Objective Background: Retrovirus-induced tumours acquire in time increasing numbers of proviruses in their genome, which are required for the activation of additional (onco)-genes that contribute to tumour progression.Insertional mutagenesis in oncogene-bearing transgenic mice is therefore a powerful strategy to identify genes that cooperate with the transgene in the formation and progression of tumours.In the host lab, the Tiam1 gene was identified by retroviral insertional mutagenesis in combination with selection for invasive T-lymphoma cells. The Tiam1 gene was also frequently activated (>70%) in T-lymphomas induced by retroviral infection of tumour-prone transgenic Em-Pim1 mice.Tiam1 thus seems to play a critical role in the initiation and progression of T-lymphomas. Tiam1 encodes an activator of the Rho-like GTPase Rac. Rho-GTPases regulate a wide variety of cellular processes including cytoskeletal rearrangements, cell migration, and gene transcription.Objectives: In this proposal we want to uncover the signalling pathways that act downstream or parallel of Tiam1and that are essential for lymphomagenesis in vivo. To this end, we propose to perform an insertional mutagenesis screen on tumour-prone transgenic Eµ-Pim1 mice in a Tiam1-deficient background.Strategy: T-lymphomas will be induced in Tiam1-deficient Eµ-Pim1 mice by Moloney Murine Leukemia virus (M-MuLV) infection. Targeted genes will be identified using improved Splinkerette PCR. The sequence data will be mapped and used to identify common insertion sites. The involvement of the gene targets in lymphomagenesis will be confirmed by in vitro and in vivo analyses.Results: The obtained results are expected to give insight into the downstream signalling pathways of Tiam that are acting in the development and progression of lymphomas in vivo. These gene products may turn out to be targets for the development of diagnostic tools or novel anti-cancer therapies. Fields of science natural sciencesbiological sciencesmicrobiologyvirologymedical and health sciencesclinical medicineoncologyleukemianatural sciencesbiological sciencesgeneticsgenomes Keywords Lymphomagenesis Mutant mice Oncogene Rac Retroviral insertional mutagenesis Tiam 1 Tumor biology Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Topic(s) MOBILITY-2.1 - Marie Curie Intra-European Fellowships (EIF) Call for proposal FP6-2002-MOBILITY-5 See other projects for this call Funding Scheme EIF - Marie Curie actions-Intra-European Fellowships Coordinator THE NETHERLANDS CANCER INSTITUTE DIVISION OF CELL BIOLOGY Address Netherlands See on map EU contribution € 0,00
