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4 Publications visible to you, out of a total of 4
Biphasic response as a mechanism against mutant takeover in tissue homeostasis circuits

Abstract (Expand)

Tissues use feedback circuits in which cells send signals to each other to control their growth and survival. We show that such feed- back circuits are inherently unstable to mutants that misread the … signal level: Mutants have a growth advantage to take over the tissue, and cannot be eliminated by known cell-intrinsic mecha- nisms. To resolve this, we propose that tissues have biphasic responses in which the signal is toxic at both high and low levels, such as glucotoxicity of beta cells, excitotoxicity in neurons, and toxicity of growth factors to T cells. This gives most of these mutants a frequency-dependent selective disadvantage, which leads to their elimination. However, the biphasic mechanisms create a new unstable fixed point in the feedback circuit beyond which runaway processes can occur, leading to risk of diseases such as diabetes and neurodegenerative disease. Hence, glucotoxicity, which is a dangerous cause of diabetes, may have a protective anti- mutant effect. Biphasic responses in tissues may provide an evolu- tionary stable strategy that avoids invasion by commonly occurring mutants, but at the same time cause vulnerability to disease.

Authors: Omer Karin, Uri Alon

Date Published: 26th Jun 2017

Publication Type: Not specified

Frequency doubling in the cyanobacterial circadian clock

Abstract (Expand)

Organisms use circadian clocks to generate 24-h rhythms in gene expression. However, the clock can interact with other pathways to generate shorter period oscillations. It remains unclear how these … different frequencies are generated. Here, we examine this problem by studying the coupling of the clock to the alternative sigma factor sigC in the cyanobacterium Synechococcus elongatus. Using single-cell microscopy, we find that psbAI, a key photosyn- thesis gene regulated by both sigC and the clock, is activated with two peaks of gene expression every circadian cycle under constant low light. This two-peak oscillation is dependent on sigC, without which psbAI rhythms revert to one oscillatory peak per day. We also observe two circadian peaks of elongation rate, which are dependent on sigC, suggesting a role for the frequency doubling in modulating growth. We propose that the two-peak rhythm in psbAI expression is generated by an incoherent feedforward loop between the clock, sigC and psbAI. Modelling and experiments suggest that this could be a general network motif to allow frequency doubling of outputs.

Authors: Bruno MC Martins, Arijit K Das, Liliana Antunes, James CW Locke

Date Published: 22nd Dec 2016

Publication Type: Not specified

Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range

Abstract (Expand)

Cellular signal transduction is governed by multiple feedback mechanisms to elicit robust cellular decisions. The specific contributions of individual feedback regulators, however, remain unclear. Based … on extensive time-resolved data sets in primary erythroid progenitor cells, we established a dynamic pathway model to dissect the roles of the two transcriptional negative feedback regulators of the suppressor of cytokine signaling (SOCS) family, CIS and SOCS3, in JAK2/STAT5 signaling. Facilitated by the model, we calculated the STAT5 response for experimentally unobservable Epo concentrations and provide a quantitative link between cell survival and the integrated response of STAT5 in the nucleus. Model predictions show that the two feedbacks CIS and SOCS3 are most effective at different ligand concentration ranges due to their distinct inhibitory mechanisms. This divided function of dual feedback regulation enables control of STAT5 responses for Epo concentrations that can vary 1000-fold in vivo. Our modeling approach reveals dose-dependent feedback control as key property to regulate STAT5-mediated survival decisions over a broad range of ligand concentrations.

Authors: J. Bachmann, A. Raue, M. Schilling, M. E. Bohm, C. Kreutz, D. Kaschek, H. Busch, N. Gretz, W. D. Lehmann, J. Timmer, U. Klingmuller

Date Published: 2011

Publication Type: Not specified

Design principles of nuclear receptor signaling: how complex networking improves signal transduction

Abstract (Expand)

The topology of nuclear receptor (NR) signaling is captured in a systems biological graphical notation. This enables us to identify a number of ‘design’ aspects of the topology of these networks that … might appear unnecessarily complex or even functionally paradoxical. In realistic kinetic models of increasing complexity, calculations show how these features correspond to potentially important design principles, e.g.: (i) cytosolic ‘nuclear’ receptor may shuttle signal molecules to the nucleus, (ii) the active export of NRs may ensure that there is sufficient receptor protein to capture ligand at the cytoplasmic membrane, (iii) a three conveyor belts design dissipating GTP-free energy, greatly aids response, (iv) the active export of importins may prevent sequestration of NRs by importins in the nucleus and (v) the unspecific nature of the nuclear pore may ensure signal-flux robustness. In addition, the models developed are suitable for implementation in specific cases of NR-mediated signaling, to predict individual receptor functions and differential sensitivity toward physiological and pharmacological ligands.

Authors: Alexey N Kolodkin, Frank J Bruggeman, Nick Plant, Martijn J Moné, Barbara M Bakker, Moray J Campbell, Johannes P T M van Leeuwen, Carsten Carlberg, Jacky L Snoep, Hans V Westerhoff

Date Published: 21st Dec 2010

Publication Type: Not specified

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