cases, skin muscle hypertrophy. When the injection was performed at E4 or E5, the number of heart tumors declined, whereas the number of skin muscle tumors increased significantly. The p110gag-myc protein was found in all tumors analyzed. When the virus was injected intravenously into E10 embryos, no tumors appeared during embryonic life, in striking contrast to the results obtained from injections at earlier stages. The monoclonal antibody 13F4, which is specific for the myogenic lineage, bound strongly to tumoral heart tissue, whereas it bound weakly to normal cardiac cells. Comparison of the peaks of tumor incidence in relationship to the timing of injection suggests that the v-myc product could interfere in vivo with an early step of the muscle lineage differentiation program. In addition, we show that the p58c-myc protein, which is supposed to play an important role in the control of cell proliferation, is only faintly detected in the heart of normal E3 embryos, in contrast to limb and tail buds, which readily express detectable levels of p58c-myc.
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- 1987
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23. Induction of proliferation or transformation of neuroretina cells by the miland mycviral oncogenes
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Bechade, C., Calothy, G., Pessac, B., Martin, P., Coll, J., Denhez, F., Saule, S., Ghysdael, J., and Stéhelin, D.
- Abstract
The genome of the avian retro virus MH2 contains, in addition to the v-myconcogene shared with three other avian retroviruses (MC29, CMII and OK-10), a second cell-derived oncogene, v-mil(refs 1–3). Like the three other viruses, which contain only v-myc, MH2 induces mainly liver and kidney carcinomas in fowl and transforms fibroblasts and macrophages in vitro4. However, MH2 and MC29 differ in their biological properties when assayed on cultures of chicken embryo neuroretina (NR) cells. Indeed, NR cells, which normally do not multiply in vitro, are induced to proliferate and become transformed upon infection with MH2, whereas infection with MC29 has no apparent effect on these cells5,6. To analyse the functions of the two oncogenes of MH2, we isolated spontaneous and in vitro-constructed mutants of this virus and investigated their effects on NR cell multiplication and transformation. We report here that expression of v-milis sufficient to induce NR cell proliferation, although it does not result in cell transformation. In addition, viruses expressing only the v-myconcogene fail to induce any detectable change in NR cells. However, cooperation of the two oncogenes is required to achieve transformation of NR cells by MH2.
- Published
- 1985
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24. The ETS1 transcription factor is expressed during epithelial-mesenchymal transitions in the chick embryo and is activated in scatter factor-stimulated MDCK epithelial cells
- Author
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Fafeur, V., David Tulasne, Quéva, C., Vercamer, C., Dimster, V., Mattot, V., Stéhelin, D., Desbiens, X., and Vandenbunder, B.
- Subjects
Transcriptional Activation ,Gene Expression ,Chick Embryo ,Epithelium ,Cell Line ,Proto-Oncogene Protein c-ets-1 ,Embryonic and Fetal Development ,Dogs ,Proto-Oncogene Proteins ,Morphogenesis ,Animals ,Collagenases ,Cysteine ,RNA, Messenger ,Fluorescent Antibody Technique, Indirect ,In Situ Hybridization ,Proto-Oncogene Proteins c-ets ,Hepatocyte Growth Factor ,Cell Differentiation ,Blotting, Northern ,Urokinase-Type Plasminogen Activator ,Microscopy, Fluorescence ,Somites ,Neural Crest ,Signal Transduction ,Transcription Factors - Abstract
In embryos and in human tumors, the expression of the ETS1 transcription factor correlates with the occurrence of invasive processes. Although this was demonstrated in cells of mesodermal origin, the expression of ETS1 was not detected in epithelial cells. In the present study, we show that during early organogenesis in the chick embryo, ETS1 mRNA expression was transiently induced in epithelial structures, during emigration of neural crest cells and dispersion of somites into the mesenchymal sclerotome. In contrast, the expression of ETS1 was not detected in situations where epithelial layers stayed cohesive while forming a new structure, such as the dermomyotome forming the myotome. The involvement of ETS1 in epithelial cell dissociation was examined in MDCK epithelial cells stimulated by scatter factor/hepatocyte growth factor (SF/HGF), a potent inducer of cell dissociation and motility. SF/HGF was found to stimulate ETS1 mRNA and protein expressions, and these increases coincided with the dispersion of cells and the expression of protease mRNAs, such as urokinase-type plasminogen activator and collagenase, but not with the protease inhibitor, plasminogen activator inhibitor type 1. Furthermore, we showed that SF/HGF was able to induce a transcriptional response involving ETS1 by using artificial as well as cellular promoters, such as the urokinase-type plasminogen activator and collagenase 1 promoters, containing RAS-responsive elements with essential ETS-binding sites. These data demonstrate expression of ETS1 during epithelial-mesenchymal transitions in the developing embryo and show that ETS1 can act as a downstream effector of SF/HGF in MDCK epithelial cells. Taken together, these data identify ETS1 as a molecular actor of epithelia cell dissociation.
25. [Origin of the transforming genes in avian acute leukemia retroviruses]
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Stéhelin D, Saule S, Martine F. Roussel, Pluquet N, Boccara M, Sergeant A, and Leprince D
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Cell Transformation, Neoplastic ,Avian Leukosis Virus ,Base Sequence ,Genes, Viral ,Acute Disease ,DNA, Viral ,Humans ,Nucleic Acid Hybridization ,RNA, Viral - Abstract
The avian defective leukemia viruses are recombinants between an avian virus of low oncogenicity and specific host nucleotide sequences. The types of hematological neoplasms correlate with the specificity of the sequences transduced. These could be differentiation genes escaping cellular control after their transduction by the virus.
26. Stromal expression of c-Ets1 transcription factor correlates with tumor invasion
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Wernert N, Gilles F, Fafeur V, Bouali F, Mb, Raes, Pyke C, Thierry Dupressoir, Seitz G, Vandenbunder B, and Stéhelin D
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Adult ,Male ,Transcription, Genetic ,Mice, SCID ,Mice ,Transforming Growth Factor beta ,Neoplasms ,Animals ,Humans ,Neoplasm Invasiveness ,Collagenases ,RNA, Messenger ,In Situ Hybridization ,Aged ,Oncogene Proteins ,Platelet-Derived Growth Factor ,Proto-Oncogene Proteins c-ets ,Metalloendopeptidases ,Fibroblasts ,Middle Aged ,Transforming Growth Factor alpha ,Urokinase-Type Plasminogen Activator ,Female ,Fibroblast Growth Factor 2 ,Matrix Metalloproteinase 3 ,Transcription Factors - Abstract
The stroma reaction has an important role in tumor growth, invasion, and metastasis. In various invasive human carcinomas, as well as in a mouse model for tumor invasion, transcripts encoding the transcription factor c-Ets1 were detected within stromal fibroblasts, whereas they were absent in epithelial tumor cells. This expression of c-Ets1 was often increased in fibroblasts directly adjacent to neoplastic cells. Endothelial cells of stromal capillaries were also positive for c-Ets1 expression. In contrast, fibroblasts of corresponding noninvasive lesions and of normal tissues were consistently negative. In cultured human fibroblasts stimulated by basic fibroblast growth factor and tumor necrosis factor alpha, the expression of c-Ets1 correlated with the accumulation of transcripts for potential target genes, collagenase-1 and stromelysin-1. The same correlation was observed in some of the invasive carcinomas investigated. These results suggest that c-Ets1 participates in the regulation of tumor invasion in vivo.
27. Les oncogènes cellulaires, clés de la cancérogenèse
- Author
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Stéhelin, D, primary
- Published
- 1985
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28. Induction of proliferation or transformation of neuroretina cells by the mil and myc viral oncogenes
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Bechade, C., primary, Calothy, G., additional, Pessac, B., additional, Martin, P., additional, Coll, J., additional, Denhez, F., additional, Saule, S., additional, Ghysdael, J., additional, and Stéhelin, D., additional
- Published
- 1985
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29. Isolation of two different c-ets-2 proto-oncogenes in Xenopus laevis.
- Author
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Wolff, C.-M., Stiegler, P., Baltzinger, M., Meyer, D., Ghysdael, J., Stéhelin, D., Befort, N., and Remy, P.
- Published
- 1990
30. Characterization of a MH2 mutant lacking the v-myc oncogene
- Author
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Martin, P., Henry, C., Denhez, F., Amouyel, P., Bechade, C., Calothy, G., Debuire, B., Stehelin, D., and Saule, S.
- Published
- 1986
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31. 22 How invasive tumours abuse their host
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Stehelin, D.
- Published
- 1995
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32. Ectopic expression of H-1 parvovirus NS1 protein induces alterations in actin filaments and cell death in human normal MRC-5 and transformed MRC-5 SV2 cells.
- Author
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Wizla P, Begue A, Loison I, Richard A, Caillet-Fauquet P, and Stéhelin D
- Subjects
- Cell Death, Cell Line, Transformed, Cells, Cultured, H-1 parvovirus genetics, Humans, Promoter Regions, Genetic, Transfection, Viral Nonstructural Proteins genetics, Actins metabolism, H-1 parvovirus pathogenicity, Viral Nonstructural Proteins physiology
- Abstract
When grown in human cell lines, oncolytic H-1 parvovirus (H-1PV) replication preferentially occurs in transformed cells, which ultimately die upon infection. H-1PV-induced cytotoxicity is mainly due to P4 promoter-driven NS1 protein expression. Infection of untransformed cells generally does not induce deleterious effects because the P4 promoter is not activated. Here, we show that ectopic CMV-driven NS1 protein expression in normal human MRC-5 cells results in alterations of actin filaments and cell death, and both effects are prevented by a serine 473 mutation. The same substitution preserves actin filaments of transfected MRC-5 SV2 cells, that are MRC-5 transformed counterparts, but does not impair NS1-induced cytotoxicity.
- Published
- 2010
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33. A revised and complete map of the chicken c-mil/raf-1 locus.
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Brummer T, Stéhelin D, Misawa Y, and Reth M
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- Animals, Base Sequence, Chickens, Exons genetics, Introns genetics, Protein Biosynthesis, Restriction Mapping, Avian Proteins genetics, Chromosome Mapping, Proto-Oncogene Proteins c-raf genetics
- Abstract
The chicken c-mil/raf-1 gene (formerly also known as c-mht) was originally identified in the search for the cellular counterpart to the v-mil oncogene of the Mill Hill 2 retrovirus and was among the first cellular proto-oncogenes discovered. Although the c-mil/raf-1 promotor, as well as the exons transduced into v-mil, were characterized in detail, an entire map of this locus has never been published. Here, we now report the location of five previously unmapped exons. In addition, we have noticed inconsistent numbering of the c-mil/raf-1 exons in the literature and the GenBank database. Thus, we provide here a complete map of the c-mil/raf-1 gene and a revision of the exon numbers. Comparison of the chicken c-mil/raf-1 gene with those of other vertebrates suggests that the numbers and lengths of the translated exons of the raf-1 locus were established early in the vertebrate lineage and have been conserved during the divergent evolution of teleosts and tetrapods.
- Published
- 2004
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34. ETS-1 transcription factor binds cooperatively to the palindromic head to head ETS-binding sites of the stromelysin-1 promoter by counteracting autoinhibition.
- Author
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Baillat D, Bègue A, Stéhelin D, and Aumercier M
- Subjects
- Base Sequence, Binding Sites, DNA, Electrophoretic Mobility Shift Assay, Genetic Vectors, Humans, Matrix Metalloproteinase 3 metabolism, Mutagenesis, Site-Directed, Photochemistry, Protein Binding, Proto-Oncogene Protein c-ets-1, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins c-ets, Surface Plasmon Resonance, Transcription Factors antagonists & inhibitors, Transcriptional Activation, Matrix Metalloproteinase 3 genetics, Proto-Oncogene Proteins metabolism, Transcription Factors metabolism
- Abstract
Stromelysin-1 (matrix metalloproteinase-3) is a member of the matrix metalloproteinase family. Regulation of its gene expression is critical for tissue homeostasis. Patterns of increased co-expression of stromelysin-1 and ETS-1 genes have been observed in pathological processes. Stromelysin-1 promoter is transactivated by ETS proteins through two palindromic head to head ETS-binding sites, an unusual configuration among metalloproteinase promoters. By using surface plasmon resonance, electrophoretic mobility shift assay, and photo-cross-linking, we showed that full-length human ETS-1 (p51) binds cooperatively to the ETS-binding site palindrome of the human stromelysin-1 promoter, with facilitated binding of the second ETS-1 molecule to form an ETS-1.DNA.ETS-1 ternary complex. The study of N-terminal deletion mutants allowed us to conclude that cooperative binding implied autoinhibition counteraction, requiring the 245-330-residue region of the protein that is encoded by exon VII of the gene. This region was deleted in the natural p42 isoform of ETS-1, which was unable to bind cooperatively to the palindrome. Transient transfection experiments showed a good correlation between DNA binding and promoter transactivation for p51. In contrast, p42 showed a poorer transactivation, reinforcing the significance of cooperative binding for full transactivation. It is the first time that ETS-1 was shown to be able to counteract its own autoinhibition.
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- 2002
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35. Identification of amino acid residues in the ETS transcription factor Erg that mediate Erg-Jun/Fos-DNA ternary complex formation.
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Verger A, Buisine E, Carrère S, Wintjens R, Flourens A, Coll J, Stéhelin D, and Duterque-Coquillaud M
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Animals, Base Sequence, Binding Sites, DNA chemistry, Dimerization, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Nucleic Acid Conformation, Oligodeoxyribonucleotides chemistry, Oligodeoxyribonucleotides metabolism, Oncogene Proteins genetics, Osteosarcoma, Protein Conformation, Protein Structure, Secondary, Proto-Oncogene Proteins chemistry, Proto-Oncogene Proteins c-ets, Proto-Oncogene Proteins c-fos chemistry, Proto-Oncogene Proteins c-jun chemistry, Rats, Sequence Alignment, Sequence Deletion, Sequence Homology, Amino Acid, Transcription Factors chemistry, Transcriptional Regulator ERG, Tumor Cells, Cultured, DNA metabolism, DNA-Binding Proteins, Oncogene Proteins chemistry, Oncogene Proteins metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-fos metabolism, Proto-Oncogene Proteins c-jun metabolism, Trans-Activators, Transcription Factors metabolism
- Abstract
Jun, Fos, and Ets proteins belong to distinct families of transcription factors that target specific DNA elements often found jointly in gene promoters. Physical and functional interactions between these families play important roles in modulating gene expression. Previous studies have demonstrated a direct interaction between the DNA-binding domains of the two partners. However, the molecular details of the interactions have not been investigated so far. Here we used the known three-dimensional structures of the ETS DNA-binding domain and Jun/Fos heterodimer to model an ETS-Jun/Fos-DNA ternary complex. Docking procedures suggested that certain ETS domain residues in the DNA recognition helix alpha3 interact with the N-terminal basic domain of Jun. To support the model, different Erg ETS domain mutants were obtained by deletion or by single amino acid substitutions and were tested for their ability to mediate DNA binding, Erg-Jun/Fos complex formation, and transcriptional activation. We identified point mutations that affect both the DNA binding properties of Erg and its physical interaction with Jun (R367K), as well as mutations that essentially prevent transcriptional synergy with the Jun/Fos heterodimer (Y371V). These results provide a framework of the ETS/bZIP interaction linked to the manifestation of functional activity in gene regulation.
- Published
- 2001
- Full Text
- View/download PDF
36. Neoplastic AIDS-associated Kaposi's sarcoma cell line KSY-1 cannot transdifferentiate into capillaries.
- Author
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Lunardi-Iskandar Y, Wernert N, Cong TH, Samnang S, Bryant JL, Vandenbunder B, and Stéhelin D
- Subjects
- Animals, Antisense Elements (Genetics), Capillaries, Female, Humans, In Situ Hybridization, Male, Mice, Mice, Nude, Mice, SCID, Neoplasm Transplantation, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ets, Sarcoma, Kaposi etiology, Sarcoma, Kaposi pathology, Species Specificity, Transcription Factors, Tumor Cells, Cultured, Acquired Immunodeficiency Syndrome complications, Neovascularization, Pathologic, Sarcoma, Kaposi blood supply
- Abstract
Objective: Kaposi's sarcoma (KS) is an acquired immunodeficiency syndrome (AIDS)-defining neoplasm histologically characterized by proliferation of spindle cells, inflammatory cells, and abundant neovascularization. When the malignant cell line KSY-1 derived from an AIDS-KS tumor is transplanted subcutaneously into nude mice, prominent neovascular features develop. Using this mouse model of neoplastic KS, we set out to determine, using c-ets 1 markers specific for mouse or human tissues, whether vascular growth and inflammatory infiltrate induced by the transplanted KSY-1 cells is of host cell or transplant origin., Study Design/methods: KS tumors were induced by subcutaneous inoculation of 5 x 10(6) KSY-1 cells/200 microL in immunodeficient mice, and species-specific mouse and human riboprobes of the c-ets 1 protooncogene were used for in situ hybridization to define cell of origin., Results: Five different tumors were examined. Tissue sections from all cases were hybridized with radiolabeled riboprobes for the presence of both mouse and human c-ets 1 mRNA. Tumor cells were labeled with the human c-ets 1 probe, whereas neovascular and inflammatory tissues were of mouse origin., Conclusions: The finding that vascular but not tumor cells are of host origin supports the model of tumor-induced vascularization via a mechanism of tumor cell-derived cytokine-medicated pathogenesis.
- Published
- 1999
37. Nuclear localization of a new c-cbl related protein, CARP 90, during in vivo thymic apoptosis in mice.
- Author
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Denis G, Mandard S, Humblet C, Verlaet M, Boniver J, Stéhelin D, Defresne MP, and Régnier D
- Subjects
- Animals, Animals, Newborn, Apoptosis drug effects, Apoptosis genetics, Cell Nucleus metabolism, Chromatin metabolism, Cytoplasm metabolism, Hydrocortisone pharmacology, Immunohistochemistry, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-cbl, RNA, Messenger genetics, RNA, Messenger metabolism, Thymus Gland drug effects, Apoptosis physiology, Proto-Oncogene Proteins metabolism, Thymus Gland cytology, Thymus Gland metabolism, Ubiquitin-Protein Ligases
- Abstract
This study investigates the involvement of the c-cbl protooncogene in thymocyte apoptosis occurring in vivo after hydrocortisone treatment. In the thymus of untreated mice, a few medullary and cortical thymocytes expressed p120cbl, mainly in the cytoplasm. In the cortex, their number and distribution resemble that of apoptotic cells evidenced by TUNEL staining. The expression of Cbl is rapidly increased when apoptosis is triggered by hydrocortisone. This Cbl-specific immunostaining was detected in the nucleus and is due to a Cbl-related 90 kDa protein (CARP 90). These results show that a c-cbl product could localize in the nucleus and suggest that it could be involved as a regulator of thymic apoptosis.
- Published
- 1999
- Full Text
- View/download PDF
38. Molecular phylogeny of the ETS gene family.
- Author
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Laudet V, Hänni C, Stéhelin D, and Duterque-Coquillaud M
- Subjects
- Amino Acid Sequence, Conserved Sequence, Helix-Turn-Helix Motifs, Peptide Fragments genetics, Proto-Oncogene Proteins c-ets, Sequence Alignment methods, Sequence Homology, Amino Acid, Evolution, Molecular, Multigene Family, Proto-Oncogene Proteins genetics, Transcription Factors classification, Transcription Factors genetics
- Abstract
We have constructed a molecular phylogeny of the ETS gene family. By distance and parsimony analysis of the ETS conserved domains we show that the family containing so far 29 different genes in vertebrates can be divided into 13 groups of genes namely ETS, ER71, GABP, PEA3, ERG, ERF, ELK, DETS4, ELF, ESE, TEL, YAN, SPI. Since the three dimensional structure of the ETS domain has revealed a similarity with the winged-helix-turn-helix proteins, we used two of them (CAP and HSF) to root the tree. This allowed us to show that the family can be divided into five subfamilies: ETS, DETS4, ELF, TEL and SPI. The ETS subfamily comprises the ETS, ER71, GABP, PEA3, ERG, ERF and the ELK groups which appear more related to each other than to any other ETS family members. The fact that some members of these subfamilies were identified in early metazoans such as diploblasts and sponges suggests that the diversification of ETS family genes predates the diversification of metazoans. By the combined analysis of both the ETS and the PNT domains, which are conserved in some members of the family, we showed that the GABP group, and not the ERG group, is the one most closely related to the ETS group. We also observed that the speed of accumulation of mutations in the various genes of the family is highly variable. Noticeably, paralogous members of the ELK group exhibit strikingly different evolutionary speed suggesting that the evolutionary pressure they support is very different.
- Published
- 1999
- Full Text
- View/download PDF
39. Targeting of PML/RARalpha is lethal to retinoic acid-resistant promyelocytic leukemia cells.
- Author
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Nason-Burchenal K, Allopenna J, Bègue A, Stéhelin D, Dmitrovsky E, and Martin P
- Subjects
- Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 17, DNA Mutational Analysis, Drug Resistance genetics, Gene Expression, Gene Targeting, Humans, Leukemia, Promyelocytic, Acute drug therapy, Promyelocytic Leukemia Protein, RNA, Catalytic metabolism, RNA, Messenger genetics, Recombinant Proteins, Transfection, Translocation, Genetic, Tumor Cells, Cultured, Tumor Suppressor Proteins, Antineoplastic Agents therapeutic use, Leukemia, Promyelocytic, Acute genetics, Neoplasm Proteins genetics, Nuclear Proteins, Oncogene Proteins, Fusion genetics, Receptors, Retinoic Acid genetics, Transcription Factors genetics, Tretinoin therapeutic use
- Abstract
Acute promyelocytic leukemia (APL) cells, containing the t(15;17) rearrangement, express the fusion protein, PML/RARalpha. Clinically, patients respond to all-trans retinoic acid (ATRA) through complete remissions associated with myeloid maturation of leukemic cells. This clinical ATRA response of APL is linked to PML/RARalpha expression. Unfortunately, these remissions are transient and relapsed APL is often ATRA-resistant. The role PML/RARalpha plays in the growth and maturation of these APL cells with acquired ATRA resistance has not been fully explored. This study uses an ATRA-resistant NB4 cell line (NB4-R1) to investigate the contribution of PML/RARalpha expression to ATRA resistance. Targeting of PML/RARalpha in NB4-R1 cells was undertaken using two approaches: homologous recombination and hammerhead ribozyme-mediated cleavage. Reducing PML/RARalpha protein in NB4-R1 cells rendered these cells more sensitive to ATRA. These cells were growth-inhibited in ATRA, apoptosis was induced, and there was no apparent signaling of differentiation. Sequence analysis identified a mutation in the ligand binding domain (LBD) of the RARalpha portion of PML/RARalpha. Results show that these retinoid-resistant NB4 cells require persistent PML/RARalpha expression for leukemic cell growth. Taken together, these findings can account for why these cells do not respond to ATRA and how reduction of PML/RARalpha abrogates the antiapoptotic effect it confers to these leukemic cells., (Copyright 1998 by The American Society of Hematology.)
- Published
- 1998
40. The H19 TATA-less promoter is efficiently repressed by wild-type tumor suppressor gene product p53.
- Author
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Dugimont T, Montpellier C, Adriaenssens E, Lottin S, Dumont L, Iotsova V, Lagrou C, Stéhelin D, Coll J, and Curgy JJ
- Subjects
- Genes, Reporter, HeLa Cells, Humans, Muscle Proteins biosynthesis, RNA, Long Noncoding, Transfection, Gene Expression Regulation, Neoplastic, Muscle Proteins genetics, RNA, Untranslated, TATA Box, Tumor Suppressor Protein p53 metabolism
- Abstract
The developmentally regulated H19 gene displays several remarkable properties: expression of an apparently non-translated mRNA, genomic imprinting (maternal allele only expressed), relaxation of the imprinting and/or epigenetic lesions demonstrated in some tumors. Despite several observations after relaxation of imprinting status of the gene, data on trans and cis-acting factors required for the human H19 gene expression are still missing. As a first approach to address identification of factors involved in the regulation of the gene, we found that cells from a p53 antisense-transfected HeLa clone displayed increased amounts of H19 transcripts when compared to the non-transfected cells. Moreover, a HeLa clone stably transfected with a temperature sensitive (ts) 143 Ala p53 mutant exhibited temperature-dependent regulation of H19 expression. This preliminary indication of the repressing effect of the p53 protein on H19 expression has been confirmed by transient cotransfection experiments in HeLa cells, using luciferase surrogate constructs under the control of the 823 bp sequence immediately upstream of the transcription start point of the H19 gene, and different constructs containing sense, antisense or a ts 143 Ala mutant p53 cDNA. We observed an increase of H19 promoter-driven activity in transient cotransfections with the antisense p53 cDNA and the temperature sensitive mutant p53 at the non-permissive temperature, but a decrease with sense wild-type p53 cDNA. Furthermore, the cotransfection experiments were repeated in a cell line lacking endogenous p53. (Calu 6 cells) and the results provided additional evidence for a down regulation of the expression of the H19 gene by the p53 protein.
- Published
- 1998
- Full Text
- View/download PDF
41. [Similarities between angiogenesis and neoplasm invasiveness ].
- Author
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Stéhelin D
- Subjects
- Animals, Humans, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-ets, Proto-Oncogene Proteins c-fos metabolism, Proto-Oncogene Proteins c-jun metabolism, Transcription Factors metabolism, Cytokines physiology, Neoplasm Invasiveness physiopathology, Neovascularization, Pathologic physiopathology
- Abstract
We have shown that given cytokines are capable of inducing the expression of transcription factors of the Ets family in two very distinct cell types: 1) endothelial cells of blood vessels, but only during neovascularization, and 2) fibrocytic cells from stroma surrounding tumors, but only if these tumors bear characteristics of invasiveness. In such cases, the fibrocytic cells also express some metalloproteinases (collagenase 1, urkinase plasminogen activator, sometimes stromelysin1). In ex vivo reconstruction experiments, we demonstrate that the corresponding genes are directly up-regulated by the Ets family transcription factors, often associated with the transcription complex Jun/Fos. The proteinases are thought to dismantle the stroma and allow invasive tumors to proceed toward further expansion. We speculate that inactivation of the Ets factors could seriously hamper both neovascularization and tumor expansion.
- Published
- 1998
42. [Experimental models of angiogenesis for the study of the Ets1 transcription factor].
- Author
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Calmels TP, Mattot V, Masse A, Stéhelin D, and Vandenbunder B
- Subjects
- Animals, Chick Embryo, Endothelium, Vascular metabolism, Gene Expression, Mice, Mice, Transgenic, Transcription Factors metabolism, Neovascularization, Pathologic genetics, Transcription Factors genetics
- Abstract
The Ets1 transcription factor gene is expressed in endothelial cells during blood vessel formation under normal or pathological conditions. The proposed hypothesis aims to involve Ets1 in the regulation of angiogenesis processes by activating the transcription of genes encoding matrix-degrading proteases. In vivo experiments allowing specific manipulation of ets1 gene expression or activity within endothelial cells are necessary to investigate the functional role of Ets1. Two experimental models using retroviruses expressing ets1 mutants have been chosen: Chicken embryo development and tumour-induced angiogenesis in mice. Another approach targeted on the vascular endothelium has been developed in order to obtain transgenic mice expressing specifically in endothelial cells an ets1 transdominant negative mutant under the control of the tek and tie promoters. These tools should allow interference with Ets1 activity at defined stages during normal or pathological development.
- Published
- 1997
43. The avian transcription factor c-Rel is induced and translocates into the nucleus of thymocytes undergoing apoptosis.
- Author
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Huguet C, Mattot V, Bouali F, Stéhelin D, Vandenbunder B, and Abbadie C
- Abstract
This study investigates the involvement of the avian transcription factor c-Rel in thymocyte apoptosis occurring either in vivo or in organotypic culture. In vivo, only a few cortical thymocytes express the c-Rel protein. Their number, localization and morphology resemble that of apoptotic cells evidenced by TUNEL staining. In organotypic culture, the expression of c-Rel is induced in medullary thymocytes as apoptosis is triggered. This induction would be post-transcriptional since no increase in the c-rel gene expression is detected. Moreover, c-Rel translocates into the nucleus of medullary thymocytes during the time course of apoptosis. This translocation is preceded by a decrease in ikba expression, the gene which encodes the avian homologue of IkappaBalpha. Altogether these results suggest that the proto-oncogene c-rel could take an active part in apoptosis of cortical thymocytes occurring in vivo during T-cell selection as well as in experimentally-induced apoptosis of medullary thymocytes.
- Published
- 1997
- Full Text
- View/download PDF
44. The ETS1 transcription factor is expressed during epithelial-mesenchymal transitions in the chick embryo and is activated in scatter factor-stimulated MDCK epithelial cells.
- Author
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Fafeur V, Tulasne D, Quéva C, Vercamer C, Dimster V, Mattot V, Stéhelin D, Desbiens X, and Vandenbunder B
- Subjects
- Animals, Blotting, Northern, Cell Line, Chick Embryo, Collagenases genetics, Cysteine metabolism, Dogs, Embryonic and Fetal Development genetics, Embryonic and Fetal Development physiology, Epithelium metabolism, Fluorescent Antibody Technique, Indirect, Gene Expression genetics, Hepatocyte Growth Factor physiology, In Situ Hybridization, Microscopy, Fluorescence, Morphogenesis genetics, Neural Crest embryology, Proto-Oncogene Protein c-ets-1, Proto-Oncogene Proteins c-ets, RNA, Messenger, Signal Transduction, Somites cytology, Somites metabolism, Transcriptional Activation, Urokinase-Type Plasminogen Activator genetics, Cell Differentiation genetics, Epithelium embryology, Morphogenesis physiology, Proto-Oncogene Proteins genetics, Transcription Factors genetics
- Abstract
In embryos and in human tumors, the expression of the ETS1 transcription factor correlates with the occurrence of invasive processes. Although this was demonstrated in cells of mesodermal origin, the expression of ETS1 was not detected in epithelial cells. In the present study, we show that during early organogenesis in the chick embryo, ETS1 mRNA expression was transiently induced in epithelial structures, during emigration of neural crest cells and dispersion of somites into the mesenchymal sclerotome. In contrast, the expression of ETS1 was not detected in situations where epithelial layers stayed cohesive while forming a new structure, such as the dermomyotome forming the myotome. The involvement of ETS1 in epithelial cell dissociation was examined in MDCK epithelial cells stimulated by scatter factor/hepatocyte growth factor (SF/HGF), a potent inducer of cell dissociation and motility. SF/HGF was found to stimulate ETS1 mRNA and protein expressions, and these increases coincided with the dispersion of cells and the expression of protease mRNAs, such as urokinase-type plasminogen activator and collagenase, but not with the protease inhibitor, plasminogen activator inhibitor type 1. Furthermore, we showed that SF/HGF was able to induce a transcriptional response involving ETS1 by using artificial as well as cellular promoters, such as the urokinase-type plasminogen activator and collagenase 1 promoters, containing RAS-responsive elements with essential ETS-binding sites. These data demonstrate expression of ETS1 during epithelial-mesenchymal transitions in the developing embryo and show that ETS1 can act as a downstream effector of SF/HGF in MDCK epithelial cells. Taken together, these data identify ETS1 as a molecular actor of epithelia cell dissociation.
- Published
- 1997
45. Erg, an Ets-family member, differentially regulates human collagenase1 (MMP1) and stromelysin1 (MMP3) gene expression by physically interacting with the Fos/Jun complex.
- Author
-
Butticè G, Duterque-Coquillaud M, Basuyaux JP, Carrère S, Kurkinen M, and Stéhelin D
- Subjects
- Binding Sites genetics, Collagenases metabolism, Enzyme Activation genetics, Humans, Matrix Metalloproteinase 3 metabolism, Oncogene Protein p65(gag-jun) metabolism, Oncogene Proteins v-fos metabolism, Proto-Oncogene Protein c-ets-2, Proto-Oncogene Proteins metabolism, Sequence Deletion, Trans-Activators metabolism, Transcription, Genetic, Transfection, Collagenases genetics, DNA-Binding Proteins, Gene Expression Regulation, Matrix Metalloproteinase 3 genetics, Promoter Regions, Genetic, Proto-Oncogene Proteins physiology, Repressor Proteins, Trans-Activators physiology, Transcription Factors
- Abstract
Collagenase1 (MMP1) and stromelysin1 (MMP3) are extracellular proteolytic enzymes that degrade connective tissue macromolecules and basement membranes. Both genes are regulated by the Ets and Fos/Jun families of transcription factors/oncoproteins. Here, we show that two members of the Ets-family, Ets2 and Erg and their combinations differentially regulate collagenase1 and stromelysin1 promoter activity. In transiently transfected cells, Ets2 activates both promoters whereas Erg induces collagenase1 but not stromelysin1 promoter activity. Moreover, Erg completely inhibits stromelysin1 promoter activation by Ets2. In gel shift assays however, the Erg protein bound little or not to the collagenase1 promoter, whereas it bound to the stromelysin1 promoter. By site-specific mutagenesis, we identified one major site at -88 that abolished collagenase1 promoter activation by Erg. Surprisingly, mutation of the collagenase1 AP1 site at -73 also abolished the activation by Erg suggesting that Erg cooperates with Fos/Jun in collagenase1 promoter regulation. Indeed, gel shift and in vitro protein interaction studies showed that Erg binds to the Fos/Jun complex. Thus, Erg represents the first example of a transcription factor that can distinguish between the collagenase1 and stromelysin1 promoters in that when Erg is recruited by Fos/Jun at the promoter, it transcriptionally activates collagenase1 gene but not stromelysin1 expression.
- Published
- 1996
46. Structure and organization of the mouse elk1 gene.
- Author
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Grévin D, Ung S, Denhez F, Dehem M, Quatannens B, Bègue A, Stéhelin D, and Martin P
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Chromosome Mapping, Genome, Humans, Mice, Molecular Sequence Data, Sequence Analysis, DNA, ets-Domain Protein Elk-1, DNA-Binding Proteins, Proto-Oncogene Proteins genetics, Transcription Factors genetics
- Abstract
In the ets gene family of transcription factors, elk1 belongs to the subfamily of Ternary Complex Factors (TCFs) which bind to the Serum Response Element (SRE) in conjunction with a dimer of Serum Response Factors (SRFs). In this communication we report the isolation of cDNAs from the mouse elk1 gene, containing the full coding sequence homologous (87% identical) to the human gene, and the structure and organization of 22 kb of the mouse elk1 locus. The coding sequence is spread through 5 exons (numbered 1 to 5): exons 1 to 4 range from 102 bp to 447 bp and exon 5 is at least 620 bp. Exon 0 was not found in the 8.5 kb sequence upstream of exon 1. The intron between exons 1 and 2 is 4 kb long and the 3 other introns are less than 500 bp long. This information will be useful to engineer targeted mutations of this gene in mice and to determine the genomic structure of the other TCF genes.
- Published
- 1996
- Full Text
- View/download PDF
47. Genomic organization of the human ERM (ETV5) gene, a PEA3 group member of ETS transcription factors.
- Author
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Monté D, Coutte L, Dewitte F, Defossez PA, Le Coniat M, Stéhelin D, Berger R, and de Launoit Y
- Subjects
- Amino Acid Sequence, Base Sequence, Exons genetics, Humans, In Situ Hybridization, Molecular Sequence Data, Multigene Family, Transcription Factors classification, Chromosomes, Human, Pair 3 genetics, DNA-Binding Proteins genetics, Genes, Transcription Factors genetics
- Abstract
The ERM protein belongs to the family of Ets transcription factors. We show here that the human ERM gene is organized into 14 exons distributed along 65 kb of genomic DNA on chromosome 3. The two main functional domains of ERM, the acidic domain and the DNA-binding ETS domain, are overlapped by three different exons each. The 3'-untranslated region of ERM is 2.1 kb, whereas the 5'-untranslated region is about 0.3 kb; this allows the transcription of ERM transcripts of approximately 4 kb. The human ERM gene is localized to the q27-q29 region of chromosome 3.
- Published
- 1996
- Full Text
- View/download PDF
48. Back-mutation of the V-Ets to the C-Ets carboxy-terminal amino acids in the P135gag-myb-ets results in chicken neuroretina cells transformation and loss of basic fibroblast growth factor responsiveness.
- Author
-
Garrido C, Leprince D, Plaza S, Aumercier M, Stéhelin D, and Saule S
- Subjects
- Animals, Base Sequence, Cell Division drug effects, Cell Line, Transformed, Chickens, DNA Probes, Genes, gag, Molecular Sequence Data, Oncogenes, Proto-Oncogene Proteins c-ets, Transcription, Genetic, Fibroblast Growth Factor 2 pharmacology, Mutation, Proto-Oncogene Proteins genetics, Retinal Ganglion Cells pathology, Retroviridae Proteins, Oncogenic genetics, Transcription Factors genetics
- Abstract
The v-Myb, v-Ets containing E26 retrovirus (called in this work E26ABC) induces the proliferation of chicken neuroretina (CNR) cells in minimal medium, strongly stimulated by basic Fibroblast Growth Factor (bFGF) which confers on them the ability to form colonies in soft agar. V-Ets differs from its cellular counterpart c-Ets-1 by two point mutations and by the replacement of the 13 last C-terminal amino acids by 16 unrelated residues as a consequence of DNA segment inversion in the viral sequence. It has been documented that this different C-terminal sequence influences DNA binding activity and specificity. Replacement in E26ABC virus of the sequence encoding the 16 v-Ets last C-terminal amino acids by the sequence encoding the 13 c-Ets-1 derived C-terminus (virus E26ABO), results in the production of a P135gag-myb-ets with modified biological properties on CNR cells. E26ABO infected CNR cells proliferate in minimal medium more efficiently than E26ABC, are unresponsive to bFGF and able to grow in soft agar. In contrast, CNR cells infected by viruses encoding Myb and Ets proteins either in the E26ABO or in the E26ABC configuration are bFGF responsive. Since Myb alone is sufficient to induce bFGF responsiveness on CNR cells, these results suggest that the c-Ets-1 C-terminus interferes with the Myb activity of the E26ABO P135gag-myb-ets protein in CNR cells.
- Published
- 1996
49. The c-ets-1 proto-oncogene is a new early-response gene differentially regulated by cytokines and growth factors in human fibroblasts.
- Author
-
Gilles F, Raes MB, Stéhelin D, Vandenbunder B, and Fafeur V
- Subjects
- Cells, Cultured cytology, Cells, Cultured enzymology, Dose-Response Relationship, Drug, Epidermal Growth Factor pharmacology, Fibroblast Growth Factor 2 pharmacology, Fibroblasts cytology, Gene Expression Regulation, Enzymologic physiology, Gene Expression Regulation, Neoplastic physiology, Humans, Infant, Newborn, Interleukin-1 pharmacology, Male, Platelet-Derived Growth Factor pharmacology, Proto-Oncogene Mas, Proto-Oncogene Proteins c-ets, RNA, Messenger analysis, Skin cytology, Time Factors, Transforming Growth Factor beta pharmacology, Tumor Cells, Cultured cytology, Tumor Cells, Cultured enzymology, Tumor Necrosis Factor-alpha pharmacology, Cytokines pharmacology, Fibroblasts enzymology, Growth Substances pharmacology, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics, Transcription Factors genetics
- Abstract
In various invasive human tumors, c-ets-1 mRNA was found to be selectively expressed in stromal fibroblasts. We have now investigated the possibility that soluble factors could regulate c-ets-1 expression in cultured human fibroblasts. We show that both conditioned media from tumor cell lines and a number of characterized cytokines and growth factors were able to induce c-ets-1 expression. TNF alpha and IL-1 alpha were the most potent c-ets-1 stimulators, inducing rapid (within 1 h) and long-lasting (19 h) increases of c-ets-1 mRNA and protein expression. In contrast, bFGF, EGF, and PDGF were mainly delayed stimulators, with maximal stimulation being detected by 19 h. In addition, these growth factors potentiated the rapid induction of c-ets-1 by TNF alpha. While all these factors were able to stimulate c-ets-1 expression, TGF beta was found to be ineffective. Using inhibitors of transcription and translation, we also found that increase of c-ets-1 mRNA by TNF alpha resulted from new transcription rather than from stabilization and did not require new protein synthesis. These results demonstrated that c-ets-1 is a new nuclear target for several factors and behaves as an early-response gene for TNF alpha.
- Published
- 1996
- Full Text
- View/download PDF
50. High incidence of loss of heterozygosity and abnormal imprinting of H19 and IGF2 genes in invasive cervical carcinomas. Uncoupling of H19 and IGF2 expression and biallelic hypomethylation of H19.
- Author
-
Douc-Rasy S, Barrois M, Fogel S, Ahomadegbe JC, Stéhelin D, Coll J, and Riou G
- Subjects
- Alleles, Female, Humans, Methylation, RNA, Long Noncoding, Chromosome Deletion, Genomic Imprinting, Insulin-Like Growth Factor II genetics, Muscle Proteins genetics, RNA, Untranslated, Uterine Cervical Neoplasms genetics
- Abstract
The few imprinted genes characterized so far include the insulin-like growth factor-2 gene (IGF2) coding for a foetal growth factor and the H19 gene whose normal function is unknown but which is likely to act as an RNA with an antitumour effect. IGF2 is expressed by the paternal allele and H19 by the maternal allele. This reciprocal expression is quite interesting because both H19 and IGF2 genes are located close to each other on chromosome 11p15.5 in a region subject to loss of heterozygosity (LOH). Moreover, loss of imprinting (LOI) or biallelic expression has been proposed as an epigenetic mechanism for tumorigenesis in a variety of human cancers including Wilms' tumour. In this study we report the LOH, LOI and methylation status of H19 and IGF2 genes in 29 invasive cervical carcinomas of different clinical stages. Fourteen (48%) and 13 (45%) tumours were heterozygous for H19 and IGF2 respectively. LOH for H19 and IGF2 genes were found in 2 of 14 (14%) and 3 of 13 (23%) informative tumours, respectively. LOI of H19 and IGF2 was detected in 2 of 12 (17%) and 5 of 10 (50%) tumours with no LOH, respectively. More interestingly, monoallelic expression of the otherwise silent H19 allele (allele switch) was observed in 2 of 12 (17%) tumours and biallelic expression of IGF2 was detected in one specimen of normal cervix adjacent to the tumour. The expressing H19 allele, and to a lower degree also the silent allele, were hypomethylated in tumours suggesting that demethylation of both H19 alleles may be associated with an early step of imprinting alteration. In cervical cancer H19 and IGF2 expressions could be independently regulated. In conclusion, our data suggest that H19 and IGF2 genes, via deletions and/or abnormal imprinting, could play a crucial role in a large proportion (58%) of cervical cancers where they may be associated with disease progression.
- Published
- 1996
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