Comparison of the molecular topologies of stress-activated transcription factors HSF1, AP-1, NRF2, and NF-κB in their induction kinetics of HMOX1

• We model the efficiency of HSF1, AP-1, NRF2, and NF-κB to remove inducers of stress.
• The TF circuits were modelled at comparable levels of abstraction.
• Two circuits (HSF1 and AP-1) seem especially suited for long-term removal of stress.
• NRF2 seems most appropriate for cellular homeostasis by efficient ROS regulation.

For cells, reacting aptly to changes in their environment is of critical importance. The protein Heme oxygenase-1 (HMOX1) plays a critical role as a guard of cellular homeostasis and is considered as a reliable indicator of cellular oxidative stress. A better insight in the regulation of HMOX1 would assist in understanding the physiological role of HMOX1 as well as improving functional interpretation of the gene as a biomarker in toxicogenomics. Remarkably, as many as four transcription factors are known to regulate the HMOX1 gene: HSF1, AP-1, NRF2, and NF-κB. To investigate induction kinetics of these transcription factors, we constructed mathematical simulation models for each of them. We included the topology of the known interactions of molecules involved in the activation of the transcription factors, and the feedback loops resulting in their down-regulation. We evaluate how the molecular circuitries associated with the different transcription factors differ in their kinetics regarding HMOX1 induction, under different scenarios of acute and less acute stress. We also evaluate the combined effect of the four transcription factors on HMOX1 expression and the resulting alleviation of stress. Overall, the results support the assumption of different biological roles for the four transcription factors, with AP-1 being a fast acting general stress response protein at the expense of efficiency, and NRF2 being important for cellular homeostasis in maintaining low levels of oxidative stress.

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