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The Ups and Downs of P53: Proc PERSPECTIVES 155. Akira, S. & Takeda, K. Toll-like receptor signalling. Nature Rev. Immunol. 4, 499–511 (2004). OPINION 156. Tsenova, L., Bergtold, A., Freedman, V. H., Young, R. A. & Kaplan, G. Tumour necrosis factor α is a determinant of pathogenesis and disease progression in mycobacterial infection in the central nervous system. The ups and downs of p53: Proc. Natl Acad. Sci. USA 96, 5657–5662 (1999). 157. Schluter, D. et al. Both lymphotoxin-α and TNF are crucial for control of Toxoplasma gondii in the central nervous system. J. Immunol. 170, 6172–6182 (2003). understanding protein dynamics 158. Pasparakis, M. et al. Peyer’s patch organogenesis is intact yet formation of B lymphocyte follicles is defective in peripheral lymphoid organs of mice deficient for in single cells tumor necrosis factor and its 55-kDa receptor. Proc. Natl Acad. Sci. USA 94, 6319–6323 (1997). 159. Kuprash, D. V. et al. Novel tumor necrosis factor- Eric Batchelor, Alexander Loewer and Galit Lahav knockout mice that lack Peyer’s patches. Eur. J. Immunol. 35, 1592–1600 (2005). 160. Grivennikov, S. I. et al. Distinct and nonredundant Abstract | Cells living in a complex environment must constantly detect, process in vivo functions of TNF produced by T cells and macrophages/neutrophils: protective and deleterious and appropriately respond to changing signals. Therefore, all cellular information effects. Immunity 22, 93–104 (2005). 161. Beutler, B. et al. Identity of tumour necrosis factor and processing is dynamic in nature. As a consequence, understanding the process of the macrophage-secreted factor cachetin. Nature 316, signal transduction often requires detailed quantitative analysis of dynamic 552–554 (1985). 162. Brennan, F. M., Jackson, A., Chantry, D., Maini, R. & behaviours. Here, we focus on the oscillatory dynamics of the tumour suppressor Feldmann, M. Inhibitory effect of TNF-alpha antibodies on synovial cell interleukin-1 production in protein p53 as a model for studying protein dynamics in single cells to better rheumatoid arthritis. Lancet 2, 244–247 (1989). 163. Williams, R. O., Feldmann, M. & Maini, R. N. Anti- understand its regulation and function. tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc. Natl Acad. Sci. USA 89, 9784–9788 (1992). How are signals received by a cell translated The analysis of cellular dynamics often 164. van Deventer, S. J. Anti-TNF antibody treatment of into decisions such as growth, death and requires measurements in single cells, as Crohn’s disease. Ann. Rheum. Dis. 58, 14–20 (1999). 165. Mease, P. J. et al. Etanercept in the treatment of movement? In the past several decades measurements of averaged dynamics in a psoriatic arthritis and psoriasis: a randomised trial. there has been a great deal of success in population of cells can be misleading. For Lancet 356, 385–390 (2000). 166. Chaudhari, U. et al. Efficacy and safety of infliximab identifying the proteins and genes that are example, in response to certain doses of anti- monotherapy for plaque-type psoriasis: a randomised activated or repressed in response to spe- biotics, some cells live but others die1. These trial. Lancet 357, 1842–1847 (2001). 167. Berry, M. A. et al. Evidence of a role of tumor necrosis cific inputs and in assembling them into different outcomes might reflect differences factor α in refractory asthma. N. Engl. J. Med. 354, signal transduction pathways. However, in the initial state of the cell (such as its cell 697–708 (2006). 168. Ashkenazi, A. Targeting death and decoy receptors of even though we now have maps of many cycle state, basal level of network components the tumor necrosis factor superfamily. Nature Rev. signalling pathways, new questions have or local environment), which in turn lead Cancer 2, 420–430 (2002). 169. Gray, P. W., Barret, K., Chantry, D., Turner, M. & arisen owing to the complexity of the path- to differences in the quantitative behaviour Feldmann, M. Cloning of human tumor necrosis factor ways they represent. How can we move of the information processing network. (TNF) receptor cDNA and expression of recombinant soluble TNF-binding protein. Proc. Natl Acad. Sci. USA beyond describing the structure of biologi- By visualizing the dynamic behaviour and 87, 7380–7384 (1990). cal networks to developing a detailed, quan- identifying how it varies among cells (or cell 170. Heller, R. A. et al. Amplified expression of tumor necrosis factor receptor in cells transfected with titative understanding of their function and types), we might be able to explain varying Epstein–Barr virus shuttle vector cDNA libraries. behaviour? One promising approach is to behaviours both within cell populations and J. Biol. Chem. 265, 5708–5717 (1990). 171. Coussens, L. M. & Werb, Z. Inflammation and cancer. investigate the dynamics of key proteins in different cell types. Nature 420, 860–867 (2002). within the network (FIG. 1). In this context, Single cell analyses of signalling systems Acknowledgements dynamics is defined as the change of any have already revealed important informa- The author would like to thank members of the Centre for variable that can be quantitatively measured tion about the role of dynamics in regulat- Cancer and Inflammation at Barts and The London Medical School and also A. Mantovani for useful discussions and over time, such as protein concentration, ing various cellular responses. For example, criticism. activity, modification state or localiza- in mammalian cells the transcription factor Competing interests statement tion. These data are complementary to the nuclear factor-κB (NF-κB) shows pulses The authors declare competing financial interests: see web information originally used to describe of nuclear localization on stimulation2,3. version for details. the network, and have great potential to Single-cell analysis of luciferase expression DATABASES provide new insight into the relationship from a synthetic NF-κB-responsive pro- Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query. between network structure and function. moter suggested that the pulses are involved fcgi?db=gene 3,4 MYC | TP53 | TSC1 | VHL For example, if the activity of a signalling in maintaining target gene expression . In National Cancer Institute Drug Dictionary: molecule is measured at only a single point Saccharomyces cerevisiae, the mitogen- http://www.cancer.gov/drugdictionary/ actinomycin D | bevacizumab | doxorubicin | etanercept | in time, the signal could be interpreted as activated protein kinase Fus3 shows oscil- infliximab | melphalan | mitomycin C binary: being either on or off. If, however, lations in activity in response to mating UniProtKB: http://www.uniprot.org 5 AID | BRAF | CCL2 | CXCL12 | CD13 | IKKβ | IL-2 | IL-6 | the signalling activity is quantitatively meas- pheromone . The Fus3 oscillations correlate lymphotoxin | MIF | MYD88 | p65 | SMAC | TERT | TLR2 | TLR4 | ured with high temporal resolution over a with oscillations in mating gene expres- TLR6 | TNF | TNFR1 | TNFR2 | TRAIL | TSC1 | versican | VHL long period it could show a large number sion and the formation of new mating FURTHER INFORMATION Frances Balkwill’s homepage: http://www.cancer.qmul.ac. of distinct behaviours. Detailed analysis of projections, as determined by fluorescence uk/research/cancer_inflammation/index.html dynamic behaviours in diverse systems and microscopy and flow cytometry using cells MolMed: http://www.molmed.com/eng/index.asp under various conditions has the potential expressing fluorescent fusion proteins5. SUPPLEMENTARY INFORMATION to provide new levels of understanding of In this Perspective, we focus on the p53 See online article: S1 (box) how cells detect inputs and translate them network as a model for studying the dynam- ALL LINKS ARE ACTIVE IN THE ONLINE PDF into outputs. ics of a signal transduction pathway in single NATURE REVIEWS | CANCER VOLUME 9 | MAY 2009 | 371 © 2009 Macmillan Publishers Limited. All rights reserved PERSPECTIVES Stress Signaling molecules Environment DNA damage. Work by Lev Bar-Or et al.11 Input e.g. radiation, ROS e.g. EGF, Wnt, Bmp e.g. osmolarity, nutrients indicated that, in response to double strand breaks (DSBs) caused by γ-irradiation, p53 levels increased dramatically then decreased in a series of damped oscillations, in which otein] the amplitude of the oscillations decreases [Pr in time (FIG. 3). Single live-cell analyses Time using fluorescently tagged p53 and higher temporal resolution revealed that these Information population studies masked the true behav- processing otein] iour of the network. Instead of damped [Pr oscillations, individual cells show series of Time undamped p53 pulses with fixed amplitude and duration, independent of the amount of ] γ-irradiation12,13 (FIG. 3). The initial character- tein ization of the pulses as damped oscillations [Pro was a result of averaging across a population Time of cells. The apparently lower amplitude of Cell fate Differentiation Homoestasis p53 in later pulses, as observed in western Output e.g. repair versus e.g. ventral versus e.g. glycerol blots, is a results of several factors, including apoptosis dorsal fate production a reduction in the number of cells pulsing Figure 1 | Dynamics in signal transduction pathways. A complex protein network senses infor- at later times12 and loss of synchronization mation about the intracellular and extracellular environment (input), processesNature the Revie information,ws | Cancer 13,14 and triggers a response (output). Currently, the information
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