Partner: E. Nelson David


Recent publications
1.Turner D., Paszek P., Woodcock D. J., Nelson David E., Horton Caroline A., Yunjiao W., Spiller David G., Rand D. A., White M., Harper C. V., Physiological levels of TNFalpha stimulation induce stochastic dynamics of NF-kappaB responses in single living cells, Journal of Cell Science, ISSN: 0021-9533, DOI: 10.1242/jcs.069641, Vol.123, No.16, pp.2834-2843, 2010
Abstract:

Nuclear factor kappa B (NF-kappaB) signalling is activated by cellular stress and inflammation and regulates cytokine expression. We applied single-cell imaging to investigate dynamic responses to different doses of tumour necrosis factor alpha (TNFalpha). Lower doses activated fewer cells and those responding showed an increasingly variable delay in the initial NF-kappaB nuclear translocation and associated IkappaBalpha degradation. Robust 100 minute nuclear:cytoplasmic NF-kappaB oscillations were observed over a wide range of TNFalpha concentrations. The result is supported by computational analyses, which identified a limit cycle in the system with a stable 100 minute period over a range of stimuli, and indicated no co-operativity in the pathway activation. These results suggest that a stochastic threshold controls functional all-or-nothing responses in individual cells. Deterministic and stochastic models simulated the experimentally observed activation threshold and gave rise to new predictions about the structure of the system and open the way for better mechanistic understanding of physiological TNFalpha activation of inflammatory responses in cells and tissues.

Keywords:

NF-

Affiliations:
Turner D.-other affiliation
Paszek P.-IPPT PAN
Woodcock D. J.-University of Warwick (GB)
Nelson David E.-other affiliation
Horton Caroline A.-other affiliation
Yunjiao W.-other affiliation
Spiller David G.-other affiliation
Rand D. A.-University of Warwick (GB)
White M.-other affiliation
Harper C. V.-University of Manchester (GB)
2.Ashall L., Horton Caroline A., Nelson David E., Paszek P., Harper Claire V.V., Sillitoe K., Ryan S., Spiller David G., Unitt John F., Broomhead David S., Kell Douglas B., Rand David A.A., Sée V., White Michael R.R., Pulsatile Stimulation Determines Timing and Specificity of NF-κB-Dependent Transcription, Science, ISSN: 0036-8075, DOI: 10.1126/science.1164860, Vol.324, No.5924, pp.242-246, 2009
Abstract:

The nuclear factor κB (NF-κB) transcription factor regulates cellular stress responses and the immune response to infection. NF-κB activation results in oscillations in nuclear NF-κB abundance. To define the function of these oscillations, we treated cells with repeated short pulses of tumor necrosis factor–α at various intervals to mimic pulsatile inflammatory signals. At all pulse intervals that were analyzed, we observed synchronous cycles of NF-κB nuclear translocation. Lower frequency stimulations gave repeated full-amplitude translocations, whereas higher frequency pulses gave reduced translocation, indicating a failure to reset. Deterministic and stochastic mathematical models predicted how negative feedback loops regulate both the resetting of the system and cellular heterogeneity. Altering the stimulation intervals gave different patterns of NF-κB–dependent gene expression, which supports the idea that oscillation frequency has a functional role.

Affiliations:
Ashall L.-other affiliation
Horton Caroline A.-other affiliation
Nelson David E.-other affiliation
Paszek P.-other affiliation
Harper Claire V.V.-University of Manchester (GB)
Sillitoe K.-other affiliation
Ryan S.-other affiliation
Spiller David G.-other affiliation
Unitt John F.-other affiliation
Broomhead David S.-other affiliation
Kell Douglas B.-other affiliation
Rand David A.A.-University of Warwick (GB)
Sée V.-other affiliation
White Michael R.R.-University of Manchester (GB)