Equipe 3

Team 3 : Jean Ehrland Ricci
REGULATION OF CASPASE DEPENDENT AND INDEPENDENT CELL DEATH

Previous activities
Metabolic control of cell deaths in cancer Our research project is centred on cell death regulation, a physiological process whose deregulation is a critical event occurring in a wide variety of pathology (cancer, neurodegenerative diseases, auto-immune disease, ...). Our research is focused on the role of two different but intertwined type of cell death (apoptosis and caspase-independent cell death) on oncogenesis. Engagement of the mitochondrial pathway of apoptosis in mammalian cells will commit a cell to die regardless if the caspases (protease involved in apoptosis) are activated or not. It is now clearly established that mitochondrial outer membrane permeabilization (MOMP) will lead to apoptosis and to caspase-independent cell death (CICD) at the same time. It appeared that apoptosis is the main and quickest response to a death signal, CICD being considered as a “back-up” mechanism resulting in the death of the cell if apoptosis is deficient, therefore preventing transformation. Using unique and original approaches we have identified key events in each type of cell death. On one side we have nailed how caspases could lead to mitochondrial dismantling during apoptosis (by cleaving the mitochondrial protein p75, Ricci et al. Cell 2004). Then we participated to the identification of p75 cleavage upon tolerance induction (Kazama H, et al. Immunity 2008). In parallel we identified the existing link between glycolysis and caspases. We determined how caspases could turn off glycolysis upon apoptosis induction. In addition we uncovered how glucose metabolism could control death receptor-induced apoptosis (Pradelli et al. submitted). On the other side we were the first to identify conditions under which cells can survive the induction of MOMP, provided subsequent caspase activation is blocked or disrupted (i.e. during CICD condition). This protection is mediated by the expression of the glycolytic enzyme GAPDH (Colell et al. Cell 2007, for review see Colell et al. Cell Death Dif 2009). We next analysed CICD's role in cancer. We demonstrated that apoptosis and CICD can occur in presence of Imatinib mesylate in cell models of Chronic Myeloid Leukemia. In addition we showed that CML cell line mutants presenting a resistance to classical treatment are overexpressing GAPDH and that a moderate modulation of this protein level is sufficient to sensitize resistant cells to treatment (Lavallard et al. Cancer Res 2009). We are currently investigating CICD role in cancer genesis using several in vivo models (transgenic and knock-out mice). Finally, we are investigating the impact of cell metabolism on CICD in patient samples suffering from a peritoneal carcinomatosis. This study is made in collaboration with Pr. Marc Raucoules-Aime and Pr. Daniel Benchimol departments of the Archet hospital, Nice, France. In conclusion, our research project will allow a better characterization of new and central aspects of cell death regulation and their connection to tumorigenesis (focusing on hematopoietic malignancies and peritoneal carcinomatosis).
Major Publications
2010 Pradelli LA, Bénéteau M, Ricci JE. Mitochondrial control of caspase-dependent and -independent cell death. Cell Mol Life Sci. 2010 May;67(10):1589-97 Pradelli LA, Bénéteau M, Chauvin C, Jacquin MA, Marchetti S, Muñoz-Pinedo C, Auberger P, Pende M, Ricci JE. Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation. Oncogene. 2010 Mar 18;29(11):1641-52. 2009 Colell A, Green DR, Ricci JE. Novel roles for GAPDH in cell death and carcinogenesis. Cell Death Differ. 2009 Dec;16(12):1573-81. Review. Marchetti S, Gamas P, Belhacène N, Grosso S, Pradelli LA, Colosetti P, Johansen C, Iversen L, Deckert M, Luciano F, Hofman P, Ortonne N, Khemis A, Mari B, Ortonne JP, Ricci JE, Auberger P. The caspase-cleaved form of LYN mediates a psoriasis-like inflammatory syndrome in mice. EMBO J. 2009 Aug 19;28(16):2449-60. Lavallard, V.J., Pradelli, L.A., Paul, A., Beneteau, M., Jacquel, A., Auberger, P., and Ricci, J.E. Modulation of caspase-independent cell death leads to resensitization of imatinib mesylate-resistant cells. Cancer research 69 : 3013-3020. Pradelli, E., Karimdjee-Soilihi, B., Michiels, J.F., Ricci, J.E., Millet, M.A., Vandenbos, F., Sullivan, T.J., Collins, T.L., Johnson, M.G., Medina, J.C., et al. Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs. International journal of cancer, 2009 Dec 1;125(11):2586-94. 2008 Bertin S, Samson M, Pons C, Guigonis JM, Gavelli A, Baque P, Brossette N, Pagnotta S, Ricci JE, and Pierrefite-Carle V. Comparative proteomics study reveals that bacterial CpG motifs induce tumor cell autophagy in vitro and in vivo. Mol Cell Proteomics, 2008, 7(12): 2311-2322. Cette publication a donnée lieu à un commentaire dans la revue Immunity, 2008, 29(1): 1-2 Kazama H, Ricci JE, Herndon JM, Hoppe G, Green DR and Ferguson TA. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity, 2008, 29(1): 21-32. Mastino A, Basu S, Brunner T, Ricci JE and Diederich M. Long live the cell death! Cell Death Differ, 2008, 15(8): 1330-1332. 2007 Colell, A.,* Ricci, J. E.,* Tait, S., Milasta, S., Maurer, U., Bouchier-Hayes, L., Fitzgerald, P., Guio-Carrion, A., Waterhouse, N. J., Wei Li, C., Mari, B., Barbry, P., Newmeyer, D. D.,. Beere, H. and Green, D. R. (2007) GAPDH and autophagy preserve cellular survival during caspase-independent cell death Cell, 129(5):983-997. co-first author. Cette publication a donnée lieu à des commentaires dans les revues Cell et Nature Cell Biology (Cell. 2007 Jun 1;129(5):861-3 -- Nat Cell Biol. (2007) Aug;9(8):869-70) Ricci, JE, Munoz-Pinedo, C, Fitzgerald, P, Bailly-Maitre, B, Perkins, GA, Yadava, N, Scheffler, IE, Ellisman, MH and Green, DR. (2004) Disruption of mitochondrial function during apoptosis is madiated by cleavage of the p75 subunit of complex I of the electron transport chain. Cell,117, 773-786. Ricci JE, Gottlieb RA, Green DR. (2003) Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis. J Cell Biol, 160, 65-75. Ricci, J. E., Waterhouse, N. J., and Green, D. R. (2003). Mitochondrial functions during cell death, a complex (I-V) dilemma. Cell Death Differ* 10,, 488-492. Ricci, J. E., Lang, V., Luciano, F., Belhacene, N., Giordanengo, V., Michel, F., Bismuth, G., and Auberger, P. (2001). An absolute requirement for Fyn in T cell receptor-induced caspase activation and apoptosis. Faseb J 15, 1777-1779 Boatright, K. M., Renatus, M., Scott, F. L., Sperandio, S., Shin, H., Pedersen, I. M., Ricci, J. E., Edris, W. A., Sutherlin, D. P., Green, D. R., and Salvesen, G. S. (2003). A unified model for apical caspase activation. Mol Cell 11, 529-541. Bailly-Maitre, B., Fondevila, C., Kaldas, F., Droin, N., Luciano, F., Ricci, J. E., Croxton, R., Krajewska, M., Zapata, J. M., Kupiec-Weglinski, J. W., Farmer, D. and Reed, J.C. (2006). Cytoprotective gene bi-1 is required for intrinsic protection from endoplasmic reticulum stress and ischemia-reperfusion injury. Proc Natl Acad Sci U S A. Zimmermann, K. C., Ricci, J. E., Droin, N. M., and Green, D. R. (2002). The role of ARK in stress-induced apoptosis in Drosophila cells. J Cell Biol156, 1077-1087 Waterhouse, N. J., Ricci, J. E., and Green, D. R. (2002). And all of a sudden it's over: mitochondrial outer-membrane permeabilization in apoptosis. Biochimie 84, 113-121. Goldstein, J. C., Munoz-Pinedo, C., Ricci, J. E., Adams, S. R., Kelekar, A., Schuler, M., Tsien, R. Y., Green, D. R. (2005) Cytochrome C is released in a single step during apoptosis, Cell Death Diff, May;12(5):453-62. Luciano, F., Zhai, D., Zhu, X., Bailly-Maitre, B., Ricci, J. E., Satterthwait, A., and Reed, J. C. (2005). Cytoprotective peptide Humanin binds and inhibits pro-apoptotic Bcl-2/Bax-family protein BimEL. J Biol Chem280: 15825-15835.

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Team leader

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Clinical researcher

Postdoc

L. MONDRAGON-MARTINEZ

Student

Research assistant


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