Instytut Podstawowych Problemów Techniki
Polskiej Akademii Nauk


Ryan Kellogg

Eidgenössische Technische Hochschule Zürich (CH)

Ostatnie publikacje
1.  Kellogg R.A., Tian C., Lipniacki T., Quake S.R., Tay S., Digital signaling decouples activation probability and population heterogeneity, eLife, ISSN: 2050-084X, DOI: 10.7554/eLife.08931, Vol.4, pp.e08931-1-26, 2015

Digital signaling enhances robustness of cellular decisions in noisy environments, but it is unclear how digital systems transmit temporal information about a stimulus. To understand how temporal input information is encoded and decoded by the NF-κB system, we studied transcription factor dynamics and gene regulation under dose- and duration-modulated inflammatory inputs. Mathematical modeling predicted and microfluidic single-cell experiments confirmed that integral of the stimulus (or area, concentration × duration) controls the fraction of cells that activate NF-κB in the population. However, stimulus temporal profile determined NF-κB dynamics, cell-to-cell variability, and gene expression phenotype. A sustained, weak stimulation lead to heterogeneous activation and delayed timing that is transmitted to gene expression. In contrast, a transient, strong stimulus with the same area caused rapid and uniform dynamics. These results show that digital NF-κB signaling enables multidimensional control of cellular phenotype via input profile, allowing parallel and independent control of single-cell activation probability and population heterogeneity.

Afiliacje autorów:
Kellogg R.A. - Eidgenössische Technische Hochschule Zürich (CH)
Tian C. - University of Copenhagen (DK)
Lipniacki T. - IPPT PAN
Quake S.R. - Stanford University (US)
Tay S. - Eidgenössische Technische Hochschule Zürich (CH)
2.  Pękalski J., Żuk P.J., Kochańczyk M., Junkin M., Kellogg R., Tay S., Lipniacki T., Spontaneous NF-κB Activation by Autocrine TNFα Signaling: A Computational Analysis, PLOS ONE, ISSN: 1932-6203, DOI: 10.1371/journal.pone.0078887, Vol.8, No.11, pp.e78887-1-14, 2013

NF-κB is a key transcription factor that regulates innate immune response. Its activity is tightly controlled by numerous feedback loops, including two negative loops mediated by NF-κB inducible inhibitors, IκBα and A20, which assure oscillatory responses, and by positive feedback loops arising due to the paracrine and autocrine regulation via TNFα, IL-1 and other cytokines. We study the NF-κB system of interlinked negative and positive feedback loops, combining bifurcation analysis of the deterministic approximation with stochastic numerical modeling. Positive feedback assures the existence of limit cycle oscillations in unstimulated wild-type cells and introduces bistability in A20-deficient cells. We demonstrated that cells of significant autocrine potential, i.e., cells characterized by high secretion of TNFα and its receptor TNFR1, may exhibit sustained cytoplasmic–nuclear NF-κB oscillations which start spontaneously due to stochastic fluctuations. In A20-deficient cells even a small TNFα expression rate qualitatively influences system kinetics, leading to long-lasting NF-κB activation in response to a short-pulsed TNFα stimulation. As a consequence, cells with impaired A20 expression or increased TNFα secretion rate are expected to have elevated NF-κB activity even in the absence of stimulation. This may lead to chronic inflammation and promote cancer due to the persistent activation of antiapoptotic genes induced by NF-κB. There is growing evidence that A20 mutations correlate with several types of lymphomas and elevated TNFα secretion is characteristic of many cancers. Interestingly, A20 loss or dysfunction also leaves the organism vulnerable to septic shock and massive apoptosis triggered by the uncontrolled TNFα secretion, which at high levels overcomes the antiapoptotic action of NF-κB. It is thus tempting to speculate that some cancers of deregulated NF-κB signaling may be prone to the pathogen-induced apoptosis.

Afiliacje autorów:
Pękalski J. - Institute of Physical Chemistry, Polish Academy of Sciences (PL)
Żuk P.J. - inna afiliacja
Kochańczyk M. - IPPT PAN
Junkin M. - Eidgenössische Technische Hochschule Zürich (CH)
Kellogg R. - Eidgenössische Technische Hochschule Zürich (CH)
Tay S. - Eidgenössische Technische Hochschule Zürich (CH)
Lipniacki T. - IPPT PAN

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