Genetic and biochemical dissection of quiescence in immune cells
The immune system maintains a vast repertoire of B and T-cells waiting to respond to microbial invasion. These cells are kept in a quiescent state, characterized by arrest in G0 and a decrease in cell size and metabolic activity, until they are activated by antigen engagement and co-stimulation to acquire their effector functions. During the past two decades, numerous types of signaling and changes in gene expression leading to lymphocyte activation, expansion, and acquisition of effector functions have been described. However, the nature and molecular enforcement of quiescence is far from being elucidated. In fact not long ago quiescence was considered equivalent to “absence of activation”, namely a default state of the cell. The factors regulating the quiescence process may have the potential to be exploited for therapeutic purposes in immune diseases, either by enhancing specific anti-pathogen and anti-tumor immune responses or by suppressing overactive, self-directed responses observed in autoimmune diseases, allergy, graft-versus-host disease, and allogeneic transplantation. Fulfillment of this potential is not yet within reach because lymphocyte quiescence is still poorly understood and many issues remain to be addressed. For example: what signals are responsible for maintaining quiescence? And what are the factors that sense those signals, translating them into activation of quiescence-maintaining transcription factors?
The aim of my research is to clarify these crucial questions. We are employing traditional molecular approaches in combination with unbiased functional forward genetic screening to provide comprehensive and integrative insights into the factors and mechanisms that establish and maintain lymphocyte quiescence. In addition, we are exploring ways how to exploit our findings in order to better treat leukemia and improve vaccines
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- Wang, Y., Su, L., Morin, M. D., Jones, B. T., Whitby, L. R., Surakattula, M. M., Huang, HS., Shi, H., Choi, J. H., Wang, K. W., Moresco, E. M., Berger, M., Zhan, X., Zhang, H., Boger, D. L., and Beutler, B. (2016) TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS, Proc Natl Acad Sci U S A 113, E884-893.
- Omar, I., Lapenna, A., Cohen-Daniel, L., Tirosh, B., and Berger, M. (2016) Schlafen2 mutation unravels a role for chronic ER stress in the loss of T cell quiescence, Oncotarget 7, 39396-39407.
- Morin, M. D., Wang, Y., Jones, B. T., Su, L., Surakattula, M. M., Berger, M., Huang, H., Beutler, E. K., Zhang, H., Beutler, B., and Boger, D. L. (2016) Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists, J Med Chem.
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- Finkin, S., Yuan, D., Stein, I., Taniguchi, K., Weber, A., Unger, K., Browning, J. L., Goossens, N., Nakagawa, S., Gunasekaran, G., Schwartz, M. E., Kobayashi, M., Kumada, H., Berger, M., Pappo, O., Rajewsky, K., Hoshida, Y., Karin, M., Heikenwalder, M., Ben-Neriah, Y., and Pikarsky, E. (2015) Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma, Nat Immunol 16, 1235-1244.
- Benhamron, S., Pattanayak, S. P., Berger, M., and Tirosh, B. (2015) mTOR activation promotes plasma cell differentiation and bypasses XBP-1 for immunoglobulin secretion, Mol Cell Biol 35, 153-166.
- Goldshtein, A., and Berger, M. (2014) Friend or foe: can activating mutations in NOTCH1 contribute to a favorable treatment outcome in patients with T-ALL?, Crit Rev Oncog 19, 399-404.
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- Arnold, C. N., Barnes, M. J., Berger, M., Blasius, A. L., Brandl, K., Croker, B., Crozat, K., Du, X., Eidenschenk, C., Georgel, P., Hoebe, K., Huang, H., Jiang, Z., Krebs, P., La Vine, D., Li, X., Lyon, S., Moresco, E. M., Murray, A. R., Popkin, D. L., Rutschmann, S., Siggs, O. M., Smart, N. G., Sun, L., Tabeta, K., Webster, V., Tomisato, W., Won, S., Xia, Y., Xiao, N., and Beutler, B. (2012) ENU-induced phenovariance in mice: inferences from 587 mutations, BMC Res Notes5, 577.
- Siggs, O. M., Berger, M., Krebs, P., Arnold, C. N., Eidenschenk, C., Huber, C., Pirie, E., Smart, N. G., Khovananth, K., Xia, Y., McInerney, G., Karlsson Hedestam, G. B., Nemazee, D., and Beutler, B. (2010) A mutation of Ikbkg causes immune deficiency without impairing degradation of IkappaB alpha, Proc Natl Acad Sci U S A 107, 3046-3051.
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- Louria-Hayon, I., Alsheich-Bartok, O., Levav-Cohen, Y., Silberman, I., Berger, M., Grossman, T., Matentzoglu, K., Jiang, Y. H., Muller, S., Scheffner, M., Haupt, S., and Haupt, Y. (2009) E6AP promotes the degradation of the PML tumor suppressor, Cell Death Differ 16, 1156-1166.
- Croker, B. A., Lawson, B. R., Rutschmann, S., Berger, M., Eidenschenk, C., Blasius, A. L., Moresco, E. M., Sovath, S., Cengia, L., Shultz, L. D., Theofilopoulos, A. N., Pettersson, S., and Beutler, B. A. (2008) Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger, Proc Natl Acad Sci U S A105, 15028-15033.
- Croker, B., Crozat, K., Berger, M., Xia, Y., Sovath, S., Schaffer, L., Eleftherianos, I., Imler, J. L., and Beutler, B. (2007) ATP-sensitive potassium channels mediate survival during infection in mammals and insects, Nat Genet 39, 1453-1460.
- Berger, M., Stahl, N., Del Sal, G., and Haupt, Y. (2005) Mutations in proline 82 of p53 impair its activation by Pin1 and Chk2 in response to DNA damage, Mol Cell Biol 25, 5380-5388.
- Haupt, S., Berger, M., Goldberg, Z., and Haupt, Y. (2003) Apoptosis – the p53 network, J Cell Sci 116, 4077-4085.
- Goldberg, Z., Vogt Sionov, R., Berger, M., Zwang, Y., Perets, R., Van Etten, R. A., Oren, M., Taya, Y., and Haupt, Y. (2002) Tyrosine phosphorylation of Mdm2 by c-Abl: implications for p53 regulation, EMBO J 21, 3715-3727.
- Sionov, R. V., Coen, S., Goldberg, Z., Berger, M., Bercovich, B., Ben-Neriah, Y., Ciechanover, A., and Haupt, Y. (2001) c-Abl regulates p53 levels under normal and stress conditions by preventing its nuclear export and ubiquitination, Mol Cell Biol 21, 5869-5878.
- Berger, M., Vogt Sionov, R., Levine, A. J., and Haupt, Y. (2001) A role for the polyproline domain of p53 in its regulation by Mdm2, J Biol Chem 276, 3785-3790.
- Muller, S., Berger,M., Lehembre, F., Seeler, J. S., Haupt, Y., and Dejean, A. (2000) c-Jun and p53 activity is modulated by SUMO-1 modification, J Biol Chem 275, 13321-13329.
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- Sionov, R. V., Moallem, E., Berger, M., Kazaz, A., Gerlitz, O., Ben-Neriah, Y., Oren, M., and Haupt, Y. (1999) c-Abl neutralizes the inhibitory effect of Mdm2 on p53, J Biol Chem 274, 8371-8374.
Book Chapter
Berger M, Haupt Y. Flow cytometric analysis of p53-induced apoptosis. Methods Mol Biol. 234:245-56 (2003).