Instytut Podstawowych Problemów Techniki
Polskiej Akademii Nauk


Kate Sillitoe

Ostatnie publikacje
1.  Paszek P., Ryan S., Ashall L., Sillitoe K., Harper C. V., Spiller David G., Rand D. A., White M., Population robustness arising from cellular heterogeneity, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, ISSN: 0027-8424, DOI: 10.1073/pnas.0913798107, Vol.107, No.25, pp.11644-11649, 2010

Heterogeneity between individual cells is a common feature of dynamic cellular processes, including signaling, transcription, and cell fate; yet the overall tissue level physiological phenotype needs to be carefully controlled to avoid fluctuations. Here we show that in the NF-κB signaling system, the precise timing of a dual-delayed negative feedback motif [involving stochastic transcription of inhibitor κB (IκB)-α and -ε] is optimized to induce heterogeneous timing of NF-κB oscillations between individual cells. We suggest that this dual-delayed negative feedback motif enables NF-κB signaling to generate robust single cell oscillations by reducing sensitivity to key parameter perturbations. Simultaneously, enhanced cell heterogeneity may represent a mechanism that controls the overall coordination and stability of cell population responses by decreasing temporal fluctuations of paracrine signaling. It has often been thought that dynamic biological systems may have evolved to maximize robustness through cell-to-cell coordination and homogeneity. Our analyses suggest in contrast, that this cellular variation might be advantageous and subject to evolutionary selection. Alternative types of therapy could perhaps be designed to modulate this cellular heterogeneity.

Afiliacje autorów:
Paszek P. - IPPT PAN
Ryan S. - inna afiliacja
Ashall L. - inna afiliacja
Sillitoe K. - inna afiliacja
Harper C. V. - University of Manchester (GB)
Spiller David G. - inna afiliacja
Rand D. A. - University of Warwick (GB)
White M. - inna afiliacja
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

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.

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

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