SHARP Pathway Database

 

 

Institut Curie node:

     Coordinator: Patrick Poullet.

     Participants: Amélie Gelay, Andrei Zinovyev, Philippe La Rosa and Emmanuel Barillot.

     Collaborators: François Radvanyi, Olivier Delattre, Yohanns Bellaiche and Jean de-Gunzburg.

SHARP global coordinator: Ron Shamir (School of Computer Science, Tel Aviv University, Israel).

 

The SHARP project:

Making sense of the intricate network of proteins and genes regulations that take place inside the cell during cell growth, differentiation and apoptosis is a critical step in understanding how these processes are controlled at the molecular level. Unfortunately, the biological knowledge collected so far is fragmented in thousands of research articles of heterogeneous quality making it difficult for researchers to comprehend globally the mechanisms involved. This knowledge must be centralized and standardized to become easily accessible. Furthermore, as the data accumulate, it becomes necessary to use computer power to store, visualize and analyze these complex regulations.

The SHARP consortium was initiated by Ron Shamir at Tel Aviv University to address this problem using a collaborative approach. Researchers from all around the world -including from the Institut Curie- have already joined this consortium. The goal of this global collaboration is to take advantage of each research group’s expertise on specific signaling pathways to collect, curate and formalize the data available from the literature or from their own laboratories. New data are regularly integrated to a central pathway database and made available to all members of the consortium (see figure below).

A SHARP software was designed and developed by Ron Shamir’s group to assist researchers through this task. This tool consists of a multi-platform (java-based) intuitive pathway visualization module which communicates with an underlying database. The user can use this interface to submit new data and to query, edit and analyze the data stored. This tool can also be used to superimposed external quantitative data such as gene expression data (microarrays) over the signaling pathways.

Our task is to provide technical support to the research groups of the Institut Curie involved in the SHARP project and to coordinate their work with that of the other members of the consortium. The data collected are then used in other projects of the Group in particular for the analysis of microarray data (e.g. Kernelchip).


 

 

The Retinoblastoma (RB) Pathway case:

Participants: Amélie Gelay, François Radvanyi, Andrei Zinovyev, Emmanuel Barillot.

 

The purpose of the present work is to collect as much information as possible on gene-regulatory networks and organize it in an exploitable way for the analysis of data from microarrays. We started with RB, a tumor suppressor gene involved in a pathway controlling the cell cycle progression, which is one of the most frequent targets of genetic alterations in human cancer.

The data are collected from public sources (reviews, publications…) and stored using CellDesigner. CellDesigner is a structured diagram editor for drawing gene-regulatory and biochemical networks. These networks are drawn based on the process diagram, with the graphical notation system proposed by Kitano, and are stored using the Systems Biology Markup Language (SBML). SBML is a standard computer-readable format for representing models of biochemical reaction networks. It is applicable to metabolic networks, cell-signaling pathways, regulatory networks, and many others. Once converted in SBML format, signaling pathway data can be imported in network visualization tools such as SHARP.


View full-size image.

References for CellDesigner:

1.        Kitano, H., Funahashi, A., Matsuoka, Y., Oda, K. (2005) Using process diagrams for the graphical representation of biological networks. Nat Biotechnol. 23(8):961-6.

2.        Kitano, H. (2003) A graphical notation for biochemical networks. BIOSILICO. 1. 169-176.

3.        Hucka, M., Finney, A., Sauro, H.M., Bolouri, H., Doyle, J.C., Kitano, H., Arkin, A.P., Bornstein, B.J., Bray, D., Cornish-Bowden, A., Cuellar, A.A., Dronov, S., Gilles, E.D., Ginkel, M., Gor, V., Goryanin, I.I., Hedley, W.J., Hodgman, T.C., Hofmeyr, J.H., Hunter, P.J., Juty, N.S., Kasberger, J.L., Kremling, A., Kummer, U., Le Novere, N., Loew, L.M., Lucio, D., Mendes, P., Minch, E., Mjolsness, E.D., Nakayama, Y., Nelson, M.R., Nielsen, P.F., Sakurada, T., Schaff, J.C., Shapiro, B.E., Shimizu, T.S., Spence, H.D., Stelling, J., Takahashi, K., Tomita, M., Wagner, J., Wang, J.; SBML Forum. (2003) The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics. 19(4):524-31

4.        Kitano, H. (2002) Systems biology: a brief overview. Science 295(5560):1662-4.

 

References for the Retinoblastoma pathway:

1.         Attwooll, C., Lazzerini Denchi, E., Helin, K. (2004) The E2F family: specific functions and overlapping interests. EMBO J. 23(24):4709-16.

2.         Attwooll, C., Oddi, S., Cartwright, P., Prosperini, E., Agger, K., Steensgaard, P., Wagener, C., Sardet, C., Moroni, M.C., Helin, K. (2005) A novel repressive E2F6 complex containing the polycomb group protein, EPC1, that interacts with EZH2 in a proliferation-specific manner. J Biol Chem. 280(2):1199-208.

3.         Bartkova, J., Horejsi, Z., Koed, K., Kramer, A., Tort, F., Zieger, K., Guldberg, P., Sehested, M., Nesland, J.M., Lukas, C., Orntoft, T., Lukas, J., Bartek, J. (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 434(7035):864-70.

4.         Blais, A., Dynlacht, B.D. (2004) Hitting their targets: an emerging picture of E2F and cell cycle control. Curr Opin Genet Dev. 14(5):527-32.

5.         Boyer Arnold, N., Korc, M. (2005) Smad7 abrogates transforming growth factor-beta1-mediated growth inhibition in COLO-357 cells through functional inactivation of the retinoblastoma protein. J Biol Chem. 280(23):21858-66.

6.         Brehm, A., Miska, E.A., McCance, D.J., Reid, J.L., Bannister, A.J., Kouzarides, T. (1998) Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature. 391(6667):597-601.

7.         Brown, VD., Phillips, R.A., Gallie, B.L. (1999) Cumulative effect of phosphorylation of pRB on regulation of E2F activity. Mol Cell Biol. 19(5):3246-56.

8.         Cam, H., Dynlacht, B.D. (2003) Emerging roles for E2F: beyond the G1/S transition and DNA replication. Cancer Cell. 3(4):311-6.

9.         Chan, H.M., La Thangue, N.B. (2001) p300/CBP proteins: HATs for transcriptional bridges and scaffolds. J Cell Sci. 114(Pt 13):2363-73.

10.      Claudio, PP., Tonini, T., Giordano, A. (2002) The retinoblastoma family: twins or distant cousins? Genome Biol. 3(9):reviews3012.

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16.      Dimova, D.K., Dyson, N.J. (2005) The E2F transcriptional network: old acquaintances with new faces. Oncogene. 24(17):2810-26.

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19.      Fang, W., Mori, T., Cobrinik, D. (2002) Regulation of PML-dependent transcriptional repression by pRB and low penetrance pRB mutants. Oncogene. 21(36):5557-65.

20.      Farkas, T., Hansen, K., Holm, K., Lukas, J., Bartek, J. (2002) Distinct phosphorylation events regulate p130- and p107-mediated repression of E2F-4. J Biol Chem. 277(30):26741-52.

21.      Ferreira, R., Naguibneva, I., Mathieu, M., Ait-Si-Ali, S., Robin, P., Pritchard, L.L., Harel-Bellan, A. (2001) Cell cycle-dependent recruitment of HDAC-1 correlates with deacetylation of histone H4 on an Rb-E2F target promoter. EMBO Rep. 2(9):794-9.

22.      Ferreira, R., Naguibneva, I., Pritchard, L.L., Ait-Si-Ali, S., Harel-Bellan, A. (2001) The Rb/chromatin connection and epigenetic control: opinion. Oncogene. 20(24):3128-33.

23.      Fortin, A., MacLaurin, J.G., Arbour, N., Cregan, S.P., Kushwaha, N., Callaghan, S.M., Park, D.S., Albert, P.R., Slack, R.S. (2004) The proapoptotic gene SIVA is a direct transcriptional target for the tumor suppressors p53 and E2F1. J Biol Chem. 279(27):28706-14.

24.      Frolov, M.V., Dyson, N.J. (2004) Molecular mechanisms of E2F-dependent activation and pRB-mediated repression. J Cell Sci. 117(Pt 11):2173-81.

25.      Gagrica, S., Hauser, S., Kolfschoten, I., Osterloh, L., Agami, R., Gaubatz, S. (2004) Inhibition of oncogenic transformation by mammalian Lin-9, a pRB-associated protein. EMBO J. 23(23):4627-38.

26.      Ginsberg, D. (2004) E2F3-a novel repressor of the ARF/p53 pathway. Dev Cell. 6(6):742-3.

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30.      Ianari, A., Gallo, R., Palma, M., Alesse, E., Gulino, A. (2004) Specific role for p300/CREB-binding protein-associated factor activity in E2F1 stabilization in response to DNA damage. J Biol Chem. 279(29):30830-5.

31.      Ishida, H., Masuhiro, Y., Fukushima, A., Argueta, J.G., Yamaguchi, N., Shiota, S., Hanazawa, S. (2005) Identification and characterization of novel isoforms of human DP-1: DP-1{alpha} regulates the transcriptional activity of E2F1 as well as cell cycle progression in a dominant-negative manner. J Biol Chem. 280(26):24642-8.

32.      Jacobs, JJ., van Lohuizen, M. (2002) Polycomb repression: from cellular memory to cellular proliferation and cancer. Biochim Biophys Acta. 1602(2):151-61.

33.      Jhanwar-Uniyal, M. (2003) BRCA1 in cancer, cell cycle and genomic stability. Front Biosci. 8:s1107-17.

34.      Johnson, DG., Schneider-Broussard, R. (1998) Role of E2F in cell cycle control and cancer. Front Biosci. 3:d447-8

35.      Knudsen, ES., Wang, J.Y. (1997) Dual mechanisms for the inhibition of E2F binding to RB by cyclin-dependent kinase-mediated RB phosphorylation. Mol Cell Biol. 17(10):5771-83.

36.      Kyrylenko, S., Korhonen, P., Kyrylenko, O., Roschier, M., Salminen, A. (2000) Expression of transcriptional repressor proteins mSin3A and 3B during aging and replicative senescence. Biochem Biophys Res Commun. 275(2):455-9.

37.      Lin, WC., Lin, F.T., Nevins, J.R. (2001) Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes Dev. 15(14):1833-44.

38.      Logan, N., Delavaine, L., Graham, A., Reilly, C., Wilson, J., Brummelkamp, T.R., Hijmans, E.M., Bernards, R., La Thangue, N.B. (2004) E2F-7: a distinctive E2F family member with an unusual organization of DNA-binding domains. Oncogene. 23(30):5138-50.

39.      Logan, N., Graham, A., Zhao, X., Fisher, R., Maiti, B., Leone, G., La Thangue, N.B. (2005) E2F-8: an E2F family member with a similar organization of DNA-binding domains to E2F-7. Oncogene. 24(31):5000-4.

40.      Ludlow, JW., Glendening, C.L., Livingston, D.M., DeCarprio, J.A. (1993) Specific enzymatic dephosphorylation of the retinoblastoma protein. Mol Cell Biol. 13(1):367-72.

41.      Lund, A.H., van Lohuizen, M. (2004) Polycomb complexes and silencing mechanisms. Curr Opin Cell Biol. 16(3):239-46.

42.      Magae, J., Wu, C.L., Illenye, S., Harlow, E., Heintz, N.H. (1996) Nuclear localization of DP and E2F transcription factors by heterodimeric partners and retinoblastoma protein family members. J Cell Sci. 109 (Pt7):1717-26.

43.      Magnaghi-Jaulin, L., Groisman, R., Naguibneva, I., Robin, P., Lorain, S., Le Villain, J.P., Troalen, F., Trouche, D., Harel-Bellan, A. (1998) Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature. 391(6667):601-5.

44.      Maiti, B., Li, J., de Bruin, A., Gordon, F., Timmers, C., Opavsky, R., Patil, K., Tuttle, J., Cleghorn, W., Leone, G. (2005) Cloning and characterization of mouse E2F8, a novel mammalian E2F family member capable of blocking cellular proliferation. J Biol Chem. 280(18):18211-20.

45.      Muchardt, C., Yaniv, M. (2001) When the SWI/SNF complex remodels...the cell cycle. Oncogene. 20(24):3067-75.

46.      Muller, H., Bracken, A.P., Vernell, R., Moroni, M.C., Christians, F., Grassilli, E., Prosperini, E., Vigo, E., Oliner, J.D., Helin, K. (2001) E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev. 15(3):267-85.

47.      Nevins, JR. (2001) The Rb/E2F pathway and cancer. Hum Mol Genet. 10(7):699-703.

48.      Nielsen, SJ., Schneider, R., Bauer, U.M., Bannister, A.J., Morrison, A., O'Carroll, D., Firestein, R., Cleary, M., Jenuwein, T., Herrera, R.E., Kouzarides, T. (2001) Rb targets histone H3 methylation and HP1 to promoters. Nature. 412(6846):561-5.

49.      Ogawa, H., Ishiguro, K., Gaubatz, S., Livingston, D.M., Nakatani, Y. (2002) A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science. 296(5570):1132-6.

50.      Parakati, R., DiMario, J.X. (2005) Dynamic transcriptional regulatory complexes, including E2F4, p107, p130, and Sp1, control fibroblast growth factor receptor 1 gene expression during myogenesis. J Biol Chem. 280(22):21284-94.

51.      Pohlers, M., Truss, M., Frede, U., Scholz, A., Strehle, M., Kuban, R.J., Hoffmann, B., Morkel, M., Birchmeier, C., Hagemeier, C. (2005) A role for E2F6 in the restriction of male-germ-cell-specific gene expression. Curr Biol. 15(11):1051-7.

52.      Polager, S., Kalma, Y., Berkovich, E., Ginsberg, D. (2002) E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis. Oncogene. 21(3):437-46.

53.      Powers, J.T., Hong, S., Mayhew, C.N., Rogers, P.M., Knudsen, E.S., Johnson, D.G. (2004) E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis. Mol Cancer Res. 2(4):203-14.

54.      Rayman, JB., Takahashi, Y., Indjeian,V.B., Dannenberg, J.H., Catchpole, S., Watson, R.J., te Riele, H., Dynlacht, B.D. (2002) E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex. Genes Dev. 16(8):933-47.

55.      Rogoff, H.A., Pickering, M.T., Frame, F.M., Debatis, M.E., Sanchez, Y., Jones, S., Kowalik, T.F. (2004) Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm/Nbs1/Chk2. Mol Cell Biol. 24(7):2968-77.

56.      Salomoni, P., Pandolfi, P.P. (2002) The role of PML in tumor suppression. Cell. 108(2):165-70.

57.      Sanchez, I., Dynlacht, B.D. (2005) New insights into cyclins, CDKs, and cell cycle control. Semin Cell Dev Biol. 16(3):311-21.

58.      Sanchez-Beato, M., Sanchez, E., Garcia, J.F., Perez-Rosado, A., Montoya, M.C., Fraga, M., Artiga, M.J., Navarrete, M., Abraira, V., Morente, M., Esteller, M., Koseki, H., Vidal, M., Piris, M.A. (2004) Abnormal PcG protein expression in Hodgkin's lymphoma. Relation with E2F6 and NFkappaB transcription factors. J Pathol. 204(5):528-37.

59.      Semizarov, D., Kroeger, P., Fesik, S. (2004) siRNA-mediated gene silencing: a global genome view. Nucleic Acids Res. 32(13):3836-45.

60.      Stanelle, J., Stiewe, T., Theseling, C.C., Peter, M., Putzer, B.M. (2002) Gene expression changes in response to E2F1 activation. Nucleic Acids Res. 30(8):1859-67.

61.      Stevens, C., Smith, L., La Thangue, N.B. (2003) Chk2 activates E2F-1 in response to DNA damage. Nat Cell Biol. 5(5):401-9.

62.      Storre, J., Elsasser, H.P., Fuchs, M., Ullmann, D., Livingston, D.M., Gaubatz, S. (2002) Homeotic transformations of the axial skeleton that accompany a targeted deletion of E2f6. EMBO Rep. 3(7):695-700.

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