PubMed · 16393786
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Maria Marino, Paolo Ascenzi. 2005. Do steroid hormones function via multiple signaling pathways?. https://doi.org/10.1080/15216540500415628
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Animal viruses (e.g., lentiviruses and herpesviruses) use transcriptional positive feedback (i.e., transactivation) to regulate their gene expression. But positive-feedback circuits are inherently unstable when turned off, which presents a particular dilemma for latent viruses that lack transcriptional repressor motifs. Here we show that a dissipative feedback resistor, composed of enzymatic interconversion of the transactivator, converts transactivation circuits into excitable systems that generate transient pulses of expression, which decay to zero. We use HIV-1 as a model system and analyze single-cell expression kinetics to explore whether the HIV-1 transactivator of transcription (Tat) uses a resistor to shut off transactivation. The Tat feedback circuit was found to lack bi-stability and Tat self-cooperativity but exhibited a pulse of activity upon transactivation, all in agreement with the feedback resistor model. Guided by a mathematical model, biochemical and genetic perturbation of the suspected Tat feedback resistor altered the circuit's stability and reduced susceptibility to molecular noise, in agreement with model predictions. We propose that the feedback resistor is a necessary, but possibly not sufficient, condition for turning off noisy transactivation circuits lacking a repressor motif (e.g., HIV-1 Tat). Feedback resistors may be a paradigm for examining other auto-regulatory circuits and may inform upon how viral latency is established, maintained, and broken.
Complex signaling cascades involve many interlocked positive and negative feedback loops which have inherent delays. Modeling these complex cascades often requires a large number of variables and parameters. Delay differential equation models have been helpful in describing inherent time lags and also in reducing the number of governing equations. However the consequences of model reduction via delay differential equations have not been fully explored. In this paper we systematically examine the effect of delays in a complex network of phosphorylation-dephosphorylation cycles (described by Gonze and Goldbeter, J. Theor. Biol., 210, (2001) 167-186), which commonly occur in many biochemical pathways. By introducing delays in the positive and negative regulatory interactions, we show that a delay differential model can indeed reduce the number of cycles actually required to describe the phosphorylation-dephosphorylation pathway. In addition, we find some of the unique properties of the network and a quantitative measure of the minimum number of delay variables required to model the network. These results can be extended for modeling complex signalling cascades.
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