Department of Microbiology & Immunology Programme Seminar Series … September 2014 Day / Date / Time: Tuesday 16 September 2014 12.00pm – 1.00pm The Role of the Putative DNA Sensor ZBP1 in Tumorigenesis Dr Stephan GASSER Venue: CeLS Auditorium @ Centre for Life Sciences, Level 1, 28 Medical Drive Singapore 117456 Convener: A/P Sylvie Alonso ALL ARE WELCOME Visit our website @ www.med.nus.edu.sg/mbio for more upcoming seminars LSI Immunology Programme & Department of Microbiology National University of Singapore Abstract The DNA-binding protein ZBP1 (also called DAI or DLM1) was suggested to be a sensor of DNA in the cytosol. However, the role of ZBP1 in cytosolic DNA recognition is not well understood. Here we report that ZBP1 is involved in sensing of DNA damage in tumor cells. Zbp1-deficiency increased the survival of Eμ-Myc mice, a mouse model for Burkitt lymphomas. No apparent lymphomas were observed in Zbp1-deficient Eμ-Myc mice that survived longer than Zbp1+/+Eμ-Myc mice. Zbp1-deficient B-cell lymphoma cells expressed higher levels of markers for DNA damage and the DNA damage response. The enhanced DNA damage correlated with elevated levels of TNF-α and cleaved CASPASE 3, 7 and 8 in Zbp1-deficient tumor cells. Inhibition of the tumor suppressor ataxia telangiectasia mutated (ATM), which controls cellular responses to DNA damage, decreased the survival of Zbp1-deficient Eμ-Myc mice. Administration of blocking TNF-α antibodies reversed the lower tumor load in Zbp1-/-Eμ-Myc mice. DLM1 or ZBP1 expression was upregulated and partially translocated to the nucleus in Bcell lymphoma of Eμ-Myc mice in response to DNA damage and in tumors of chronic lymphocytic leukemia (CLL) patients. In summary, we show that ZBP1 deficiency promotes DNA damage in tumor cells and suppresses B-cell lymphomagenesis in Eμ-Myc mice. Recent Publications Chwee J.Y., Lee S.K., Peiwen M.C.A. and Gasser S. (2014) Pam3CSK4 Synergizes with the Anticancer Effect of Ara-C in Mouse Non-Hodgkin Lymphoma Cells. Clinical Cancer Res (in press). Le Bert N., Lam A.R., Ho S.S.W., Shen Y.J., Liu M.M. and Gasser S. (2014) Sting-dependent cytosolic DNA sensor pathways regulate NKG2D ligand expression. OncoImmunology (in press). Lam A.R., Le Bert N., Ho S.S.W., Shen Y.J., Tang L.F.M, Xiong, G.M., Croxford J.L., Pan M.F., Huang C.W., Koo C.X., Ishii K.J., Akira S., Raulet D.H. and Gasser S. (2014) RAE-1 ligands for the NKG2D receptor are regulated by STINGdependent DNA sensor pathways in lymphoma. Cancer Res. 74(8):2193-203. Le Bert N. and Gasser S. (2014). Advances in NKG2D ligand recognition and responses by NK cells. Immunol and Cell Biol. 92(3):230-6.
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