Deciphering the circuitry leading cancer cells to premature senescence
Consortium leader: professor TOMI MÄKELÄ
Center of Excellence in Translational Genome-Scale Biology, University of Helsinki, http://tgsb.vtt.fi/ http://www.hi.helsinki.fi/tm/sysbio
Other project leaders of the consortium:
Päivi Ojala, MoleCenter of Excellence in Translational Genome-Scale Biology. University of Helsinki
Juha Klefström Institute of Biomedicine, University of Helsinki
Marc Vidal, Dana Farber Cancer Institute, Harvard Medical School
Imre Västrik, European Bioinformatics Institute, EMBL Outstation - Hinxton
Doctoral students of the consortium:
Niina Kaipio, M.Sc (Biotechnology)
Annika Järviluoma, M.Sc. (Microbiology) - Doctoral dissertation (11/2007)
Other researchers of the consortium:
Niklas Ekman, Ph.D
Thomas Westerling, Ph.D.
Jianmin WU, Ph.D.
Marjukka Nevalainen, B.Sc
Johanna Partanen, M.Sc
Katja Helenius, M.Sc.
Pekka Katajisto, M. Sc.
Emilia Kuuluvainen, M.Sc.
Key words: cancer, failsafe mechanism, premature senescence, genomics, proteomics, interactomics, circuitry modelling
Project desciption and main results:
The goal of the Cancer Circuitry Research Consortium http://www.hi.helsinki.fi/tm/sysbio) is to first understand and then exploit the propensity of cancer cells to arrest their growth by undergoing premature enescence. For this objective it is essential to unravel the signaling networks involved in emature senescence. To achieve this we analyze this phenomenon using a systems biology approach by combining i) discovery-based high-throughput genetic retro/lentiviral siRNA screens ii) datasets from global expression and proteome analyses from our models of premature senescence iii) large-scale two-hybrid protein interaction analyses with identified candidate genes - to be extended to the C. elegans orthologues forming part of the as of yet unpublished C. elegans interactome.
Bioinformatics will play a central integrating role initially in data collection from the experiments and additionally from accessible databases to a Premature Senescence KnowledgeBase and subsequently in modeling the premature senescence circuitry. In validation of the circuitry a high-throughput cell-based functional assay will form the initial platform, which also will feed data back into the knowledgebase. When appropriate further validation will consist of mouse models in which specific genes are knocked down by using lentiviral vectors expressing small interfering RNAs.
The multidisciplinary international consortium has been formed to ensure expertise in the fields of retro- and lentiviral gene transfer (Klefstrom), genome-wide protein interaction maps and systems biology (Vidal), bioinformatics and network modeling (Västrik), high-throughput cell-based functional assays (Ojala) and in vivo tumor models and gene knockdowns (Mäkelä). The ultimate goal of this integrative multidisciplinary approach is to produce tools to analyze the role of premature senescence in human tumors and to provide new targets for drug development in this area.
Currently published results reflect more single biological observations made within the work, and indeed some of the original observations this application was based on have later turned not to hold the test of time including the link between Lkb1 and senescence. Therefore the efforts have been retargeted toward understanding signaling networks of Lkb1, Myc and v-cyclin, and their potential overlaps with emphasis on combining gene knockdowns, expression analyses, and large-scale two-hybrid interactions. Several interesting novel links have been identified expanding our uderstanding of these cancer-relevant genes.
Original publications:
Nieminen A, Partanen J, Hau A, Klefstrom J: c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis. EMBO J, 26, 1444-1455, 2007.
Partanen J, Nieminen A, Makela T, Klefstrom J: Suppression of oncogenic properties of c-Myc by Lkb1 controlled epithelial organization, PNAS, 104, 14694-14699, 2007
Sano M, Izumi Y, Helenius K, Asakura M, Rossi DJ, Xie M, Taffet G, Hu L, Pautler RG, Wilson CR, Boudina S, Abel ED, Taegtmeyer H, Scaglia F, Graham BH, Kralli A, Shimizu N, Tanaka H, Mäkelä TP, Schneider MD. Ménage-à-trois 1 is critical for the transcriptional function of PPARgamma coactivator 1. Cell Metab. 2007 Feb;5(2):129-42.
Sarek, G., Kurki, S., Enbäck, J., Iotzova. G., Haas, J., Laakkonen., Laiho, M., and Ojala. P.M. 2007: Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas. J. Clin. Invest. Apr;117(4):1019-28.
Epub 2007 Mar 15. Koopal, S., Furuhjelm, J.H., Järviluoma, A., Jäämaa, S., Pyakurel, P., Pussinen, C., Wirzenius, M., Biberfeld, P., Alitalo, K., Laiho, M., and Ojala, P.M. 2007: Viral oncogene-induced DNA damage response is activated in Kaposi¹s sarcoma tumorigenesis. PLoS Pathogens, 2007 Sep 7;3(9):1348-60.
Westerling T, Kuuluvainen E, Mäkelä TP. Cdk8 is essential for preimplantation mouse development. Mol Cell Biol. 2007 Sep;27(17):6177-82. Epub 2007 Jul 9.
Vastrik I, D'Eustachio P, Schmidt E, Joshi-Tope G, Gopinath G, Croft D, de Bono B, Gillespie M, Jassal B, Lewis S, Matthews L, Wu G, Birney E, Stein L. Reactome: a knowledge base of biologic pathways and processes. Genome Biol. 2007;8(3):R39.
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Futreal PA, Stratton MR. Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8.
Pujana MA, Han JD, Starita LM, Stevens KN, Tewari M, Ahn JS, Rennert G, Moreno V, Kirchhoff T, Gold B, Assmann V, Elshamy WM, Rual JF, Levine D, Rozek LS, Gelman RS, Gunsalus KC, Greenberg RA, Sobhian B, Bertin N, Venkatesan K, Ayivi-Guedehoussou N, Solé X, Hernández P, Lázaro C, Nathanson KL, Weber BL, Cusick ME, Hill DE, Offit K, Livingston DM, Gruber SB, Parvin JD, Vidal M. Network modeling links breast cancer susceptibility and centrosome dysfunction. Nat Genet. 2007 Nov;39(11):1338-1349.
Yzldzrzm MA, Goh KI, Cusick ME, Barabási AL, Vidal M. Abstract Drug-target network. Nat Biotechnol. 2007 Oct;25(10):1119-1126.
Järviluoma, A., Child, E.S., Sarek, G., Sirimongkolkasem, P., Ojala, P.M., and Mann, D.J. 2006: Phosphorylation of the cyclin-dependent kinase inhibitor p21Cip1 on serine 130 is essential for viral cyclin-mediated bypass of a p21-imposed G1 arrest. Mol. Cell. Biol. 2006 Mar;26(6): 2430-40.
Sarek, G., Järviluoma, A., and Ojala P.M. 2006: KSHV viral cyclin inactivates p27Kip1 through Ser-10 and Thr-187 phosphorylation in proliferating primary effusion lymphomas. Blood, 2006 Jan 15;107(2):725-32. Epub 2005 Sep 13.
Alhopuro P, Katajisto P, Lehtonen R, Ylisaukko-Oja SK, Näätsaari L, Karhu A, Westerman AM, Wilson JH, de Rooij FW, Vogel T, Moeslein G, Tomlinson IP, Aaltonen LA, Mäkelä TP, Launonen V. Mutation analysis of three genes encoding novel LKB1-interacting proteins, BRG1, STRADalpha, and MO25alpha, in Peutz-Jeghers syndrome. Br J Cancer. 2005 Mar 28;92(6):1126-9.
Reviews:
Nieminen AI, Partanen JI, Klefstrom J.: c-Myc blazing a Trail of death: Coupling of the mitochondrial and death receptor pathways by c-Myc. Cell Cycle, invited perspectyive (review), in press.
Katajisto P, Vallenius T, Vaahtomeri K, Ekman N, Udd L, Tiainen M, Mäkelä TP.The LKB1 tumor suppressor kinase in human disease. Biochim Biophys Acta. 2007 Jan;1775(1):63-75. Review.