“Senescence influence multiple biological processes including aging and cancer”

Cellular senescence is a highly stable cell cycle arrest that limits the replication of aged or damaged cells. Senescence can be triggered by replicative exhaustion, oncogene activation or chemotherapeutic drugs. As a consequence, senescence influences the outcome of physiological processes such as aging, development, wound healing, fibrosis and cancer. Senescent cells not only exit cell cycle but also undergo profound changes in their transcriptional program, chromatin organization, metabolism and secretome. In particular, the senescence-associated secretory phenotype (SASP) mediates a range of paradoxical functions in vivo.

The main goal of our research program is to understand the molecular mechanisms behind the implementation and regulation of senescence. To this end, we use different human primary cell systems, including IMR90 ER:RAS cells as an inducible system of oncogene-induced senescence. Our experimental approaches integrate information from shRNA functional screenings, cellular and molecular biology, high-throughput microscopy, genomics and proteomics.

Alongside our general interest in senescence, we aim to address two related questions: what are the epigenetic mechanisms controlling senescence? And what are the regulation, composition and functions of the senescence secretome? First, we want to identify epigenetic mechanisms controlling senescence in general and, in particular, the INK4/ARF locus, by integrating functional screenings, proteomic and genomics control senescence. Finally, to dissect the function and understand the regulation of the SASP, we will pursue the characterization of factors already identified in functional experiments with new screens designed to identify global regulators of the SASP. Overall, we expect that our research would result in a better knowledge of how senescence impacts aging, cancer and other diseases, opening possibilities to manipulate it for therapeutic advantage.

Cell Proliferation

Senescent cells express a complex secretome that mediate multiple cell autonomous and non-cell autonomous functions. IMR90 ER:RAS cells undergoing oncogene-induced senescence (OIS) express IL-8 (red) and IL-6 (green).

Selected Publications

Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W. W., Lasitschka, F., Andrulis, M., Pascual, G., Morris, K. J., Khan, S., Jin, H., Dharmalingam, G., Snijders, A. P., Carroll, T., Capper, D., Pritchard, C., Inman, G. J., Longerich, T., Sansom, O. J., Aznar, S., Zender, L., & Gil, J. (2013). A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature Cell Biology.

Martin, N., Popov, N., Aguilo, F., O’Loghlen, A., Raguz, S., Snijders, A. P., Dharmalingam, G., Li, S., Thymiakou, E., Carroll, T., Zeisig, B. B., Eric, C. W., Peters, G., Episkopou, V., Walsh, M. J., & Gil, J. (2013). Interplay between homeobox proteins and polycomb repressive complexes in p16INK4a regulation. The EMBO Journal.

O’Loghlen, A., Muñoz Cabello, A. M., Gaspar-Maia, A., Wu, H.-A. A., Banito, A., Kunowska, N., Racek, T., Pemberton, H. N., Beolchi, P., Lavial, F., Masui, O., Vermeulen, M., Carroll, T., Graumann, J., Heard, E., Dillon, N., Azuara, V., Snijders, A. P., Peters, G., Bernstein, E., & Gil, J. (2012). MicroRNA regulation of cbx7 mediates a switch of polycomb orthologs during ESC differentiation. Cell Stem Cell, 10(1), 33–46.

Banito, A., Rashid, S. T., Acosta, J. C., Li, S., Pereira, C. F., Geti, I., Pinho, S., Silva, J. C., Azuara, V., Walsh, M., Vallier, L., & Gil, J. A. (2009). Senescence impairs successful reprogramming to pluripotent stem cells. Genes & Development, 23(18), 2134–2139.

Barradas, M., Anderton, E., Carlos, J., Li, S., Banito, A., Rodriguez-Niedenführ, M., Maertens, G., Banck, M., Zhou, M.-M. M., Walsh, M. J., Peters, G., & Gil, J. (2009). Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes & Development, 23(10), 1177–1182.

Acosta, J. C., O’Loghlen, A., Banito, A., Guijarro, M. V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., Takatsu, Y., Melamed, J., d’Adda di Fagagna, F., Bernard, D., Hernando, E., & Gil, J. (2008). Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell, 133(6), 1006–1018.

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