98 results on '"Leprince D"'
Search Results
2. Requirement for chromatin-remodeling complex in novel tumor suppressor HIC1-mediated transcriptional repression and growth control
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Zhang, B, Chambers, K J, Leprince, D, Faller, D V, and Wang, S
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- 2009
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3. Novel BTB/POZ domain zinc-finger protein, LRF, is a potential target of the LAZ-3/BCL-6 oncogene
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Davies, J M, Hawe, N, Kabarowski, J, Huang, Q-H, Zhu, J, Brand, N J, Leprince, D, Dhordain, P, Cook, M, Morriss-Kay, G, and Zelent, A
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- 1999
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4. Requirement for chromatin-remodeling complex in novel tumor suppressor HIC1-mediated transcriptional repression and growth control
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Zhang, B, Chambers, KJ, Leprince, D, Faller, DV, and Wang, S
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- 2011
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5. Retraction Note: Requirement for chromatin-remodeling complex in novel tumor suppressor HIC1-mediated transcriptional repression and growth control
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Zhang, B, Chambers, K J, Leprince, D, Faller, D V, and Wang, S
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- 2011
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6. The c-ets proto-oncogenes encode transcription factors that cooperate with c-Fos and c-Jun for transcriptional activation
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Wasylyk, B., Wasylyk, C., Flores, P., Begue, A., Leprince, D., and Stehelin, D.
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Genetic transcription -- Identification and classification ,Cancer -- Genetic aspects ,Genetic transcription -- Research ,Oncogenes -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Oncogenes, genes involved in cancer formation, can cause cell transformation, which leads to uncontrolled growth of the cells and changes in the expression of other genes. During transformation, two factors, AP-1 and PEA3, which bind to DNA and regulate transcription (a process necessary for the synthesis of proteins from genes), are activated, and this allows the transcription of many different types of oncogenes, growth factors, and TPA (12-O-tetradecanoylphorbol-13-acetate), a factor that promotes tumor growth. The oncogenes Ets-1 and Ets-2 also encode transcription factors, which bind to DNA. The Ets-1 protein product interacts with two proto-oncogenes (the normal cellular counterparts of oncogenes), c-Fos and c-Jun, which are also components of transcription factors. The three proteins encoded by oncogenes may act together in the regulation of the growth of cells. (Consumer Summary produced by Reliance Medical Information, Inc.)
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- 1990
7. The Transcription Factor Encyclopedia
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Yusuf, D, Butland, SL, Swanson, MI, Bolotin, E, Ticoll, A, Cheung, WA, Zhang, XYC, Dickman, CTD, Fulton, DL, Lim, JS, Schnabl, JM, Ramos, OHP, Vasseur-Cognet, M, de Leeuw, CN, Simpson, EM, Ryffel, GU, Lam, EW-F, Kist, R, Wilson, MSC, Marco-Ferreres, R, Brosens, JJ, Beccari, LL, Bovolenta, P, Benayoun, BA, Monteiro, LJ, Schwenen, HDC, Grontved, L, Wederell, E, Mandrup, S, Veitia, RA, Chakravarthy, H, Hoodless, PA, Mancarelli, MM, Torbett, BE, Banham, AH, Reddy, SP, Cullum, RL, Liedtke, M, Tschan, MP, Vaz, M, Rizzino, A, Zannini, M, Frietze, S, Farnham, PJ, Eijkelenboom, A, Brown, PJ, Laperriere, D, Leprince, D, de Cristofaro, T, Prince, KL, Putker, M, del Peso, L, Camenisch, G, Wenger, RH, Mikula, M, Rozendaal, M, Mader, S, Ostrowski, J, Rhodes, SJ, Van Rechem, C, Boulay, G, Olechnowicz, SWZ, Breslin, MB, Lan, MS, Nanan, KK, Wegner, M, Hou, J, Mullen, RD, Colvin, SC, Noy, PJ, Webb, CF, Witek, ME, Ferrell, S, Daniel, JM, Park, J, Waldman, SA, Peet, DJ, Taggart, M, Jayaraman, P-S, Karrich, JJ, Blom, B, Vesuna, F, O'Geen, H, Sun, Y, Gronostajski, RM, Woodcroft, MW, Hough, MR, Chen, E, Europe-Finner, GN, Karolczak-Bayatti, M, Bailey, J, Hankinson, O, Raman, V, LeBrun, DP, Biswal, S, Harvey, CJ, DeBruyne, JP, Hogenesch, JB, Hevner, RF, Heligon, C, Luo, XM, Blank, MC, Millen, KJ, Sharlin, DS, Forrest, D, Dahlman-Wright, K, Zhao, C, Mishima, Y, Sinha, S, Chakrabarti, R, Portales-Casamar, E, Sladek, FM, Bradley, PH, Wasserman, WW, Yusuf, D, Butland, SL, Swanson, MI, Bolotin, E, Ticoll, A, Cheung, WA, Zhang, XYC, Dickman, CTD, Fulton, DL, Lim, JS, Schnabl, JM, Ramos, OHP, Vasseur-Cognet, M, de Leeuw, CN, Simpson, EM, Ryffel, GU, Lam, EW-F, Kist, R, Wilson, MSC, Marco-Ferreres, R, Brosens, JJ, Beccari, LL, Bovolenta, P, Benayoun, BA, Monteiro, LJ, Schwenen, HDC, Grontved, L, Wederell, E, Mandrup, S, Veitia, RA, Chakravarthy, H, Hoodless, PA, Mancarelli, MM, Torbett, BE, Banham, AH, Reddy, SP, Cullum, RL, Liedtke, M, Tschan, MP, Vaz, M, Rizzino, A, Zannini, M, Frietze, S, Farnham, PJ, Eijkelenboom, A, Brown, PJ, Laperriere, D, Leprince, D, de Cristofaro, T, Prince, KL, Putker, M, del Peso, L, Camenisch, G, Wenger, RH, Mikula, M, Rozendaal, M, Mader, S, Ostrowski, J, Rhodes, SJ, Van Rechem, C, Boulay, G, Olechnowicz, SWZ, Breslin, MB, Lan, MS, Nanan, KK, Wegner, M, Hou, J, Mullen, RD, Colvin, SC, Noy, PJ, Webb, CF, Witek, ME, Ferrell, S, Daniel, JM, Park, J, Waldman, SA, Peet, DJ, Taggart, M, Jayaraman, P-S, Karrich, JJ, Blom, B, Vesuna, F, O'Geen, H, Sun, Y, Gronostajski, RM, Woodcroft, MW, Hough, MR, Chen, E, Europe-Finner, GN, Karolczak-Bayatti, M, Bailey, J, Hankinson, O, Raman, V, LeBrun, DP, Biswal, S, Harvey, CJ, DeBruyne, JP, Hogenesch, JB, Hevner, RF, Heligon, C, Luo, XM, Blank, MC, Millen, KJ, Sharlin, DS, Forrest, D, Dahlman-Wright, K, Zhao, C, Mishima, Y, Sinha, S, Chakrabarti, R, Portales-Casamar, E, Sladek, FM, Bradley, PH, and Wasserman, WW
- Abstract
Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.
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- 2012
8. Requirement for chromatin-remodeling complex in novel tumor suppressor HIC1-mediated transcriptional repression and growth control
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Zhang, B, primary, Chambers, K J, additional, Leprince, D, additional, Faller, D V, additional, and Wang, S, additional
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- 2008
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9. Function of ets genes is conserved between vertebrates and Drosophila
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Albagli, O., primary, Klaes, A., additional, Ferreira, E., additional, Leprince, D., additional, and Klämbt, C., additional
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- 1996
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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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Garrido, C, primary, Leprince, D, additional, Lipsick, J S, additional, Stehelin, D, additional, Gospodarowicz, D, additional, and Saule, S, additional
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- 1992
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11. v-myb and v-ets cooperate for the mitogenic stimulation of primary fibroblasts by avian E26 retrovirus
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Ravel-Chapuis, P, primary, Leprince, D, additional, Pain, B, additional, Li, R, additional, Domenget, C, additional, Stehelin, D, additional, Samarut, J, additional, and Jurdic, P, additional
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- 1991
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12. Evolutionary divergence in the broad complex, tramtrack and bric a brac/poxviruses and zinc finger domain from the candidate tumor suppressor gene hypermethylated in cancer
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Guerardel, C., Deltour, S., and Leprince, D.
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- 1999
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13. Molecular cloning and characterization of the chicken DNA locus related to the oncogene erbB of avian erythroblastosis virus.
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Sergeant, A., Saule, S., Leprince, D., Begue, A., Rommens, C., and Stehelin, D.
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Chicken cell DNA contains sequences which are homologous to the avian erythroblastosis virus oncogene v‐erb. These cellular sequences (c‐erb) have been isolated from a library of chicken cell DNA fragments generated by partial digestion with AluI and HaeIII and shown to be shared by at least two loci in the chicken DNA. One of them, denoted c‐erbB, contains approximately 1.8 kilobase pairs of chicken DNA homologous to the 3′ part of the v‐erb oncogene (v‐erbB). Restriction mapping studies show that the c‐erbB DNA sequences homologous to v‐erbB are distributed among six EcoRI fragments located in a single genomic region. Heteroduplexes between v‐erbB in viral RNA and cloned c‐erbB DNA show that the chicken DNA sequences homologous to v‐erbB are interrupted by 11 DNA sequences not present in the v‐erb oncogene. We conclude from our data that the c‐erbB locus might represent the cellular progenitor for the v‐erbB domain of the v‐erb oncogene.
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- 1982
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14. Identification in chicken macrophages of a set of proteins related to, but distinct from, the chicken cellular c‐ets‐encoded protein p54c‐ets.
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Ghysdael, J., Gegonne, A., Pognonec, P., Boulukos, K., Leprince, D., Dernis, D., Lagrou, C., and Stehelin, D.
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Using an antiserum to a bacterially expressed polypeptide corresponding to 56 amino acids of v‐ets, we previously identified in chicken tissues a protein of 54 kd (p54c‐ets) which shares extensive sequence homology to the v‐ets‐encoded domain of the E26‐transforming protein p135gag‐myb‐ets and is thus apparently encoded by the c‐ets proto‐oncogene. We report here that the anti‐ets serum specifically identifies in chicken cells a second set of proteins of 60 kd (p60), 62 kd (p62) and 64 kd (p64) which appear to be highly related to each other but display only a limited domain of homology with p54c‐ets and p135gag‐myb‐ets and are thus probably encoded by a gene(s) partially related to, but different from c‐ets. In contrast to p54c‐ets which is expressed at high levels in chicken lymphoid tissues, prominent syntheses of p62 and p64 were found in both normal and transformed chicken macrophages but not in avian cells corresponding to immature stages of the myeloid differentiation pathway. These observations together with the fact that differentiation of avian myeloblastosis virus‐transformed myeloblasts into macrophage‐like cells after treatment with 12‐O‐tetradecanoylphorbol‐13‐acetate is accompanied by the synthesis of p62 and p64 suggest a role for these proteins in chicken macrophage differentiation or function. Induction of differentiation of human leukemia cell lines HL60 and U937 into macrophages is also accompanied by the increased synthesis of c‐ets‐encoded 68 kd, 62 kd and 58 kd proteins.
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- 1986
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15. The human DNA locus related to the oncogene myb of avian myeloblastosis virus (AMV): molecular cloning and structural characterization.
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Leprince, D., Saule, S., de Taisne, C., Gegonne, A., Begue, A., Righi, M., and Stehelin, D.
- Abstract
Chicken and human cell DNA contains sequences homologous to the avian myeloblastosis virus oncogene, v‐myb. These cellular sequences, c‐myb (human) and c‐myb (chicken), were isolated from libraries of human or chicken cell DNA fragments, generated by partial digestion with the restriction enzymes AluI and HaeIII, and compared. The chicken c‐myb locus isolated from two distinct overlapping recombinant phages, contained five contiguous EcoRI fragments of 5.4, 1.1, 2.1, 2.2 and 9 kbp, accounting for all the bands seen with a v‐myb probe in a complete EcoRI digest of chicken cellular DNA. Likewise, the screening of the human library yielded a recombinant phage hybridizing with the v‐myb specific probe, that contained five EcoRI fragments of 2.8, 2.6, 2.0, 1.2 and 5.0 kbp (the last ending with an artificial EcoRI site, due to the construction of the library) belonging to the c‐myb (human) locus. Probes using the EcoRI chicken DNA cloned fragments revealed corresponding contiguous EcoRI fragments in the human clone. Subsequent analyses of cellular polyadenylated mRNA extracted from human and chicken cells allowed the identification of single RNA species of 3.8 and 4.0 kb, respectively, as the representative transcripts of the c‐myb locus in the two species. Thus, c‐myb appears as a single locus in man and chicken, conserved with a similar structure in the two distantly related species. Our preparation of a specific human c‐myb probe with an increased sensitivity on DNA/RNA blots should facilitate analyses concerning this gene in human normal or tumour cells or tissues.
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- 1983
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16. Multiple domains for the chicken cellular sequences homologous to the v-ets oncogene of the E26 retrovirus
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Gegonne, A, Leprince, D, Duterque-Coquillaud, M, Vandenbunder, B, Flourens, A, Ghysdael, J, Debuire, B, and Stehelin, D
- Abstract
We have investigated the structure of chicken genomic DNA homologous to v-ets, the second cell-derived oncogene of avian retrovirus E26. We isolated a c-ets locus spanning ca. 30.0 kilobase pairs (kbp) in the chicken genome with homologies to 1,202 nucleotides (nt) of v-ets (total length, 1,508 nt) distributed in six clusters along 18.0 kbp of the cloned DNA. The 5'-distal part of v-ets (224 nt) was homologous to chicken cellular sequences contained upstream within a single 16.0-kbp EcoRI fragment as two typical exons but not found transcribed into the major 7.5-kb c-ets (or 4.0-kb c-myb) RNA species. Between these two v-ets-related cellular sequences we found ca 40.0 kbp of v-ets-unrelated DNA. Finally, the most 3' region of homology to v-ets in the cloned DNA was shown to consist of a truncated exon lacking the nucleotides coding for the 16 carboxy-terminal amino acids of the viral protein but colinear to one of the two human c-ets loci, c-ets-2.
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- 1987
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17. Alternative splicing within the chicken c-ets-1 locus: implications for transduction within the E26 retrovirus of the c-ets proto-oncogene
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Leprince, D, Duterque-Coquillaud, M, Li, R P, Henry, C, Flourens, A, Debuire, B, and Stehelin, D
- Abstract
Two overlapping c-ets-1 cDNA clones were isolated which contained the alpha and beta genomic sequences homologous to the 5' end of v-ets not detected in the previously described c-ets RNA species or proteins. Nucleotide sequencing demonstrated that these cDNAs corresponded to the splicing of alpha and beta to a common set of 3' exons (a through F) already found in the p54c-ets-1 mRNA. They contained an open reading frame of 1,455 nucleotides which could encode a polypeptide of 485 amino acids with a predicted molecular mass of 53 kilodaltons. However, when expressed in COS-1 cells, the cDNAs directed the synthesis of a protein with an apparent molecular mass in sodium dodecyl sulfate-polyacrylamide gel electrophoresis of 68 kilodaltons, p68c-ets-1, comigrating with a protein expressed at low levels in normal chicken spleen cells. These two proteins were shown to be identical by partial digestion with protease V8. Northern (RNA) blot hybridization analysis with the p68c-ets-1 -specific sequence and RNase protection experiments showed that the corresponding mRNA was expressed in normal chicken spleen and not in normal chicken thymus or in various T lymphoid cell lines. Thus, two closely related proteins, having distinct amino-terminal parts, are generated within the same locus by alternative addition of different 5' exons, alpha and beta or I54, respectively, onto a common set of 3' exons (a to F). Finally, we demonstrate that an aberrant splicing event between a cryptic splice donor site in c-myb exon E6 and the normal splice acceptor site of c-ets-1 exon alpha involved in the genesis of the E26 myb-ets sequence.
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- 1988
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18. A putative second cell-derived oncogene of the avian leukaemia retrovirus E26.
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Leprince, D., Gegonne, A., Coll, J., de Taisne, C., Schneeberger, A., Lagrou, C., and Stehelin, D.
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- 1983
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19. Alternative splicing within the chicken c-ets-1 locus: implications for transduction within the E26 retrovirus of the c-ets proto-oncogene
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D. Stehelin, Leprince D, Anne Flourens, C Henry, Martine Duterque-Coquillaud, B Debuire, and R P Li
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RNA Splicing ,Immunology ,Molecular Sequence Data ,Biology ,Transfection ,Microbiology ,Peptide Mapping ,Exon ,Transduction, Genetic ,Virology ,Proto-Oncogene Proteins ,Sequence Homology, Nucleic Acid ,Proto-Oncogenes ,Animals ,RNA, Messenger ,Cloning, Molecular ,Gel electrophoresis ,Messenger RNA ,Splice site mutation ,Avian Leukosis Virus ,Base Sequence ,Proto-Oncogene Proteins c-ets ,Alternative splicing ,RNA ,Exons ,Molecular biology ,Molecular Weight ,Open reading frame ,Insect Science ,RNA splicing ,DNA, Viral ,Electrophoresis, Polyacrylamide Gel ,Chickens ,Research Article ,Transcription Factors - Abstract
Two overlapping c-ets-1 cDNA clones were isolated which contained the alpha and beta genomic sequences homologous to the 5' end of v-ets not detected in the previously described c-ets RNA species or proteins. Nucleotide sequencing demonstrated that these cDNAs corresponded to the splicing of alpha and beta to a common set of 3' exons (a through F) already found in the p54c-ets-1 mRNA. They contained an open reading frame of 1,455 nucleotides which could encode a polypeptide of 485 amino acids with a predicted molecular mass of 53 kilodaltons. However, when expressed in COS-1 cells, the cDNAs directed the synthesis of a protein with an apparent molecular mass in sodium dodecyl sulfate-polyacrylamide gel electrophoresis of 68 kilodaltons, p68c-ets-1, comigrating with a protein expressed at low levels in normal chicken spleen cells. These two proteins were shown to be identical by partial digestion with protease V8. Northern (RNA) blot hybridization analysis with the p68c-ets-1 -specific sequence and RNase protection experiments showed that the corresponding mRNA was expressed in normal chicken spleen and not in normal chicken thymus or in various T lymphoid cell lines. Thus, two closely related proteins, having distinct amino-terminal parts, are generated within the same locus by alternative addition of different 5' exons, alpha and beta or I54, respectively, onto a common set of 3' exons (a to F). Finally, we demonstrate that an aberrant splicing event between a cryptic splice donor site in c-myb exon E6 and the normal splice acceptor site of c-ets-1 exon alpha involved in the genesis of the E26 myb-ets sequence.
20. Les élections communales / par D. Leprince
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Leprince, D.. Auteur du texte and Leprince, D.. Auteur du texte
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Avec mode texte
21. EcoRI RFLP linked to the humanmybgene
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Dozier, C., primary, Walbaum, S., additional, Leprince, D., additional, and Stehelin, D., additional
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- 1986
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22. A Novel Toxoplasma gondii Nuclear Factor TgNF3 Is a Dynamic Chromatin-Associated Component, Modulator of Nucleolar Architecture and Parasite Virulence
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Agnès Hovasse, Christine Schaeffer-Reiss, Alain Van Dorsselaer, Thomas Mouveaux, Alejandro Olguin-Lamas, Stanislas Tomavo, Edwige Madec, Christian Slomianny, Elisabeth Werkmeister, Stéphane Delhaye, Isabelle Callebaut, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Rôle des canaux ioniques membranaires et du calcium intracellulaire dans la physiopathologie de la prostate, Université de Lille, Sciences et Technologies-Institut National de la Santé et de la Recherche Médicale (INSERM), This research was funded by the Centre National de la Recherche Scientifique (CNRS), Institut National de la Sante et de la Recherche Medicale(INSERM), Institut Pasteur de Lille (IPL). The funders had no role in study design, data collection and analysis, decision to publish, or preparationof the manuscript., We would like to thank Dewailly E and Mortuaire M for excellent technical assistance, especially in the earlier phase of this study. We acknowledge Drs Harb O and Roos DS (University of Pennsylvania) for providing the nucleotide sequence of T. gondii rDNA 18S. We are indebted to Drs Hakimi A and Leprince D for providing nucleosome and antibodies specific to core histones, respectively. Special thanks to Drs Gordon Langsley and Robert Walker for critical reading the manuscript and all members of the lab for fruitful discussions., Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), and Thomas, Danielle
- Subjects
Proteomics ,MESH: Sequence Analysis, Protein ,Protozoan Proteins ,Antibodies, Protozoan ,MESH: Toxoplasma/pathogenicity ,MESH: DNA-Binding Proteins/chemistry ,Regulatory Sequences, Nucleic Acid ,Mass Spectrometry ,MESH: Protozoan Proteins/chemistry ,Histones ,MESH: Cell Nucleolus/metabolism ,Sequence Analysis, Protein ,MESH: Reverse Transcriptase Polymerase Chain Reaction ,Transcriptional regulation ,MESH: Gene Silencing ,Nuclear protein ,MESH: Ribosomes/metabolism ,Promoter Regions, Genetic ,MESH: High-Throughput Nucleotide Sequencing ,lcsh:QH301-705.5 ,MESH: Promoter Regions, Genetic ,Regulation of gene expression ,MESH: Chromatin Immunoprecipitation ,MESH: Nuclear Proteins/metabolism ,0303 health sciences ,MESH: Histones/metabolism ,Reverse Transcriptase Polymerase Chain Reaction ,MESH: Proteomics ,030302 biochemistry & molecular biology ,High-Throughput Nucleotide Sequencing ,Nuclear Proteins ,Chromatin ,3. Good health ,DNA-Binding Proteins ,MESH: Staining and Labeling ,Histone ,Toxoplasma ,MESH: Nuclear Proteins/genetics ,Cell Nucleolus ,Research Article ,lcsh:Immunologic diseases. Allergy ,Chromatin Immunoprecipitation ,Immunology ,MESH: Protozoan Proteins/genetics ,MESH: Microscopy, Electron ,Biology ,MESH: DNA-Binding Proteins/metabolism ,Microbiology ,MESH: Toxoplasma/metabolism ,Tacrolimus Binding Proteins ,03 medical and health sciences ,Virology ,Genetics ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Nucleosome ,MESH: Antibodies, Protozoan ,MESH: Regulatory Sequences, Nucleic Acid ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Gene Silencing ,Molecular Biology/Chromatin Structure ,Molecular Biology ,MESH: Protozoan Proteins/metabolism ,030304 developmental biology ,MESH: Protozoan Proteins/biosynthesis ,MESH: Mass Spectrometry ,MESH: DNA-Binding Proteins/genetics ,Staining and Labeling ,MESH: Nuclear Proteins/biosynthesis ,Infectious Diseases/Protozoal Infections ,Promoter ,Molecular biology ,MESH: Tacrolimus Binding Proteins/chemistry ,MESH: Cell Nucleolus/genetics ,MESH: Nuclear Proteins/chemistry ,Microscopy, Electron ,lcsh:Biology (General) ,Molecular Biology/Nucleolus and Nuclear Bodies ,MESH: Chromatin/metabolism ,biology.protein ,Parasitology ,MESH: Toxoplasma/genetics ,lcsh:RC581-607 ,Chromatin immunoprecipitation ,Ribosomes - Abstract
In Toxoplasma gondii, cis-acting elements present in promoter sequences of genes that are stage-specifically regulated have been described. However, the nuclear factors that bind to these cis-acting elements and regulate promoter activities have not been identified. In the present study, we performed affinity purification, followed by proteomic analysis, to identify nuclear factors that bind to a stage-specific promoter in T. gondii. This led to the identification of several nuclear factors in T. gondii including a novel factor, designated herein as TgNF3. The N-terminal domain of TgNF3 shares similarities with the N-terminus of yeast nuclear FK506-binding protein (FKBP), known as a histone chaperone regulating gene silencing. Using anti-TgNF3 antibodies, HA-FLAG and YFP-tagged TgNF3, we show that TgNF3 is predominantly a parasite nucleolar, chromatin-associated protein that binds specifically to T. gondii gene promoters in vivo. Genome-wide analysis using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) identified promoter occupancies by TgNF3. In addition, TgNF3 has a direct role in transcriptional control of genes involved in parasite metabolism, transcription and translation. The ectopic expression of TgNF3 in the tachyzoites revealed dynamic changes in the size of the nucleolus, leading to a severe attenuation of virulence in vivo. We demonstrate that TgNF3 physically interacts with H3, H4 and H2A/H2B assembled into bona fide core and nucleosome-associated histones. Furthermore, TgNF3 interacts specifically to histones in the context of stage-specific gene silencing of a promoter that lacks active epigenetic acetylated histone marks. In contrast to virulent tachyzoites, which express the majority of TgNF3 in the nucleolus, the protein is exclusively located in the cytoplasm of the avirulent bradyzoites. We propose a model where TgNF3 acts essentially to coordinate nucleolus and nuclear functions by modulating nucleosome activities during the intracellular proliferation of the virulent tachyzoites of T. gondii., Author Summary Apicomplexa including Toxoplasma gondii are responsible for a variety of deadly infections. These intracellular parasites have complex life cycles within different hosts and their infectivity relies on their capacity to regulate gene expression in response to different environments. However, to date, little is known about nuclear factors that regulate their gene expression. Here, we have characterized parasite nuclear factors that bind to a stage-specific promoter. We identified several nuclear factors including a novel factor, designated herein as TgNF3. The N-terminal domain of TgNF3 shares similarities with the N-terminus of yeast nuclear FK506-binding protein (FKBP), known as a histone chaperone regulating gene silencing. We show that TgNF3 is predominantly a nucleolar, chromatin-associated protein that specifically binds to T. gondii nucleosome-associated histones and promoters. Genome-wide analysis identified promoter occupancies by TgNF3 and we demonstrated a direct role for this factor in transcriptional control of genes involved in parasite metabolism, transcription and translation. Ectopic expression of TgNF3 induces dynamic changes in the size of the nucleolus, and a severe attenuation of parasite virulence in vivo. In avirulent bradyzoites, TgNF3 is found exclusively in the cytoplasm, suggesting a potential role in regulating nucleolar and nuclear functions in the virulent tachyzoites of T. gondii.
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- 2011
23. HIC1 (Hypermethylated in Cancer 1) modulates the contractile activity of prostate stromal fibroblasts and directly regulates CXCL12 expression.
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Dubuissez M, Paget S, Abdelfettah S, Spruyt N, Dehennaut V, Boulay G, Loison I, de Schutter C, Rood BR, Duterque-Coquillaud M, Leroy X, and Leprince D
- Abstract
HIC1 ( Hypermethylated In Cancer 1 ) a tumor suppressor gene located at 17p13.3, is frequently deleted or epigenetically silenced in many human tumors. HIC1 encodes a transcriptional repressor involved in various aspects of the DNA damage response and in complex regulatory loops with P53 and SIRT1. HIC1 expression in normal prostate tissues has not yet been investigated in detail. Here, we demonstrated by immunohistochemistry that detectable HIC1 expression is restricted to the stroma of both normal and tumor prostate tissues. By RT-qPCR, we showed that HIC1 is poorly expressed in all tested prostate epithelial lineage cell types: primary (PrEC), immortalized (RWPE1) or transformed androgen-dependent (LnCAP) or androgen-independent (PC3 and DU145) prostate epithelial cells. By contrast, HIC1 is strongly expressed in primary PrSMC and immortalized (WMPY-1) prostate myofibroblastic cells. HIC1 depletion in WPMY-1 cells induced decreases in α-SMA expression and contractile capability. In addition to SLUG , we identified stromal cell-derived factor 1/C-X-C motif chemokine 12 ( SDF1/ CXCL12) as a new HIC1 direct target-gene. Thus, our results identify HIC1 as a tumor suppressor gene which is poorly expressed in the epithelial cells targeted by the tumorigenic process. HIC1 is expressed in stromal myofibroblasts and regulates CXCL12/SDF1 expression, thereby highlighting a complex interplay mediating the tumor promoting activity of the tumor microenvironment. Our studies provide new insights into the role of HIC1 in normal prostatic epithelial-stromal interactions through direct repression of CXCL12 and new mechanistic clues on how its loss of function through promoter hypermethylation during aging could contribute to prostatic tumors., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2020 Dubuissez et al.)
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- 2020
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24. O -GlcNAcylation Links Nutrition to the Epigenetic Downregulation of UNC5A during Colon Carcinogenesis.
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Decourcelle A, Very N, Djouina M, Loison I, Thévenet J, Body-Malapel M, Lelièvre E, Coqueret O, Leprince D, El Yazidi-Belkoura I, and Dehennaut V
- Abstract
While it is now accepted that nutrition can influence the epigenetic modifications occurring in colorectal cancer (CRC), the underlying mechanisms are not fully understood. Among the tumor suppressor genes frequently epigenetically downregulated in CRC, the four related genes of the UNC5 family: UNC5A , UNC5B , UNC5C and UNC5D encode dependence receptors that regulate the apoptosis/survival balance. Herein, in a mouse model of CRC, we found that the expression of UNC5A , UNC5B and UNC5C was diminished in tumors but only in mice subjected to a High Carbohydrate Diet (HCD) thus linking nutrition to their repression in CRC. O -GlcNAcylation is a nutritional sensor which has enhanced levels in CRC and regulates many cellular processes amongst epigenetics. We then investigated the putative involvement of O -GlcNAcylation in the epigenetic downregulation of the UNC5 family members. By a combination of pharmacological inhibition and RNA interference approaches coupled to RT-qPCR (Reverse Transcription-quantitative Polymerase Chain Reaction) analyses, promoter luciferase assay and CUT&RUN (Cleavage Under Target & Release Using Nuclease) experiments, we demonstrated that the O -GlcNAcylated form of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2) represses the transcription of UNC5A in human colon cancer cells. Collectively, our data support the hypothesis that O -GlcNAcylation could represent one link between nutrition and epigenetic downregulation of key tumor suppressor genes governing colon carcinogenesis including UNC5A .
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- 2020
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25. hPCL3S promotes proliferation and migration of androgen-independent prostate cancer cells.
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Abdelfettah S, Boulay G, Dubuissez M, Spruyt N, Garcia SP, Rengarajan S, Loison I, Leroy X, Rivera MN, and Leprince D
- Abstract
Polycomb repressive complex 2 (PRC2) allows the deposition of H3K27me3. PRC2 facultative subunits modulate its activity and recruitment such as hPCL3/PHF19, a human ortholog of Drosophila Polycomb-like protein (PCL). These proteins contain a TUDOR domain binding H3K36me3, two PHD domains and a "Winged-helix" domain involved in GC-rich DNA binding. The human PCL3 locus encodes the full-length hPCL3L protein and a shorter isoform, hPCL3S containing the TUDOR and PHD1 domains only. In this study, we demonstrated by RT-qPCR analyses of 25 prostate tumors that hPCL3S is frequently up-regulated. In addition, hPCL3S is overexpressed in the androgen-independent DU145 and PC3 cells, but not in the androgen-dependent LNCaP cells. hPCL3S knockdown decreased the proliferation and migration of DU145 and PC3 whereas its forced expression into LNCaP increased these properties. A mutant hPCL3S unable to bind H3K36me3 (TUDOR-W50A) increased proliferation and migration of LNCaP similarly to wt hPCL3S whereas inactivation of its PHD1 domain decreased proliferation. These effects partially relied on the up-regulation of genes known to be important for the proliferation and/or migration of prostate cancer cells such as S100A16, PlexinA2 , and Spondin1 . Collectively, our results suggest hPCL3S as a new potential therapeutic target in castration resistant prostate cancers., Competing Interests: CONFLICTS OF INTEREST The authors declare no disclosure of potential conflicts of interest.
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- 2020
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26. Regulation of Polycomb Repression by O -GlcNAcylation: Linking Nutrition to Epigenetic Reprogramming in Embryonic Development and Cancer.
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Decourcelle A, Leprince D, and Dehennaut V
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Epigenetic modifications are major actors of early embryogenesis and carcinogenesis and are sensitive to nutritional environment. In recent years, the nutritional sensor O -GlcNAcylation has been recognized as a key regulator of chromatin remodeling. In this review, we summarize and discuss recent clues that OGT and O -GlcNAcylation intimately regulate the functions of the Polycomb group proteins at different levels especially during Drosophila melanogaster embryonic development and in human cancer cell lines. These observations define an additional connection between nutrition and epigenetic reprogramming associated to embryonic development and cancer.
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- 2019
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27. HIC1 (hypermethylated in cancer 1) SUMOylation is dispensable for DNA repair but is essential for the apoptotic DNA damage response (DDR) to irreparable DNA double-strand breaks (DSBs).
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Paget S, Dubuissez M, Dehennaut V, Nassour J, Harmon BT, Spruyt N, Loison I, Abbadie C, Rood BR, and Leprince D
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- Antineoplastic Agents pharmacology, Ataxia Telangiectasia Mutated Proteins metabolism, Cell Line, Tumor, Checkpoint Kinase 2 metabolism, Etoposide pharmacology, Histone Deacetylases metabolism, Humans, Models, Molecular, Neoplasms genetics, Neoplasms metabolism, Promoter Regions, Genetic, Protein Binding, Repressor Proteins metabolism, Sirtuin 1 genetics, Sumoylation, Trans-Activators, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Apoptosis genetics, DNA Breaks, Double-Stranded, DNA Repair, Kruppel-Like Transcription Factors metabolism
- Abstract
The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor mediating the p53-dependent apoptotic response to irreparable DNA double-strand breaks (DSBs) through direct transcriptional repression of SIRT1. HIC1 is also essential for DSB repair as silencing of endogenous HIC1 in BJ-hTERT fibroblasts significantly delays DNA repair in functional Comet assays. HIC1 SUMOylation favours its interaction with MTA1, a component of NuRD complexes. In contrast with irreparable DSBs induced by 16-hours of etoposide treatment, we show that repairable DSBs induced by 1 h etoposide treatment do not increase HIC1 SUMOylation or its interaction with MTA1. Furthermore, HIC1 SUMOylation is dispensable for DNA repair since the non-SUMOylatable E316A mutant is as efficient as wt HIC1 in Comet assays. Upon induction of irreparable DSBs, the ATM-mediated increase of HIC1 SUMOylation is independent of its effector kinase Chk2. Moreover, irreparable DSBs strongly increase both the interaction of HIC1 with MTA1 and MTA3 and their binding to the SIRT1 promoter. To characterize the molecular mechanisms sustained by this increased repression potential, we established global expression profiles of BJ-hTERT fibroblasts transfected with HIC1-siRNA or control siRNA and treated or not with etoposide. We identified 475 genes potentially repressed by HIC1 with cell death and cell cycle as the main cellular functions identified by pathway analysis. Among them, CXCL12, EPHA4, TGFβR3 and TRIB2, also known as MTA1 target-genes, were validated by qRT-PCR analyses. Thus, our data demonstrate that HIC1 SUMOylation is important for the transcriptional response to non-repairable DSBs but dispensable for DNA repair.
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- 2017
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28. Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4+ T-Cell Activation.
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Dubuissez M, Loison I, Paget S, Vorng H, Ait-Yahia S, Rohr O, Tsicopoulos A, and Leprince D
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- HEK293 Cells, Histone Deacetylases metabolism, Humans, Interleukin-2 metabolism, Jurkat Cells, Kruppel-Like Factor 4, Lymphocyte Activation, Neoplasm Proteins metabolism, Phosphorylation, Repressor Proteins chemistry, Retinoblastoma-Binding Protein 7 metabolism, Trans-Activators, Tumor Suppressor Proteins chemistry, CD4-Positive T-Lymphocytes immunology, Mi-2 Nucleosome Remodeling and Deacetylase Complex metabolism, Protein Kinase C metabolism, Repressor Proteins metabolism, Serine metabolism, Tumor Suppressor Proteins metabolism
- Abstract
The transcription factor BCL11B/CTIP2 is a major regulatory protein implicated in various aspects of development, function and survival of T cells. Mitogen-activated protein kinase (MAPK)-mediated phosphorylation and SUMOylation modulate BCL11B transcriptional activity, switching it from a repressor in naive murine thymocytes to a transcriptional activator in activated thymocytes. Here, we show that BCL11B interacts via its conserved N-terminal MSRRKQ motif with endogenous MTA1 and MTA3 proteins to recruit various NuRD complexes. Furthermore, we demonstrate that protein kinase C (PKC)-mediated phosphorylation of BCL11B Ser2 does not significantly impact BCL11B SUMOylation but negatively regulates NuRD recruitment by dampening the interaction with MTA1 or MTA3 (MTA1/3) and RbAp46 proteins. We detected increased phosphorylation of BCL11B Ser2 upon in vivo activation of transformed and primary human CD4(+) T cells. We show that following activation of CD4(+) T cells, BCL11B still binds to IL-2 and Id2 promoters but activates their transcription by recruiting P300 instead of MTA1. Prolonged stimulation results in the direct transcriptional repression of BCL11B by KLF4. Our results unveil Ser2 phosphorylation as a new BCL11B posttranslational modification linking PKC signaling pathway to T-cell receptor (TCR) activation and define a simple model for the functional switch of BCL11B from a transcriptional repressor to an activator during TCR activation of human CD4(+) T cells., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
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- 2016
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29. HIC1 Tumor Suppressor Loss Potentiates TLR2/NF-κB Signaling and Promotes Tissue Damage-Associated Tumorigenesis.
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Janeckova L, Pospichalova V, Fafilek B, Vojtechova M, Tureckova J, Dobes J, Dubuissez M, Leprince D, Baloghova N, Horazna M, Hlavata A, Stancikova J, Sloncova E, Galuskova K, Strnad H, and Korinek V
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- Animals, Azoxymethane, Cell Line, Tumor, Cell Proliferation, Colonic Neoplasms, Dextran Sulfate, Disease Models, Animal, Epithelial Cells, Gene Knockdown Techniques, Humans, Intestines cytology, Mice, Mice, Transgenic, Up-Regulation, Carcinogenesis metabolism, Kruppel-Like Transcription Factors genetics, Kruppel-Like Transcription Factors metabolism, NF-kappa B metabolism, Signal Transduction, Toll-Like Receptor 2 metabolism, Tumor Suppressor Proteins metabolism
- Abstract
Unlabelled: Hypermethylated in cancer 1 (HIC1) represents a prototypic tumor suppressor gene frequently inactivated by DNA methylation in many types of solid tumors. The gene encodes a sequence-specific transcriptional repressor controlling expression of several genes involved in cell cycle or stress control. In this study, a Hic1 allele was conditionally deleted, using a Cre/loxP system, to identify genes influenced by the loss of Hic1. One of the transcripts upregulated upon Hic1 ablation is the toll-like receptor 2 (TLR2). Tlr2 expression levels increased in Hic1-deficient mouse embryonic fibroblasts (MEF) and cultured intestinal organoids or in human cells upon HIC1 knockdown. In addition, HIC1 associated with the TLR2 gene regulatory elements, as detected by chromatin immunoprecipitation, indicating that Tlr2 indeed represents a direct Hic1 target. The Tlr2 receptor senses "danger" signals of microbial or endogenous origin to trigger multiple signaling pathways, including NF-κB signaling. Interestingly, Hic1 deficiency promoted NF-κB pathway activity not only in cells stimulated with Tlr2 ligand, but also in cells treated with NF-κB activators that stimulate different surface receptors. In the intestine, Hic1 is mainly expressed in differentiated epithelial cells and its ablation leads to increased Tlr2 production. Finally, in a chemical-induced mouse model of carcinogenesis, Hic1 absence resulted in larger Tlr2-positive colonic tumors that showed increased proportion of proliferating cells., Implications: The tumor-suppressive function of Hic1 in colon is related to its inhibitory action on proproliferative signaling mediated by the Tlr2 receptor present on tumor cells., (©2015 American Association for Cancer Research.)
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- 2015
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30. O-GlcNAcylation, an Epigenetic Mark. Focus on the Histone Code, TET Family Proteins, and Polycomb Group Proteins.
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Dehennaut V, Leprince D, and Lefebvre T
- Abstract
There are increasing evidences that dietary components and metabolic disorders affect gene expression through epigenetic mechanisms. These observations support the notion that epigenetic reprograming-linked nutrition is connected to the etiology of metabolic diseases and cancer. During the last 5 years, accumulating data revealed that the nutrient-sensing O-GlcNAc glycosylation (O-GlcNAcylation) may be pivotal in the modulation of chromatin remodeling and in the regulation of gene expression by being part of the "histone code," and by identifying OGT (O-GlcNAc transferase) as an interacting partner of the TET family proteins of DNA hydroxylases and as a member of the polycomb group proteins. Thus, it is suggested that O-GlcNAcylation is a post-translational modification that links nutrition to epigenetic. This review summarizes recent findings about the interplay between O-GlcNAcylation and the epigenome and enlightens the contribution of the glycosylation to epigenetic reprograming.
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- 2014
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31. HIC1 interacts with and modulates the activity of STAT3.
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Lin YM, Wang CM, Jeng JC, Leprince D, and Shih HM
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- Amino Acid Sequence, Binding Sites, Cell Line, Tumor, Genes, Reporter, Humans, Interleukin-6 genetics, Interleukin-6 metabolism, Kruppel-Like Transcription Factors metabolism, Luciferases genetics, Molecular Sequence Data, Oncostatin M genetics, Oncostatin M metabolism, Promoter Regions, Genetic, Protein Binding, Protein Interaction Domains and Motifs, Proto-Oncogene Proteins c-myc metabolism, STAT3 Transcription Factor metabolism, Signal Transduction, Vascular Endothelial Growth Factor A metabolism, Gene Expression Regulation, Neoplastic, Kruppel-Like Transcription Factors genetics, Proto-Oncogene Proteins c-myc genetics, STAT3 Transcription Factor genetics, Transcription, Genetic, Vascular Endothelial Growth Factor A genetics
- Abstract
HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene, expression of which is frequently suppressed in human cancers. Very little is known about the molecular basis of HIC1 in antagonizing oncogenic pathways. Here, we report that HIC1 forms complexes with the signal transducers and activators of transcription 3 (STAT3) and attenuates STAT3-mediated transcription. STAT3 was identified as a HIC1-interacting protein by affinity capture and followed by mass spectrometry analysis. Overexpression or depletion of HIC1 resulted in decreased or increased levels of interleukin-6 (IL-6)/oncostatin M (OSM)-induced STAT3-mediated reporter activity and expression of target genes such as VEGF and c-Myc, respectively. Furthermore, HIC1 suppressing the VEGF and c-Myc promoter activity and the colony formation of MDA-MB 231 cells were STAT3-dependent. Further studies showed that HIC1 interacts with the DNA binding domain of STAT3 and suppresses the binding of STAT3 to its target gene promoters. Domain mapping study revealed that HIC1 C-terminal domain binds to STAT3. HIC1 mutant defective in STAT3 interaction reduced its repressive effect on STAT3 DNA binding activity, the reporter activity and gene expression of the VEGF and c-Myc genes, and cell growth in MDA-MB 231 cells. Altogether, our findings not only provide a novel role of HIC1 in antagonizing STAT3-mediated activation of VEGF and c-Myc gene expression and cell growth, but also elucidate a molecular basis underlying the inhibitory effect of HIC1 on STAT3 transcriptional potential.
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- 2013
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32. A SUMOylation-dependent pathway regulates SIRT1 transcription and lung cancer metastasis.
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Sun L, Li H, Chen J, Dehennaut V, Zhao Y, Yang Y, Iwasaki Y, Kahn-Perles B, Leprince D, Chen Q, Shen A, and Xu Y
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- Animals, Blotting, Western, Down-Regulation, Humans, Immunoprecipitation, Lung Neoplasms genetics, Mice, Mice, Nude, Neoplasm Staging, Poly-ADP-Ribose Binding Proteins, Real-Time Polymerase Chain Reaction, Signal Transduction, Sumoylation, Transcription, Genetic, Tumor Cells, Cultured, Up-Regulation, Cell Hypoxia, Epithelial-Mesenchymal Transition, Lung Neoplasms pathology, Protein Inhibitors of Activated STAT metabolism, Sirtuin 1 genetics, Sirtuin 1 metabolism
- Abstract
Background: Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in lung cancer metastasis. The class III deacetylase sirtuin 1 (SIRT1) possesses both pro- and anticarcinogenic properties. The role of SIRT1 in lung cancer EMT is largely undefined., Methods: The effect of SIRT1 on migration of lung cancer cells was evaluated by wound healing assay in vitro and metastasis assay in nude mice in vivo. Protein expression in human lung cancers and cultured lung cancer cells was assessed by western blotting and immunohistochemistry. Interaction between protein and DNA was measured by chromatin immunoprecipitation assay. SIRT1 promoter activity was determined by reporter assay., Results: SIRT1 activation antagonized migration of lung cancer cells by suppressing EMT in vitro. Activation of SIRT1 by resveratrol also statistically significantly hampered (by 68.33%; P < .001, two-sided test) lung cancer cell metastasis in vivo. Hypoxia repressed SIRT1 transcription through promoting the competition between Sp1 and HIC1 on the SIRT1 proximal promoter in a SUMOylation-dependent manner. Disruption of SUMOylation by targeting either Ubc9 or PIASy restored SIRT1 expression in and favored an epithelial-like phenotype of cancer cells, thereby preventing metastasis. Decreased SIRT1 combined with elevated PIASy expression was implicated in more-invasive types of lung cancers in humans., Conclusions: We have identified a novel pathway that links SIRT1 down-regulation to hypoxia-induced EMT in lung cancer cells and may shed light on the development of novel antitumor therapeutics.
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- 2013
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33. DNA double-strand breaks lead to activation of hypermethylated in cancer 1 (HIC1) by SUMOylation to regulate DNA repair.
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Dehennaut V, Loison I, Dubuissez M, Nassour J, Abbadie C, and Leprince D
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- Acetylation drug effects, Animals, Antineoplastic Agents, Phytogenic pharmacology, COS Cells, Cell Transformation, Neoplastic drug effects, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Chlorocebus aethiops, DNA Repair drug effects, Etoposide pharmacology, Fibroblasts cytology, Histone Deacetylases genetics, Histone Deacetylases metabolism, Humans, Kruppel-Like Transcription Factors genetics, Mi-2 Nucleosome Remodeling and Deacetylase Complex genetics, Mi-2 Nucleosome Remodeling and Deacetylase Complex metabolism, Mutation, Repressor Proteins genetics, Repressor Proteins metabolism, Sirtuin 1 genetics, Sirtuin 1 metabolism, Sumoylation drug effects, Trans-Activators, DNA Breaks, Double-Stranded, DNA Repair physiology, Fibroblasts metabolism, Kruppel-Like Transcription Factors biosynthesis, Sumoylation physiology
- Abstract
HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene frequently epigenetically silenced in human cancers. HIC1 encodes a transcriptional repressor involved in the regulation of growth control and DNA damage response. We previously demonstrated that HIC1 can be either acetylated or SUMOylated on lysine 314. This deacetylation/SUMOylation switch is governed by an unusual complex made up of SIRT1 and HDAC4 which deacetylates and thereby favors SUMOylation of HIC1 by a mechanism not yet fully deciphered. This switch regulates the interaction of HIC1 with MTA1, a component of the NuRD complex and potentiates the repressor activity of HIC1. Here, we show that HIC1 silencing in human fibroblasts impacts the repair of DNA double-strand breaks whereas ectopic expression of wild-type HIC1, but not of nonsumoylatable mutants, leads to a reduced number of γH2AX foci induced by etoposide treatment. In this way, we demonstrate that DNA damage leads to (i) an enhanced HDAC4/Ubc9 interaction, (ii) the activation of SIRT1 by SUMOylation (Lys-734), and (iii) the SUMO-dependent recruitment of HDAC4 by SIRT1 which permits the deacetylation/SUMOylation switch of HIC1. Finally, we show that this increase of HIC1 SUMOylation favors the HIC1/MTA1 interaction, thus demonstrating that HIC1 regulates DNA repair in a SUMO-dependent way. Therefore, epigenetic HIC1 inactivation, which is an early step in tumorigenesis, could contribute to the accumulation of DNA mutations through impaired DNA repair and thus favor tumorigenesis.
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- 2013
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34. Hypermethylated in cancer 1 (HIC1) recruits polycomb repressive complex 2 (PRC2) to a subset of its target genes through interaction with human polycomb-like (hPCL) proteins.
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Boulay G, Dubuissez M, Van Rechem C, Forget A, Helin K, Ayrault O, and Leprince D
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- Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Carrier Proteins genetics, Carrier Proteins metabolism, Cerebellum embryology, Cerebellum metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Enhancer of Zeste Homolog 2 Protein, Female, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Humans, Kruppel-Like Transcription Factors genetics, Mice, Neoplasm Proteins, Nuclear Proteins genetics, Nuclear Proteins metabolism, Polycomb Repressive Complex 2, Polycomb-Group Proteins, Repressor Proteins genetics, Transcription Factors genetics, Transcription Factors metabolism, Zinc Fingers, Kruppel-Like Transcription Factors metabolism, Repressor Proteins metabolism
- Abstract
HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene epigenetically silenced or deleted in many human cancers. HIC1 is involved in regulatory loops modulating p53- and E2F1-dependent cell survival, growth control, and stress responses. HIC1 is also essential for normal development because Hic1-deficient mice die perinatally and exhibit gross developmental defects throughout the second half of development. HIC1 encodes a transcriptional repressor with five C(2)H(2) zinc fingers mediating sequence-specific DNA binding and two repression domains: an N-terminal BTB/POZ domain and a central region recruiting CtBP and NuRD complexes. By yeast two-hybrid screening, we identified the Polycomb-like protein hPCL3 as a novel co-repressor for HIC1. Using multiple biochemical strategies, we demonstrated that HIC1 interacts with hPCL3 and its paralog PHF1 to form a stable complex with the PRC2 members EZH2, EED, and Suz12. Confirming the implication of HIC1 in Polycomb recruitment, we showed that HIC1 shares some of its target genes with PRC2, including ATOH1. Depletion of HIC1 by siRNA interference leads to a partial displacement of EZH2 from the ATOH1 promoter. Furthermore, in vivo, ATOH1 repression by HIC1 is associated with Polycomb activity during mouse cerebellar development. Thus, our results identify HIC1 as the first transcription factor in mammals able to recruit PRC2 to some target promoters through its interaction with Polycomb-like proteins.
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- 2012
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35. Loss of Hypermethylated in Cancer 1 (HIC1) in breast cancer cells contributes to stress-induced migration and invasion through β-2 adrenergic receptor (ADRB2) misregulation.
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Boulay G, Malaquin N, Loison I, Foveau B, Van Rechem C, Rood BR, Pourtier A, and Leprince D
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- Breast Neoplasms genetics, Breast Neoplasms physiopathology, Cell Adhesion genetics, Cell Line, Tumor, Female, Fibroblasts cytology, Fibroblasts metabolism, Humans, Kruppel-Like Transcription Factors deficiency, Kruppel-Like Transcription Factors genetics, Neoplasm Invasiveness, Neoplasm Metastasis, RNA Interference, RNA, Small Interfering genetics, Receptors, Adrenergic, beta-2 deficiency, Breast Neoplasms pathology, Cell Movement genetics, Kruppel-Like Transcription Factors metabolism, Receptors, Adrenergic, beta-2 genetics, Stress, Physiological genetics
- Abstract
The transcriptional repressor HIC1 (Hypermethylated in Cancer 1) is a tumor suppressor gene inactivated in many human cancers including breast carcinomas. In this study, we show that HIC1 is a direct transcriptional repressor of β-2 adrenergic receptor (ADRB2). Through promoter luciferase activity, chromatin immunoprecipitation (ChIP) and sequential ChIP experiments, we demonstrate that ADRB2 is a direct target gene of HIC1, endogenously in WI-38 cells and following HIC1 re-expression in breast cancer cells. Agonist-mediated stimulation of ADRB2 increases the migration and invasion of highly malignant MDA-MB-231 breast cancer cells but these effects are abolished following HIC1 re-expression or specific down-regulation of ADRB2 by siRNA treatment. Our results suggest that early inactivation of HIC1 in breast carcinomas could predispose to stress-induced metastasis through up-regulation of the β-2 adrenergic receptor.
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- 2012
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36. The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1).
- Author
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Foveau B, Boulay G, Pinte S, Van Rechem C, Rood BR, and Leprince D
- Subjects
- Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Tumor, Disease Progression, Down-Regulation genetics, Fibroblasts metabolism, Gene Expression Regulation, Neoplastic genetics, Gene Knockdown Techniques, Gene Silencing, HEK293 Cells, Histone Deacetylases metabolism, Humans, Kruppel-Like Transcription Factors deficiency, Kruppel-Like Transcription Factors genetics, Mammary Glands, Human cytology, Mammary Glands, Human metabolism, Mammary Glands, Human pathology, Promoter Regions, Genetic genetics, Protein Binding, RNA, Messenger genetics, RNA, Messenger metabolism, Repressor Proteins metabolism, Trans-Activators, Kruppel-Like Transcription Factors metabolism, Receptor, EphA2 genetics
- Abstract
The tumor suppressor gene hypermethylated in cancer 1 (HIC1), which encodes a transcriptional repressor, is epigenetically silenced in many human tumors. Here, we show that ectopic expression of HIC1 in the highly malignant MDA-MB-231 breast cancer cell line severely impairs cell proliferation, migration, and invasion in vitro. In parallel, infection of breast cancer cell lines with a retrovirus expressing HIC1 also induces decreased mRNA and protein expression of the tyrosine kinase receptor EphA2. Moreover, chromatin immunoprecipitation (ChIP) and sequential ChIP experiments demonstrate that endogenous HIC1 proteins are bound, together with the MTA1 corepressor, to the EphA2 promoter in WI38 cells. Taken together, our results identify EphA2 as a new direct target gene of HIC1. Finally, we observe that inactivation of endogenous HIC1 through RNA interference in normal breast epithelial cells results in the up-regulation of EphA2 and is correlated with increased cellular migration. To conclude, our results involve the tumor suppressor HIC1 in the transcriptional regulation of the tyrosine kinase receptor EphA2, whose ligand ephrin-A1 is also a HIC1 target gene. Thus, loss of the regulation of this Eph pathway through HIC1 epigenetic silencing could be an important mechanism in the pathogenesis of epithelial cancers.
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- 2012
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37. The transcription factor encyclopedia.
- Author
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Yusuf D, Butland SL, Swanson MI, Bolotin E, Ticoll A, Cheung WA, Zhang XY, Dickman CT, Fulton DL, Lim JS, Schnabl JM, Ramos OH, Vasseur-Cognet M, de Leeuw CN, Simpson EM, Ryffel GU, Lam EW, Kist R, Wilson MS, Marco-Ferreres R, Brosens JJ, Beccari LL, Bovolenta P, Benayoun BA, Monteiro LJ, Schwenen HD, Grontved L, Wederell E, Mandrup S, Veitia RA, Chakravarthy H, Hoodless PA, Mancarelli MM, Torbett BE, Banham AH, Reddy SP, Cullum RL, Liedtke M, Tschan MP, Vaz M, Rizzino A, Zannini M, Frietze S, Farnham PJ, Eijkelenboom A, Brown PJ, Laperrière D, Leprince D, de Cristofaro T, Prince KL, Putker M, del Peso L, Camenisch G, Wenger RH, Mikula M, Rozendaal M, Mader S, Ostrowski J, Rhodes SJ, Van Rechem C, Boulay G, Olechnowicz SW, Breslin MB, Lan MS, Nanan KK, Wegner M, Hou J, Mullen RD, Colvin SC, Noy PJ, Webb CF, Witek ME, Ferrell S, Daniel JM, Park J, Waldman SA, Peet DJ, Taggart M, Jayaraman PS, Karrich JJ, Blom B, Vesuna F, O'Geen H, Sun Y, Gronostajski RM, Woodcroft MW, Hough MR, Chen E, Europe-Finner GN, Karolczak-Bayatti M, Bailey J, Hankinson O, Raman V, LeBrun DP, Biswal S, Harvey CJ, DeBruyne JP, Hogenesch JB, Hevner RF, Héligon C, Luo XM, Blank MC, Millen KJ, Sharlin DS, Forrest D, Dahlman-Wright K, Zhao C, Mishima Y, Sinha S, Chakrabarti R, Portales-Casamar E, Sladek FM, Bradley PH, and Wasserman WW
- Subjects
- Access to Information, Animals, Encyclopedias as Topic, Humans, Internet, Mice, Rats, Transcription, Genetic, Computational Biology, Databases, Protein supply & distribution, Transcription Factors genetics
- Abstract
Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.
- Published
- 2012
- Full Text
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38. Differential regulation of HIC1 target genes by CtBP and NuRD, via an acetylation/SUMOylation switch, in quiescent versus proliferating cells.
- Author
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Van Rechem C, Boulay G, Pinte S, Stankovic-Valentin N, Guérardel C, and Leprince D
- Subjects
- Acetylation, Alcohol Oxidoreductases genetics, Animals, Base Sequence, Binding Sites genetics, Cell Line, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p57 genetics, DNA genetics, DNA metabolism, DNA-Binding Proteins genetics, Genes, bcl-1, Histone Deacetylases genetics, Histone Deacetylases metabolism, Humans, In Vitro Techniques, Interphase, Kruppel-Like Transcription Factors chemistry, Mi-2 Nucleosome Remodeling and Deacetylase Complex genetics, Mice, Models, Biological, NIH 3T3 Cells, Promoter Regions, Genetic, Protein Processing, Post-Translational, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Repressor Proteins genetics, Repressor Proteins metabolism, Sirtuin 1 genetics, Small Ubiquitin-Related Modifier Proteins metabolism, Trans-Activators, Transcriptional Activation, Two-Hybrid System Techniques, Alcohol Oxidoreductases metabolism, DNA-Binding Proteins metabolism, Kruppel-Like Transcription Factors genetics, Kruppel-Like Transcription Factors metabolism, Mi-2 Nucleosome Remodeling and Deacetylase Complex metabolism
- Abstract
The tumor suppressor gene HIC1 encodes a transcriptional repressor involved in regulatory loops modulating P53-dependent and E2F1-dependent cell survival, growth control, and stress responses. Despite its importance, few HIC1 corepressors and target genes have been characterized thus far. Using a yeast two-hybrid approach, we identify MTA1, a subunit of the NuRD complex, as a new HIC1 corepressor. This interaction is regulated by two competitive posttranslational modifications of HIC1 at lysine 314, promotion by SUMOylation, and inhibition by acetylation. Consistent with the role of HIC1 in growth control, we demonstrate that HIC1/MTA1 complexes bind on two new target genes, Cyclin D1 and p57KIP2 in quiescent but not in growing WI38 cells. In addition, HIC1/MTA1 and HIC1/CtBP complexes differentially bind on two mutually exclusive HIC1 binding sites (HiRE) on the SIRT1 promoter. SIRT1 transcriptional activation induced by short-term serum starvation coincides with loss of occupancy of the distal sites by HIC1/MTA1 and HIC1/CtBP. Upon longer starvation, both complexes are found but on a newly identified proximal HiRE that is evolutionarily conserved and specifically enriched with repressive histone marks. Our results decipher a mechanistic link between two competitive posttranslational modifications of HIC1 and corepressor recruitment to specific genes, leading to growth control.
- Published
- 2010
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39. Scavenger chemokine (CXC motif) receptor 7 (CXCR7) is a direct target gene of HIC1 (hypermethylated in cancer 1).
- Author
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Van Rechem C, Rood BR, Touka M, Pinte S, Jenal M, Guérardel C, Ramsey K, Monté D, Bégue A, Tschan MP, Stephan DA, and Leprince D
- Subjects
- Adenoviridae genetics, Alcohol Oxidoreductases metabolism, Base Sequence, Cell Line, Tumor, Cell Proliferation, Chromatin Immunoprecipitation, Conserved Sequence, DNA-Binding Proteins metabolism, Down-Regulation genetics, Fibroblasts metabolism, Gene Expression Regulation, Neoplastic, Genes, Neoplasm, Genetic Vectors genetics, Humans, Kruppel-Like Transcription Factors genetics, Molecular Sequence Data, Oligonucleotide Array Sequence Analysis, Osteosarcoma genetics, Osteosarcoma pathology, Phylogeny, Promoter Regions, Genetic genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, CXCR metabolism, Sirtuin 1, Sirtuins genetics, Sirtuins metabolism, Kruppel-Like Transcription Factors metabolism, Receptors, CXCR genetics
- Abstract
The tumor suppressor gene HIC1 (Hypermethylated in Cancer 1) that is epigenetically silenced in many human tumors and is essential for mammalian development encodes a sequence-specific transcriptional repressor. The few genes that have been reported to be directly regulated by HIC1 include ATOH1, FGFBP1, SIRT1, and E2F1. HIC1 is thus involved in the complex regulatory loops modulating p53-dependent and E2F1-dependent cell survival and stress responses. We performed genome-wide expression profiling analyses to identify new HIC1 target genes, using HIC1-deficient U2OS human osteosarcoma cells infected with adenoviruses expressing either HIC1 or GFP as a negative control. These studies identified several putative direct target genes, including CXCR7, a G-protein-coupled receptor recently identified as a scavenger receptor for the chemokine SDF-1/CXCL12. CXCR7 is highly expressed in human breast, lung, and prostate cancers. Using quantitative reverse transcription-PCR analyses, we demonstrated that CXCR7 was repressed in U2OS cells overexpressing HIC1. Inversely, inactivation of endogenous HIC1 by RNA interference in normal human WI38 fibroblasts results in up-regulation of CXCR7 and SIRT1. In silico analyses followed by deletion studies and luciferase reporter assays identified a functional and phylogenetically conserved HIC1-responsive element in the human CXCR7 promoter. Moreover, chromatin immunoprecipitation (ChIP) and ChIP upon ChIP experiments demonstrated that endogenous HIC1 proteins are bound together with the C-terminal binding protein corepressor to the CXCR7 and SIRT1 promoters in WI38 cells. Taken together, our results implicate the tumor suppressor HIC1 in the transcriptional regulation of the chemokine receptor CXCR7, a key player in the promotion of tumorigenesis in a wide variety of cell types.
- Published
- 2009
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- View/download PDF
40. The tumor suppressor gene hypermethylated in cancer 1 is transcriptionally regulated by E2F1.
- Author
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Jenal M, Trinh E, Britschgi C, Britschgi A, Roh V, Vorburger SA, Tobler A, Leprince D, Fey MF, Helin K, and Tschan MP
- Subjects
- Base Sequence, Binding Sites, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular metabolism, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Cell Line, Tumor, DNA Methylation, E2F1 Transcription Factor metabolism, Etoposide pharmacology, Gene Expression, Gene Expression Regulation, Neoplastic, Humans, Kruppel-Like Transcription Factors biosynthesis, Liver Neoplasms genetics, Liver Neoplasms metabolism, Lung Neoplasms genetics, Lung Neoplasms metabolism, Molecular Sequence Data, Promoter Regions, Genetic, RNA, Messenger genetics, RNA, Messenger metabolism, Sequence Alignment, Transcription, Genetic, Up-Regulation drug effects, E2F1 Transcription Factor genetics, Kruppel-Like Transcription Factors genetics
- Abstract
The Hypermethylated in Cancer 1 (HIC1) gene encodes a zinc finger transcriptional repressor that cooperates with p53 to suppress cancer development. We and others recently showed that HIC1 is a transcriptional target of p53. To identify additional transcriptional regulators of HIC1, we screened a set of transcription factors for regulation of a human HIC1 promoter reporter. We found that E2F1 strongly activates the full-length HIC1 promoter reporter. Promoter deletions and mutations identified two E2F responsive elements in the HIC1 core promoter region. Moreover, in vivo binding of E2F1 to the HIC1 promoter was shown by chromatin immunoprecipitation assays in human TIG3 fibroblasts expressing tamoxifen-activated E2F1. In agreement, activation of E2F1 in TIG3-E2F1 cells markedly increased HIC1 expression. Interestingly, expression of E2F1 in the p53(-/-) hepatocellular carcinoma cell line Hep3B led to an increase of endogenous HIC1 mRNA, although bisulfite genomic sequencing of the HIC1 promoter revealed that the region bearing the two E2F1 binding sites is hypermethylated. In addition, endogenous E2F1 induced by etoposide treatment bound to the HIC1 promoter. Moreover, inhibition of E2F1 strongly reduced the expression of etoposide-induced HIC1. In conclusion, we identified HIC1 as novel E2F1 transcriptional target in DNA damage responses.
- Published
- 2009
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41. An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity.
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Stankovic-Valentin N, Deltour S, Seeler J, Pinte S, Vergoten G, Guérardel C, Dejean A, and Leprince D
- Subjects
- Acetylation, Amino Acid Motifs, Amino Acid Sequence, Animals, Cell Line, Cell Nucleus metabolism, Conserved Sequence, DNA-Binding Proteins genetics, Histone Deacetylases metabolism, Humans, Kruppel-Like Transcription Factors, Lysine metabolism, Molecular Sequence Data, Mutation, Phosphorylation, Phylogeny, RNA, Small Interfering genetics, Sirtuin 1, Sirtuins genetics, Transcription Factors genetics, Transcription, Genetic, DNA-Binding Proteins metabolism, SUMO-1 Protein metabolism, Sirtuins metabolism, Transcription Factors metabolism, p300-CBP Transcription Factors metabolism
- Abstract
Tumor suppressor HIC1 (hypermethylated in cancer 1) is a gene that is essential for mammalian development, epigenetically silenced in many human tumors, and involved in a complex pathway regulating P53 tumor suppression activity. HIC1 encodes a sequence-specific transcriptional repressor containing five Krüppel-like C(2)H(2) zinc fingers and an N-terminal BTB/POZ repression domain. Here, we show that endogenous HIC1 is SUMOylated in vivo on a phylogenetically conserved lysine, K314, located in the central region which is a second repression domain. K314R mutation does not influence HIC1 subnuclear localization but significantly reduces its transcriptional repression potential, as does the mutation of the other conserved residue in the psiKXE consensus, E316A, or the overexpression of the deSUMOylase SSP3/SENP2. Furthermore, HIC1 is acetylated in vitro by P300/CBP. Strikingly, the K314R mutant is less acetylated than wild-type HIC1, suggesting that this lysine is a target for both SUMOylation and acetylation. We further show that HIC1 transcriptional repression activity is positively controlled by two types of deacetylases, SIRT1 and HDAC4, which increase the deacetylation and SUMOylation, respectively, of K314. Knockdown of endogenous SIRT1 by the transfection of short interfering RNA causes a significant loss of HIC1 SUMOylation. Thus, this dual-deacetylase complex induces either a phosphorylation-dependent acetylation-SUMOylation switch through a psiKXEXXSP motif, as previously shown for MEF2, or a phosphorylation-independent switch through a psiKXEP motif, as shown here for HIC1, since P317A mutation severely impairs HIC1 acetylation. Finally, our results demonstrate that HIC1 is a target of the class III deacetylase SIRT1 and identify a new posttranslational modification step in the P53-HIC1-SIRT1 regulatory loop.
- Published
- 2007
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42. Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex.
- Author
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Zhang Q, Wang SY, Fleuriel C, Leprince D, Rocheleau JV, Piston DW, and Goodman RH
- Subjects
- Animals, Cell Hypoxia drug effects, Cells, Cultured, Deoxyglucose pharmacology, Gene Expression Regulation, Humans, Kruppel-Like Transcription Factors, Mice, NAD metabolism, Promoter Regions, Genetic genetics, Protein Binding, Repressor Proteins genetics, Sirtuin 1, Sirtuins genetics, Alcohol Oxidoreductases metabolism, DNA-Binding Proteins metabolism, Metabolic Networks and Pathways, Repressor Proteins metabolism, Sirtuins metabolism, Transcription Factors metabolism, Transcription, Genetic genetics
- Abstract
The Sir2 histone deacetylases are important for gene regulation, metabolism, and longevity. A unique feature of these enzymes is their utilization of NAD(+) as a cosubstrate, which has led to the suggestion that Sir2 activity reflects the cellular energy state. We show that SIRT1, a mammalian Sir2 homologue, is also controlled at the transcriptional level through a mechanism that is specific for this isoform. Treatment with the glycolytic blocker 2-deoxyglucose (2-DG) decreases association of the redox sensor CtBP with HIC1, an inhibitor of SIRT1 transcription. We propose that the reduction in transcriptional repression mediated by HIC1, due to the decrease of CtBP binding, increases SIRT1 expression. This mechanism allows the specific regulation of SIRT1 in response to nutrient deprivation.
- Published
- 2007
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43. A L225A substitution in the human tumour suppressor HIC1 abolishes its interaction with the corepressor CtBP.
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Stankovic-Valentin N, Verger A, Deltour-Balerdi S, Quinlan KG, Crossley M, and Leprince D
- Subjects
- Alcohol Oxidoreductases, Amino Acid Sequence, Animals, COS Cells, Cell Line, Tumor, Chlorocebus aethiops, Co-Repressor Proteins, DNA-Binding Proteins chemistry, Eye Proteins chemistry, Genes, Tumor Suppressor, Humans, Kruppel-Like Transcription Factors, Leucine chemistry, Molecular Sequence Data, Nerve Tissue Proteins, Phosphoproteins chemistry, Point Mutation, Sequence Homology, Amino Acid, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, DNA-Binding Proteins physiology, Eye Proteins metabolism, Phosphoproteins metabolism, Transcription Factors genetics, Transcription Factors physiology
- Abstract
HIC1 (hypermethylated in cancer) is a tumour suppressor gene located in 17p13.3, a region frequently hypermethylated or deleted in many types of prevalent human tumour. HIC1 is also a candidate for a contiguous-gene syndrome, the Miller-Dieker syndrome, a severe form of lissencephaly accompanied by developmental anomalies. HIC1 encodes a BTB/POZ-zinc finger transcriptional repressor. HIC1 represses transcription via two autonomous repression domains, an N-terminal BTB/POZ and a central region, by trichostatin A-insensitive and trichostatin A-sensitive mechanisms, respectively. The HIC1 central region recruits the corepressor CtBP (C-terminal binding protein) through a conserved GLDLSKK motif, a variant of the consensus C-terminal binding protein interaction domain PxDLSxK/R. Here, we show that HIC1 interacts with both CtBP1 and CtBP2 and that this interaction is stimulated by agents increasing NADH levels. Furthermore, point mutation of two CtBP2 residues forming part of the structure of the recognition cleft for a PxDLS motif also ablates the interaction with a GxDLS motif. Conversely, in perfect agreement with the structural data and the universal conservation of this residue in all C-terminal binding protein-interacting motifs, mutation of the central leucine residue (leucine 225 in HIC1) abolishes the interaction between HIC1 and CtBP1 or CtBP2. As expected from the corepressor activity of CtBP, this mutation also impairs the HIC1-mediated transcriptional repression. These results thus demonstrate a strong conservation in the binding of C-terminal binding protein-interacting domains despite great variability in their amino acid sequences. Finally, this L225A point mutation could also provide useful knock-in animal models to study the role of the HIC1-CtBP interaction in tumorigenesis and in development.
- Published
- 2006
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44. [Chromosome arm 17p13.3: could HIC1 be the one ?].
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Chopin V and Leprince D
- Subjects
- Animals, Chromosome Mapping, Disease Models, Animal, Genetic Markers, Histone Deacetylases metabolism, Humans, Kruppel-Like Transcription Factors, Loss of Heterozygosity, Mice, Neoplasms genetics, Tumor Suppressor Protein p53 genetics, Chromosomes, Human, Pair 17, DNA-Binding Proteins genetics, Transcription Factors genetics
- Abstract
Loss of heterozygosity (LOH) of the short arm of chromosome 17 (17p) is one of the most frequent genetic alterations in human cancers. Most often, allelic losses coincide with p53 mutations at 17p13.1. However, in many types of solid tumors including sporadic breast cancers, ovarian cancers, medulloblastomas and small cell lung carcinomas, frequent LOH or DNA methylation changes occur in a more telomeric region at 17p13.3, in absence of any p53 genetic alterations. These results suggest that one or more tumor suppressor genes located at 17p13.3 could be involved in tumorigenesis. In addition, the 17p13.3 region has also been implicated in the Miller-Dieker syndrome (MDS), a severe form of lissencephaly accompanied by developmental anomalies caused by heterozygous gene deletions. Analyses of deletion mapping and CpG island methylation patterns have resulted in the identification of two tumor suppressor genes at 17p13.3, HIC1 (hypermethylated in cancer 1) and OVCA1 (ovarian cancer gene 1). HIC1 is a tumor suppressor gene that encodes a transcriptional repressor with five Krüppel-like C2H2 zinc finger motifs and a N-terminal BTB/POZ domain. Clues to the tumor suppressor function of HIC1 have come from the study of heterozygous Hic1+/- mice, which develop spontaneous malignant tumors of different types. Generation of double heterozygous knockout mice Hic1+/- p53+/- provides strong evidence that epigenetically silenced genes such as HIC1 can significantly influence tumorigenesis driven by mutations of classic tumor suppressor genes. This functional cooperation between HIC1 and p53 is interesting and recently, its has been demonstrated that HIC1 was involved in a certain feedback regulation for p53 in tumor suppression through the histone deacetylase SIRT1. However, despite the fact that epigenetic oncogenesis is one of the most vibrant areas of biologic research, the determinants between genetic versus epigenetic routes of tumor suppressor gene inactivation remain elusive.
- Published
- 2006
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- View/download PDF
45. [Epigenetics and cancer].
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Deltour S, Chopin V, and Leprince D
- Subjects
- Animals, DNA Methylation, Histones genetics, Humans, Epigenesis, Genetic, Neoplasms genetics
- Abstract
Epigenetics is defined as "the study of mitotically and/or meiotically heritable changes in gene expression that cannot be explained by changes in the DNA sequence". Setting up the epigenetic program is crucial for correct development and its stable inheritance throughout its lifespan is essential for the maintenance of the tissue- and cell-specific functions of the organism. For many years, the genetic causes of cancer have hold centre stage. However, the recent wealth of information about the molecular mechanisms which, by modulating the chromatin structure, can regulate gene expression has high-lighted the predominant role of epigenetic modifications in the initiation and progression of numerous pathologies, including cancer. The nucleosome is the major target of these epigenetic regulation mechanisms. They include a series of tightly interconnected steps which starting with the setting ("writing") of the epigenetic mark till its "reading" and interpretation will result in long-term gene regulation. The major epigenetic changes associated with tumorigenesis are aberrant DNA methylation of CpG islands located in the promoter region of tumor suppressor gene, global genomic hypomethylation and covalent modifications of histone N-terminal tails which are protruding out from the nucleosome core. In sharp contrast with genetic modifications, epigenetic modifications are highly dynamic and reversible. The characterization of specific inhibitors directed against some key epigenetic players has opened a new and promising therapeutic avenue, the epigenetic therapy, since some inhibitors are already used in clinical trials.
- Published
- 2005
- Full Text
- View/download PDF
46. The tumor suppressor HIC1 (hypermethylated in cancer 1) is O-GlcNAc glycosylated.
- Author
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Lefebvre T, Pinte S, Guérardel C, Deltour S, Martin-Soudant N, Slomianny MC, Michalski JC, and Leprince D
- Subjects
- Acetylglucosamine analogs & derivatives, Acetylglucosamine chemistry, Animals, CHO Cells, COS Cells, Cells, Cultured, Chlorocebus aethiops, Chromatography, Affinity, Cricetinae, DNA Methylation, Electrophoretic Mobility Shift Assay, Glycoconjugates chemistry, Glycoconjugates metabolism, Glycosylation, Kruppel-Like Transcription Factors, Neoplasms pathology, Peptide Fragments chemistry, Protein Conformation, Trypsin pharmacology, Wheat Germ Agglutinins metabolism, Acetylglucosamine metabolism, Genes, Tumor Suppressor, Neoplasms metabolism, Peptide Fragments metabolism, Transcription Factors metabolism
- Abstract
HIC1 (hypermethylated in cancer 1) is a transcriptional repressor containing five Krüppel-like C(2)H(2) zinc fingers and an N-terminal dimerization and autonomous repression domain called BTB/POZ. Here, we demonstrate that full-length HIC1 proteins are modified both in vivo and in vitro with O-linked N-acetylglucosamine (O-GlcNAc). This is a highly dynamic glycosylation found within the cytosolic and the nuclear compartments of eukaryotes. Analysis of [(3)H]Gal-labeled tryptic peptides indicates that HIC1 has three major sites for O-GlcNAc glycosylation. Using C-terminal deletion mutants, we have shown that O-GlcNAc modification of HIC1 proteins occurred preferentially in the DNA-binding domain. Nonglycosylated and glycosylated forms of full-length HIC1 proteins separated by wheat germ agglutinin affinity purification, displayed the same specific DNA-binding activity in electrophoretic mobility shift assays proving that the O-GlcNAc modification is not directly implicated in the specific DNA recognition of HIC1. Intriguingly, N-terminal truncated forms corresponding to BTB-POZ-deleted proteins exhibited a strikingly differential activity, as the glycosylated truncated forms are unable to bind DNA whereas the unglycosylated ones do. Electrophoretic mobility shift assays performed with separated pools of glycosylated and unglycosylated forms of a construct exhibiting only the DNA-binding domain and the C-terminal tail of HIC1 (residues 399-714) and supershift experiments with wheat germ agglutinin or RL-2, an antibody raised against O-GlcNAc residues, fully corroborated these results. Interestingly, these truncated proteins are O-GlcNAc modified in their C-terminal tail (residues 670-711) and not in the DNA-binding domain, as for the full-length proteins. Thus, the O-GlcNAc modification of HIC1 does not affect its specific DNA-binding activity and is highly sensitive to conformational effects, notably its dimerization through the BTB/POZ domain.
- Published
- 2004
- Full Text
- View/download PDF
47. The tumor suppressor gene HIC1 (hypermethylated in cancer 1) is a sequence-specific transcriptional repressor: definition of its consensus binding sequence and analysis of its DNA binding and repressive properties.
- Author
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Pinte S, Stankovic-Valentin N, Deltour S, Rood BR, Guérardel C, and Leprince D
- Subjects
- Amino Acid Motifs, Animals, Base Sequence, Binding Sites, Blotting, Northern, Blotting, Western, COS Cells, Cell Line, Tumor, Cell Nucleus metabolism, Chromatin metabolism, DNA chemistry, DNA Mutational Analysis, Dimerization, Genes, Reporter, Glutathione Transferase metabolism, Humans, Kruppel-Like Transcription Factors, Molecular Sequence Data, Mutation, Plasmids metabolism, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Rabbits, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins metabolism, Time Factors, Transcription Factors biosynthesis, Transfection, Zinc Fingers, DNA metabolism, Transcription Factors physiology, Transcription, Genetic
- Abstract
HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene located at chromosome 17p13.3, a region frequently hypermethylated or deleted in human tumors and in a contiguous-gene syndrome, the Miller-Dieker syndrome. HIC1 is a transcriptional repressor containing five Krüppel-like C(2)H(2) zinc fingers and an N-terminal dimerization and autonomous repression domain called BTB/POZ. Although some of the HIC1 transcriptional repression mechanisms have been recently deciphered, target genes are still to be discovered. In this study, we determined the consensus binding sequence for HIC1 and investigated its DNA binding properties. Using a selection and amplification of binding sites technique, we identified the sequence 5'-(C)/(G)NG(C)/(G)GGGCA(C)/(A) CC-3' as an optimal binding site. In silico and functional analyses fully validated this consensus and highlighted a GGCA core motif bound by zinc fingers 3 and 4. The BTB/POZ domain inhibits the binding of HIC1 to a single site but mediates cooperative binding to a probe containing five concatemerized binding sites, a property shared by other BTB/POZ proteins. Finally, full-length HIC1 proteins transiently expressed in RK13 cells and more importantly, endogenous HIC1 proteins from the DAOY medulloblastoma cell line, repress the transcription of a reporter gene through their direct binding to these sites, as confirmed by chromatin immunoprecipitation experiments. The definition of the HIC1-specific DNA binding sequence as well as the requirement for multiple sites for optimal binding of the full-length protein are mandatory prerequisites for the identification and analyses of bona fide HIC1 target genes.
- Published
- 2004
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- View/download PDF
48. Identification of a second G-C-rich promoter conserved in the human, murine and rat tumor suppressor genes HIC1.
- Author
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Pinte S, Guérardel C, Deltour-Balerdi S, Godwin AK, and Leprince D
- Subjects
- Animals, Base Sequence, Female, Humans, Kruppel-Like Transcription Factors, Mice, Molecular Sequence Data, Ovary metabolism, Rabbits, Rats, Conserved Sequence, Genes, Tumor Suppressor, Promoter Regions, Genetic, Transcription Factors genetics
- Abstract
The BTB/POZ transcriptional repressor HIC1 (Hypermethylated in Cancer 1) is a tumor suppressor gene located at chromosome 17p13.3, a region frequently hypermethylated or deleted in human tumors and in a contiguous-gene syndrome, the Miller-Dieker syndrome. The human and murine HIC1 genes are composed of two alternative 5' exons, 1a and 1b fused to a large second coding exon 2. Exon 1a is a noncoding exon associated with a major G-C-rich promoter whereas exon 1b is a downstream coding exon associated with a minor TATA box promoter. By human-mouse genome comparison, we have identified a short upstream conserved sequence containing G-C boxes which were shown to be functional. Transcripts initiating from this new promoter were detected in various human and mouse tissues and contained a long 5'-UTR sequence, called 1c which encompass the G-C-rich promoter associated with exon 1a and uses the same splice donor site. RT-PCR analyses of two primary breast epithelial cell lines identified two other 5'-UTRs generated by alternative splicing within exon 1c. Our results thus highlight the existence of an unexpected complex transcriptional regulation of HIC1.
- Published
- 2004
- Full Text
- View/download PDF
49. The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif.
- Author
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Deltour S, Pinte S, Guerardel C, Wasylyk B, and Leprince D
- Subjects
- Alcohol Oxidoreductases, Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, COS Cells metabolism, Cell Nucleus Structures metabolism, Cells, Cultured, Conserved Sequence, Cricetinae, DNA-Binding Proteins genetics, Dimerization, Evolution, Molecular, Genes, Tumor Suppressor, Histone Deacetylases metabolism, Humans, Kruppel-Like Transcription Factors, Phosphoproteins genetics, Rabbits, Repressor Proteins genetics, Repressor Proteins metabolism, Transcription Factors genetics, Two-Hybrid System Techniques, DNA-Binding Proteins metabolism, Phosphoproteins metabolism, Transcription Factors metabolism
- Abstract
HIC1 (hypermethylated in cancer) and its close relative HRG22 (HIC1-related gene on chromosome 22) encode transcriptional repressors with five C(2)H(2) zinc fingers and an N-terminal BTB/POZ autonomous transcriptional repression domain that is unable to recruit histone deacetylases (HDACs). Alignment of the HIC1 and HRG22 proteins from various species highlighted a perfectly conserved GLDLSKK/R motif highly related to the consensus CtBP interaction motif (PXDLSXK/R), except for the replacement of the virtually invariant proline by a glycine. HIC1 strongly interacts with mCtBP1 both in vivo and in vitro through this conserved GLDLSKK motif, thus extending the CtBP consensus binding site. The BTB/POZ domain does not interact with mCtBP1, but the dimerization of HIC1 through this domain is required for the interaction with mCtBP1. When tethered to DNA by fusion with the Gal4 DNA-binding domain, the HIC1 central region represses transcription through interactions with CtBP in a trichostatin A-sensitive manner. In conclusion, our results demonstrate that HIC1 mediates transcriptional repression by both HDAC-independent and HDAC-dependent mechanisms and show that CtBP is a HIC1 corepressor that is recruited via a variant binding site.
- Published
- 2002
- Full Text
- View/download PDF
50. Identification in the human candidate tumor suppressor gene HIC-1 of a new major alternative TATA-less promoter positively regulated by p53.
- Author
-
Guerardel C, Deltour S, Pinte S, Monte D, Begue A, Godwin AK, and Leprince D
- Subjects
- Alternative Splicing, Amino Acid Sequence, Animals, Base Sequence, DNA, Complementary analysis, Exons, Genes, Tumor Suppressor genetics, Genome, Human, Humans, Kruppel-Like Transcription Factors, Mice, Molecular Sequence Data, Proteins, Sequence Homology, Transcription, Genetic, Gene Expression Regulation, Promoter Regions, Genetic genetics, Transcription Factors genetics, Tumor Suppressor Protein p53 physiology
- Abstract
HIC-1 (hypermethylated in cancer 1), a BTB/POZ transcriptional repressor, was isolated as a candidate tumor suppressor gene located at 17p13.3, a region hypermethylated or subject to allelic loss in many human cancers and in the Miller-Dieker syndrome. The human HIC-1 gene is composed of two exons, a short 5'-untranslated exon and a large second coding exon. Recently, two murine HIC-1 isoforms generated by alternative splicing have been described. To determine whether such isoforms also exist in human, we have further analyzed the human HIC-1 locus. Here, we describe and extensively characterize a novel alternative noncoding upstream exon, exon 1b, associated with a major GC-rich promoter. We demonstrate using functional assays that the murine exon 1b previously described as coding from computer analyses of genomic sequences is in fact a noncoding exon highly homologous to its human counterpart. In addition, we report that the human untranslated exon is presumably a coding exon, renamed exon 1a, both in mice and humans. Both types of transcripts are detected in various normal human tissues with a predominance for exon 1b containing transcripts and are up-regulated by TP53, confirming that HIC-1 is a TP53 target gene. Thus, HIC-1 function in the cell is controlled by a complex interplay of transcriptional and translational regulation, which could be differently affected in many human cancers.
- Published
- 2001
- Full Text
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