Tessa E. Pronk, Jochem W. van der Veen, Rob J. Vandebriel, Henk van Loveren, 
Erik P. de Vink, Jeroen L. Pennings 
Comparison of the molecular topologies of stress-activated transcription 
factors HSF1, AP-1, NRF2, and NF-B in their induction kinetics of HMOX1 
in Biosystems, to appear

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
understanding of the regulation of HMOX1 would assist to understand
the physiological role of HMOX1 as well as to improve functional
interpretation of the gene as a biomarker in for instance
toxicogenomics. Remarkably, no less than 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 terms of 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.