Research interest
Our two main research subjects are to understand the tumorigenic process and DNA-damage pathways in humans. Most human tumors harbor multiple genetic alterations that activate oncogenes, inhibit tumor suppressors and induce genomic instability. As each tumor contains many genetic alterations, the study of the contribution of each variation to carcinogenesis and to the maintenance the cancerous phenotype was obscured. In the past, we developed a vector-based system that mediates suppression of gene expression through RNA interference (pSUPER). We used, and are still using, this gene inactivation system to study the importance of tumor-suppressors and DNA-damage checkpoints in protecting humans from cancer. We also applied high-throughput RNAi libraries to uncover novel tumor suppressors and DNA-damage checkpoint genes and characterize their role in cancer prevention. Lately, we developed a novel microRNA (miRNA) expression vector, library and a barcode array. These tools are used extensively in our lab in search for cancerous miRNAs.
Key publications
le Sage C. and Agami R.* Immense Promises for Tiny Molecules: Uncovering miRNA Functions Cell Cycle. 2006 Jul;5(13):1415-21. Epub 2006 Jul 1.
Voorhoeve PM, le Sage C, Schrier M, Gillis AJM, Stoop H, Nagel R, Liu YP, van Duijse Y, Drost J, Griekspoor A, Zlotorynski E, Yabuta N, De Vita G,Nojima H, Looijenga, LHJ and Agami R. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell. 2006 Mar 24;124(6):1169-81.
Duursma A, Agami R. CDK-dependent stabilization of Cdc6: linking growth and stress signals to activation of DNA replication. Cell Cycle. 2005 Dec;4(12):1725-8. Epub 2005 Dec 22.
Schwartz M, Zlotorynski E, Goldberg M, Ozeri E, Rahat A, le Sage C, Chen BP, Chen DJ, Agami R, Kerem B. Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability. Genes Dev. 2005 Nov 15;19(22):2715-26.
Duursma A, Agami R. p53-dependent regulation of Cdc6 protein stability controls cellular proliferation. Mol Cell Biol. 2005 Aug;25(16):6937-47.
Kolfschoten IG, van Leeuwen B, Berns K, Mullenders J, Beijersbergen RL, Bernards R, Voorhoeve PM, Agami R. A Genetic Screen Identifies PITX1 as a Suppressor of RAS Activity and Tumorigenicity. Cell. 2005 Jun 17;121(6):849-58.
Einav Y, Agami R, Canaani D. shRNA-mediated RNA interference as a tool for genetic synthetic lethality screening in mouse embryo fibroblasts. FEBS Lett. Jan 3;579(1):199-202.
Gagrica, S., Hauser, S., Kolfschoten, I., Osterloh, L., Agami, R., and Gaubatz, S. Inhibition of oncogenic transformation by mammalian Lin-9, a pRB-associated protein. EMBO J 23, 4627-4638.
Zhong, X., Shen, Y., Ballar, P., Apostolou, A., Agami, R., and Fang, S. . AAA ATPase p97/valosin-containing protein interacts with gp78, a ubiquitin ligase for endoplasmic reticulum-associated degradation. J Biol Chem 279, 45676-45684.
Berns K, Hijmans EM, Mullenders J, Brummelkamp TR, Velds A, Heimerikx M, Kerkhoven RM, Madiredjo M, Nijkamp W, Weigelt B, Agami R, Ge W, Cavet G, Linsley PS, Beijersbergen RL, Bernards R. A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature 428, 431-437.
Voorhoeve, P. M., and Agami, R. Unraveling human tumor suppressor pathways: a tale of the INK4A locus. Cell Cycle 3, 616-620.
Voorhoeve, P. M., and Agami, R. The tumor suppressive functions of the human INK4A locus. Cancer Cell, 4, 311-319.
Kolfschoten I., and Agami, R. Allelic gene inactivation: pinpointing the problem. Gene Therapy, 10, 1931-1932.
Duursma A. M. and Agami, R. Ras interference as cancer therapy. Seminars in Cancer Biology, 13, 267-273.
van de Wetering, M., Oving, I., Muncan, V., Pon Fong, M. T., Brantjes, H., van Leenen, D., Holstege, F. C., Brummelkamp, T. R., Agami, R., and Clevers, H. Specific inhibition of gene expression using a stably integrated, inducible small-interfering-RNA vector. EMBO Rep., 4, 609-615.
Lens, S. M., Wolthuis, R. M., Klompmaker, R., Kauw, J., Agami, R., Brummelkamp, T., Kops, G., and Medema, R. H. Survivin is required for a sustained spindle checkpoint arrest in response to lack of tension. EMBO J., 22, 2934-2947.
Voorhoeve PM, Agami R. Knockdown stands up. Trends Biotechnol. 2003 Jan;21(1):2-4.
Agami R. RNAi and related mechanisms and their potential use for therapy. Curr Opin Chem Biol. 2002 Dec;6(6):829-34. [PubMed - in process]
Makimura H, Mizuno TM, Mastaitis JW, Agami R, Mobbs CV. Reducing hypothalamic AGRP by RNA interference increases metabolic rate and decreases body weight without influencing food intake. BMC Neurosci. 2002 Nov 7;3(1):18.
Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell. 2002 Sep;2(3):243-7.
Brummelkamp TR, Bernards R, Agami R. A system for stable expression of short interfering RNAs in mammalian cells. Science. 2002 Apr 19;296(5567):550-3.
Agami R, Bernards R. Convergence of mitogenic and DNA damage signaling in the G1 phase of the cell cycle. Cancer Lett. 2002 Mar 28;177(2):111-8. Review.
Shamay M, Agami R, Shaul Y. HBV integrants of hepatocellular carcinoma cell lines contain an active enhancer. Oncogene. 2001 Oct 18;20(47):6811-9.
Agami R, Bernards R. Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Cell. 2000 Jul 7;102(1):55-66.
Agami R, Blandino G, Oren M, Shaul Y. Interaction of c-Abl and p73alpha and their ollaboration to induce apoptosis. Nature. 1999 Jun 24;399(6738):809-13.
Agami R, Shaul Y. The kinase activity of c-Abl but not v-Abl is potentiated by direct interaction with RFXI, a protein that binds the enhancers of several viruses and cell-cycle regulated genes. Oncogene. 1998 Apr 9;16(14):1779-88.
More publications by Reuven Agami on PubMed
Biographic sketch
Reuven Agami performed his PhD research (Thesis: Cell cycle and apoptosis control induced by the tyrosine kinase c-Abl) within the department of molecular genetics at the Weizmann Institute of Science, Israel. During his research he identified a novel DNA-damage-induced apoptosis pathway that requires the activation of c-Abl kinase and tyrosine phosphorylation of the p53 homologue- p73a. As a post-doc in the group of Prof. Rene Bernards he initiated his own line of research to identify rapid molecular events that initiate a p53 independent DNA damage response. In September 2001 he started his own group at the Netherlands Cancer Institute, which consists now of a senior postdoc, four postdocs, five PhD students and two technician. At this time developed an RNAi vector system (pSUPER), which is used extensively in the two main research topics in his group. The first research line focuses on identification of novel DNA damage checkpoint genes that govern cell cycle responses following genotoxic stress. The second research line is the identification of novel tumor suppressor genes using transformation assays of primary human cells. Lately, his group has developed a (microRNA) miRNA expression vector and library containing almost all annotated miRNAs known in the human genome. This library was used to identify oncogenic miRNAs acting to bypass oncogenic-stress induced senescence. At present, this library is used to identify additional oncogenic miRNAs, tumor suppressor miRNAs and miRNAs that allow cells resist cancer-therapeutic protocols.
Co-workers
Rani Elkon Postdoctoral fellow
Nicolas Léveillé Postdoctoral fellow
Gijs van Haaften Postdoctoral fellow
Adam Morris Postdoctoral fellow
Mathias Jenal Postdoctoral fellow
Pieter van Breugel Postdoctoral fellow
Fabricio Loyza Postdoctoral fellow
Jarno Drost PhD student
Marieke van Kouwenhove PhD student
Arnold Bos PhD student
Carlos Melo PhD student
Sih-Chen Cheng PhD student
Hailey Moore PhD student
Koos Rooijers PhD student
Mariëtte Schrier Technical staff
Joachim Oude Vrielink Technical staff